Blocking the deadly effects of the NMDA receptor in stroke.

Excessive activation of NMDA glutamate receptors contributes to neuronal death after stroke. In this issue, Tu et al. (2010) demonstrate that ischemic injury promotes the association of death-associated protein kinase 1 with the NMDA receptor, thereby potentiating its activity, and show that disrupting this association reduces damage to the brain.

Selective removal of misfolded SOD1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough in the search for effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS. METHODS: Based on the chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4 and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying the pathogenesis of ALS. RESULTS: Expression of the plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the G93A-hSOD1 plasmids at various ratios demonstrated a dose-dependent knockdown efficiency on G93A-hSOD1, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full-length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10 mg/kg to the G93A-hSOD1 reduced human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h in presymptomatic ALS mice. Intraperitoneal administration of the CT4 peptide starting from 60 days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A-hSOD1 mice. CONCLUSIONS: The CT4 peptide directs the degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study proves that selective removal of misfolded SOD1 is a promising treatment for ALS.

Inhibiting NLRP3 inflammasome signaling pathway promotes neurological recovery following hypoxic-ischemic brain damage by increasing p97-mediated surface GluA1-containing AMPA receptors.

BACKGROUND: The nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is believed to be a key mediator of neuroinflammation and subsequent secondary brain injury induced by ischemic stroke. However, the role and underlying mechanism of the NLRP3 inflammasome in neonates with hypoxic-ischemic encephalopathy (HIE) are still unclear. METHODS: The protein expressions of the NLRP3 inflammasome including NLRP3, cysteinyl aspartate specific proteinase-1 (caspase-1) and interleukin-1ß (IL-1ß), the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) subunit, and the ATPase valosin-containing protein (VCP/p97), were determined by Western blotting. The interaction between p97 and AMPA glutamate receptor 1 (GluA1) was determined by co-immunoprecipitation. The histopathological level of hypoxic-ischemic brain damage (HIBD) was determined by triphenyltetrazolium chloride (TTC) staining. Polymerase chain reaction (PCR) and Western blotting were used to confirm the genotype of the knockout mice. Motor functions, including myodynamia and coordination, were evaluated by using grasping and rotarod tests. Hippocampus-dependent spatial cognitive function was measured by using the Morris-water maze (MWM). RESULTS: We reported that the NLRP3 inflammasome signaling pathway, such as NLRP3, caspase-1 and IL-1ß, was activated in rats with HIBD and oxygen-glucose deprivation (OGD)-treated cultured primary neurons. Further studies showed that the protein level of the AMPAR GluA1 subunit on the hippocampal postsynaptic membrane was significantly decreased in rats with HIBD, and it could be restored to control levels after treatment with the specific caspase-1 inhibitor AC-YVAD-CMK. Similarly, in vitro studies showed that OGD reduced GluA1 protein levels on the plasma membrane in cultured primary neurons, whereas AC-YVAD-CMK treatment restored this reduction. Importantly, we showed that OGD treatment obviously enhanced the interaction between p97 and GluA1, while AC-YVAD-CMK treatment promoted the dissociation of p97 from the GluA1 complex and consequently facilitated the localization of GluA1 on the plasma membrane of cultured primary neurons. Finally, we reported that the deficits in motor function, learning and memory in animals with HIBD, were ameliorated by pharmacological intervention or genetic ablation of caspase-1. CONCLUSION: Inhibiting the NLRP3 inflammasome signaling pathway promotes neurological recovery in animals with HIBD by increasing p97-mediated surface GluA1 expression, thereby providing new insight into HIE therapy.

Molecular subtyping based on immune cell marker genes predicts prognosis and therapeutic response in patients with lung adenocarcinoma.

OBJECTIVE: Lung adenocarcinoma (LA) is one of the most common malignancies and is responsible for the greatest number of tumor-related deaths. Our research aimed to explore the molecular subtype signatures of LA to clarify the correlation among the immune microenvironment, clinical outcomes, and therapeutic response. METHODS: The LA immune cell marker genes (LICMGs) identified by single-cell RNA sequencing (scRNA-seq) analysis were used to discriminate the molecular subtypes and homologous immune and metabolic traits of GSE72094 LA cases. In addition, the model-building genes were identified from 1441 LICMGs by Cox-regression analysis, and a LA immune difference score (LIDscore) was developed to quantify individual differences in each patient, thereby predicting prognosis and susceptibility to immunotherapy and chemotherapy of LA patients. RESULTS: Patients of the GSE72094 cohort were divided into two distinct molecular subtypes based on LICMGs: immune activating subtype (Cluster-C1) and metabolically activating subtype (cluster-C2). The two molecular subtypes have distinct characteristics regarding prognosis, clinicopathology, genomics, immune microenvironment, and response to immunotherapy. Among the LICMGs, LGR4, GOLM1, CYP24A1, SFTPB, COL1A1, HLA-DQA1, MS4A7, PPARG, and IL7R were enrolled to construct a LIDscore model. Low-LIDscore patients had a higher survival rate due to abundant immune cell infiltration, activated immunity, and lower genetic variation, but probably the higher levels of Treg cells in the immune microenvironment lead to immune cell dysfunction and promote tumor immune escape, thus decreasing the responsiveness to immunotherapy compared with that of the high-LIDscore patients. Overall, high-LIDscore patients had a higher responsiveness to immunotherapy and a higher sensitivity to chemotherapy than the low-LIDscore group. CONCLUSIONS: Molecular subtypes based on LICMGs provided a promising strategy for predicting patient prognosis, biological characteristics, and immune microenvironment features. In addition, they helped identify the patients most likely to benefit from immunotherapy and chemotherapy.

AMPA and NMDA Receptor Trafficking at Cocaine-Generated Synapses.

Cocaine experience generates AMPA receptor (AMPAR)-silent synapses in the nucleus accumbens (NAc), which are thought to be new synaptic contacts enriched in GluN2B-containing NMDA receptors (NMDARs). After drug withdrawal, some of these synapses mature by recruiting AMPARs, strengthening the newly established synaptic transmission. Silent synapse generation and maturation are two consecutive cellular steps through which NAc circuits are profoundly remodeled to promote cue-induced cocaine seeking after drug withdrawal. However, the basic cellular processes that mediate these two critical steps remains underexplored. Using a combination of electrophysiology, viral-mediated gene transfer, and confocal imaging in male rats as well as knock-in (KI) mice of both sexes, our current study characterized the dynamic roles played by AMPARs and NMDARs in generation and maturation of silent synapses on NAc medium spiny neurons after cocaine self-administration and withdrawal. We report that cocaine-induced generation of silent synapses not only required synaptic insertion of GluN2B-containing NMDARs, but also, counterintuitively, involved insertion of AMPARs, which subsequently internalized, resulting in the AMPAR-silent state on withdrawal day 1. Furthermore, GluN2B NMDARs functioned to maintain these cocaine-generated synapses in the AMPAR-silent state during drug withdrawal, until they were replaced by nonGluN2B NMDARs, a switch that allowed AMPAR recruitment and maturation of silent synapses. These results reveal dynamic interactions between AMPARs and NMDARs during the generation and maturation of silent synapses after cocaine experience and provide a mechanistic basis through which new synaptic contacts and possibly new neural network patterns created by these synapses can be manipulated for therapeutic benefit.SIGNIFICANCE STATEMENT Studies over the past decade reveal a critical role of AMPA receptor-silent, NMDA receptor-containing synapses in forming cocaine-related memories that drive cocaine relapse. However, it remains incompletely understood how AMPA and NMDA receptors traffic at these synapses during their generation and maturation. The current study characterizes a two-step AMPA receptor trafficking cascade that contributes to the generation of silent synapses in response to cocaine experience, and a two-step NMDA receptor trafficking cascade that contributes to the maturation of these synapses after cocaine withdrawal. These results depict a highly regulated cellular procedure through which nascent glutamatergic synapses are generated in the adult brain after drug experience and provide significant insight into the roles of glutamate receptors in synapse formation and maturation.

Mitochondrial dysfunction triggers the pathogenesis of Parkinson's disease in neuronal C/EBPß transgenic mice.

Respiratory chain complex I deficiency elicits mitochondrial dysfunction and reactive oxidative species (ROS), which plays a crucial role in Parkinson's disease (PD) pathogenesis. However, it remains unclear whether the impairment in other complexes in the mitochondrial oxidative phosphorylation chain is also sufficient to trigger PD onset. Here we show that inhibition of Complex II or III in the electron transport chain (ETC) induces the motor disorder and PD pathologies in neuronal Thy1-C/EBPß transgenic mice. Through a cell-based screening of mitochondrial respiratory chain inhibitors, we identified TTFA (complex II inhibitor) and Atovaquone (complex III inhibitor), which robustly block the oxidative phosphorylation functions, strongly escalate ROS, and activate C/EBPß/AEP pathway that triggers dopaminergic neuronal cell death. Oral administration of these inhibitors to Thy1-C/EBPß mice elicits constipation and motor defects, associated with Lewy body-like inclusions. Deletion of SDHD (Succinate dehydrogenase) gene from the complex II in the Substantia Nigra of Thy1-C/EBPß mice triggers ROS and PD pathologies, resulting in motor disorders. Hence, our findings demonstrate that mitochondrial ETC inactivation triggers PD pathogenesis via activating C/EBPß/AEP pathway.

GCAEMDA: Predicting miRNA-disease associations via graph convolutional autoencoder.

microRNAs (miRNAs) are small non-coding RNAs related to a number of complicated biological processes. A growing body of studies have suggested that miRNAs are closely associated with many human diseases. It is meaningful to consider disease-related miRNAs as potential biomarkers, which could greatly contribute to understanding the mechanisms of complex diseases and benefit the prevention, detection, diagnosis and treatment of extraordinary diseases. In this study, we presented a novel model named Graph Convolutional Autoencoder for miRNA-Disease Association Prediction (GCAEMDA). In the proposed model, we utilized miRNA-miRNA similarities, disease-disease similarities and verified miRNA-disease associations to construct a heterogeneous network, which is applied to learn the embeddings of miRNAs and diseases. In addition, we separately constructed miRNA-based and disease-based sub-networks. Combining the embeddings of miRNAs and diseases, graph convolutional autoencoder (GCAE) was utilized to calculate association scores of miRNA-disease on two sub-networks, respectively. Furthermore, we obtained final prediction scores between miRNAs and diseases by adopting an average ensemble way to integrate the prediction scores from two types of subnetworks. To indicate the accuracy of GCAEMDA, we applied different cross validation methods to evaluate our model whose performances were better than the state-of-the-art models. Case studies on a common human diseases were also implemented to prove the effectiveness of GCAEMDA. The results demonstrated that GCAEMDA was beneficial to infer potential associations of miRNA-disease.

SCMFMDA: Predicting microRNA-disease associations based on similarity constrained matrix factorization.

miRNAs belong to small non-coding RNAs that are related to a number of complicated biological processes. Considerable studies have suggested that miRNAs are closely associated with many human diseases. In this study, we proposed a computational model based on Similarity Constrained Matrix Factorization for miRNA-Disease Association Prediction (SCMFMDA). In order to effectively combine different disease and miRNA similarity data, we applied similarity network fusion algorithm to obtain integrated disease similarity (composed of disease functional similarity, disease semantic similarity and disease Gaussian interaction profile kernel similarity) and integrated miRNA similarity (composed of miRNA functional similarity, miRNA sequence similarity and miRNA Gaussian interaction profile kernel similarity). In addition, the L2 regularization terms and similarity constraint terms were added to traditional Nonnegative Matrix Factorization algorithm to predict disease-related miRNAs. SCMFMDA achieved AUCs of 0.9675 and 0.9447 based on global Leave-one-out cross validation and five-fold cross validation, respectively. Furthermore, the case studies on two common human diseases were also implemented to demonstrate the prediction accuracy of SCMFMDA. The out of top 50 predicted miRNAs confirmed by experimental reports that indicated SCMFMDA was effective for prediction of relationship between miRNAs and diseases.

Distinct Functional Alterations and Therapeutic Options of Two Pathological De Novo Variants of the T292 Residue of GABRA1 Identified in Children with Epileptic Encephalopathy and Neurodevelopmental Disorders.

Mutations of GABAAR have reportedly led to epileptic encephalopathy and neurodevelopmental disorders. We have identified a novel de novo T292S missense variant of GABRA1 from a pediatric patient with grievous global developmental delay but without obvious epileptic activity. This mutation coincidentally occurs at the same residue as that of a previously reported GABRA1 variant T292I identified from a pediatric patient with severe epilepsy. The distinct phenotypes of these two patients prompted us to compare the impacts of the two mutants on the receptor function and to search for suitable therapeutics. In this study, we used biochemical techniques and patch-clamp recordings in HEK293 cells overexpressing either wild-type or mutated rat recombinant GABAARs. We found that the α1T292S variant significantly increased GABA-evoked whole-cell currents, shifting the dose-response curve to the left without altering the maximal response. In contrast, the α1T292I variant significantly reduced GABA-evoked currents, shifting the dose-response curve to the right with a severely diminished maximum response. Single-channel recordings further revealed that the α1T292S variant increased, while the α1T292I variant decreased the GABAAR single-channel open time and open probability. Importantly, we found that the T292S mutation-induced increase in GABAAR function could be fully normalized by the negative GABAAR modulator thiocolchicoside, whereas the T292I mutation-induced impairment of GABAAR function was largely rescued with a combination of the GABAAR positive modulators diazepam and verapamil. Our study demonstrated that α1T292 is a critical residue for controlling GABAAR channel gating, and mutations at this residue may produce opposite impacts on the function of the receptors. Thus, the present work highlights the importance of functionally characterizing each individual GABAAR mutation for ensuring precision medicine.

Disruption of Long-Term Depression Potentiates Latent Inhibition: Key Role for Central Nucleus of the Amygdala.

BACKGROUND: Latent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified. METHODS: Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure. RESULTS: Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region-specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect. CONCLUSIONS: These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.

MiRNA-disease association prediction via hypergraph learning based on high-dimensionality features.

BACKGROUND: MicroRNAs (miRNAs) have been confirmed to have close relationship with various human complex diseases. The identification of disease-related miRNAs provides great insights into the underlying pathogenesis of diseases. However, it is still a big challenge to identify which miRNAs are related to diseases. As experimental methods are in general expensive and time-consuming, it is important to develop efficient computational models to discover potential miRNA-disease associations. METHODS: This study presents a novel prediction method called HFHLMDA, which is based on high-dimensionality features and hypergraph learning, to reveal the association between diseases and miRNAs. Firstly, the miRNA functional similarity and the disease semantic similarity are integrated to form an informative high-dimensionality feature vector. Then, a hypergraph is constructed by the K-Nearest-Neighbor (KNN) method, in which each miRNA-disease pair and its k most relevant neighbors are linked as one hyperedge to represent the complex relationships among miRNA-disease pairs. Finally, the hypergraph learning model is designed to learn the projection matrix which is used to calculate uncertain miRNA-disease association score. RESULT: Compared with four state-of-the-art computational models, HFHLMDA achieved best results of 92.09% and 91.87% in leave-one-out cross validation and fivefold cross validation, respectively. Moreover, in case studies on Esophageal neoplasms, Hepatocellular Carcinoma, Breast Neoplasms, 90%, 98%, and 96% of the top 50 predictions have been manually confirmed by previous experimental studies. CONCLUSION: MiRNAs have complex connections with many human diseases. In this study, we proposed a novel computational model to predict the underlying miRNA-disease associations. All results show that the proposed method is effective for miRNA-disease association predication.

Graph regularized L2,1-nonnegative matrix factorization for miRNA-disease association prediction.

BACKGROUND: The aberrant expression of microRNAs is closely connected to the occurrence and development of a great deal of human diseases. To study human diseases, numerous effective computational models that are valuable and meaningful have been presented by researchers. RESULTS: Here, we present a computational framework based on graph Laplacian regularized L2, 1-nonnegative matrix factorization (GRL2, 1-NMF) for inferring possible human disease-connected miRNAs. First, manually validated disease-connected microRNAs were integrated, and microRNA functional similarity information along with two kinds of disease semantic similarities were calculated. Next, we measured Gaussian interaction profile (GIP) kernel similarities for both diseases and microRNAs. Then, we adopted a preprocessing step, namely, weighted K nearest known neighbours (WKNKN), to decrease the sparsity of the miRNA-disease association matrix network. Finally, the GRL2,1-NMF framework was used to predict links between microRNAs and diseases. CONCLUSIONS: The new method (GRL2, 1-NMF) achieved AUC values of 0.9280 and 0.9276 in global leave-one-out cross validation (global LOOCV) and five-fold cross validation (5-CV), respectively, showing that GRL2, 1-NMF can powerfully discover potential disease-related miRNAs, even if there is no known associated disease.

Activation of caspase-6 and cleavage of caspase-6 substrates is an early event in NMDA receptor-mediated excitotoxicity.

Excitotoxicity, due to overstimulation of N-methyl D-aspartate receptors (NMDARs), has a pivotal role in many neurological disorders. However, NMDAR antagonists often cause side effects, and identifying more druggable therapeutic targets for NMDAR excitotoxicity is an important goal. Activation of caspases is a downstream effect of excitotoxicity that may be critically involved in NMDAR-mediated cell death. Caspase-6 (casp6) in particular has been shown to play a key role in the pathogenesis of stroke, Huntington disease, and Alzheimer disease. Using N-methyl D-aspartate (NMDA)-induced excitotoxic injuries of primary rat neurons, we demonstrate that there is an early increase in caspase profiles after an excitotoxic event at the level of mRNA, protein, and activity. Casp6 is elevated and activated first, followed by caspase-8 and caspase-3. Similarly, known casp6 substrates huntingtin, as well as novel casp6 substrates serine/threonine kinase 3 and death domain-associated protein, are cleaved in similar temporal patterns post NMDA. On the basis of these data, we propose that casp6 may be an initiator caspase in apoptotic cascades leading to neuronal death after an excitotoxic event and suggest casp6 as a potential therapeutic target for neurological disorders where NMDAR-mediated excitotoxicity has been shown to play a role.

Blocking Synaptic Removal of GluA2-Containing AMPA Receptors Prevents the Natural Forgetting of Long-Term Memories.

The neurobiological processes underpinning the natural forgetting of long-term memories are poorly understood. Based on the critical role of GluA2-containing AMPA receptors (GluA2/AMPARs) in long-term memory persistence, we tested in rats whether their synaptic removal underpins time-dependent memory loss. We found that blocking GluA2/AMPAR removal with the interference peptides GluA23Y or G2CT in the dorsal hippocampus during a memory retention interval prevented the normal forgetting of established, long-term object location memories, but did not affect their acquisition. The same intervention also preserved associative memories of food-reward conditioned place preference that would otherwise be lost over time. We then explored whether this forgetting process could play a part in behavioral phenomena involving time-dependent memory change. We found that infusing GluA23Y into the dorsal hippocampus during a 2 week retention interval blocked generalization of contextual fear expression, whereas infusing it into the infralimbic cortex after extinction of auditory fear prevented spontaneous recovery of the conditioned response. Exploring possible physiological mechanisms that could be involved in this form of memory decay, we found that bath application of GluA23Y prevented depotentiation, but not induction of long-term potentiation, in a hippocampal slice preparation. Together, these findings suggest that a decay-like forgetting process that involves the synaptic removal of GluA2/AMPARs erases consolidated long-term memories in the hippocampus and other brain structures over time. This well regulated forgetting process may critically contribute to establishing adaptive behavior, whereas its dysregulation could promote the decline of memory and cognition in neuropathological disorders. SIGNIFICANCE STATEMENT: The neurobiological mechanisms involved in the natural forgetting of long-term memory and its possible functions are not fully understood. Based on our previous work describing the role of GluA2-containing AMPA receptors in memory maintenance, here, we tested their role in forgetting of long-term memory. We found that blocking their synaptic removal after long-term memory formation extended the natural lifetime of several forms of memory. In the hippocampus, it preserved spatial memories and inhibited contextual fear generalization; in the infralimbic cortex, it blocked the spontaneous recovery of extinguished fear. These findings suggest that a constitutive decay-like forgetting process erases long-term memories over time, which, depending on the memory removed, may critically contribute to developing adaptive behavioral responses.

Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism.

The molecular mechanisms underlying major depressive disorder remain poorly understood, and current antidepressant treatments have many shortcomings. The recent discovery that a single intravenous infusion of ketamine at a subanesthetic dose had robust, rapid and sustained antidepressant effects in individuals with treatment-resistant depression inspired tremendous interest in investigating the molecular mechanisms mediating ketamine's clinical efficacy as well as increased efforts to identify new targets for antidepressant action. We review the clinical utility of ketamine and recent insights into its mechanism of action as an antidepressant, including the roles of N-methyl-D-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor upregulation, activation of downstream synaptogenic signalling pathways and the production of an active ketamine metabolite, hydroxynorketamine. Emerging knowledge of the molecular mechanisms underlying both ketamine's positive therapeutic and detrimental side effects will aid the development of a new generation of much-needed superior antidepressant agents.

Cognitive flexibility and long-term depression (LTD) are impaired following ß-catenin stabilization in vivo.

The cadherin/ß-catenin adhesion complex is a key mediator of the bidirectional changes in synapse strength which are believed to underlie complex learning and memory. In the present study, we demonstrate that stabilization of ß-catenin in the hippocampus of adult mice results in significant impairments in cognitive flexibility and spatial reversal learning, including impaired extinction during the reversal phase of the Morris water maze and deficits in a delayed nonmatch to place T-maze task. In accordance with these deficits, ß-catenin stabilization was found to abolish long-term depression by stabilizing cadherin at the synaptic membrane and impairing AMPA receptor endocytosis, while leaving basal synaptic transmission and long-term potentiation unaffected. These results demonstrate that the ß-catenin/cadherin adhesion complex plays an important role in learning and memory and that aberrant increases in synaptic adhesion can have deleterious effects on cognitive function.

Determination of Component Contents of Blend Oil Based on Characteristics Peak Value Integration.

Edible blend oil market is confused at present. It has some problems such as confusing concepts, randomly named, shoddy and especially the fuzzy standard of compositions and ratios in blend oil. The national standard fails to come on time after eight years. The basic reason is the lack of qualitative and quantitative detection of vegetable oils in blend oil. Edible blend oil is mixed by different vegetable oils according to a certain proportion. Its nutrition is rich. Blend oil is eaten frequently in daily life. Different vegetable oil contains a certain components. The mixed vegetable oil can make full use of their nutrients and make the nutrients more balanced in blend oil. It is conducive to people's health. It is an effectively way to monitor blend oil market by the accurate determination of single vegetable oil content in blend oil. The types of blend oil are known, so we only need for accurate determination of its content. Three dimensional fluorescence spectra are used for the contents in blend oil. A new method of data processing is proposed with calculation of characteristics peak value integration in chosen characteristic area based on Quasi-Monte Carlo method, combined with Neural network method to solve nonlinear equations to obtain single vegetable oil content in blend oil. Peanut oil, soybean oil and sunflower oil are used as research object to reconcile into edible blend oil, with single oil regarded whole, not considered each oil's components. Recovery rates of 10 configurations of edible harmonic oil is measured to verify the validity of the method of characteristics peak value integration. An effective method is provided to detect components content of complex mixture in high sensitivity. Accuracy of recovery rats is increased, compared the common method of solution of linear equations used to detect components content of mixture. It can be used in the testing of kinds and content of edible vegetable oil in blend oil for the food quality detection, and provide an effective reference for the creation of national standards.

[Research on the Medicinal Effective Component and Characterization of Virus-Free Breeding and Sulfur Smoked Qi Chrysanthemum Based on FTIR and FT-Raman].

Based on Fourier transform infrared (FTIR) and Raman spectroscopy (FT - Raman), the effective medicinal composition and its content change of Qi chrysanthemum are directly and quickly determined among the virus-free breeding and sulfur smoked samples of three different groups. FTIR and FT-Raman spectra of three groups of Qi chrysanthemum sample are compared and analyzed. The results show that the intensities of multiple infrared absorption peaks are obvious different within the range of 1 800~500 cm-1 and the characteristic peak shapes are slightly different in the FTIR spectra of the three groups with obvious differences of characteristic peak shapes in FT - Raman spectrum have. FTIR and FT - Raman spectrum directly reflect that the stem tip virus-free breeding will make the volatile oil, flavonoids and other medicinal component content increase in Qi Chrysanthemum, but the sulfur smoked reduce. The FTIR, FT Raman spectroscopy for detection of effective medicinal composition changes in Qi Chrysanthemum caused by virus-free breeding or sulfur smoked establishes a scientific basis, also an effective method to test their component content.

[Research on Spectroscopy Spectrum De-Noising of Mineral Oil Based on Lifting Scheme Wavelet Transform].

The use of the mineral oil is an important cause of air pollution such as fog. The effectiveness and rapidity of the de-noising processing in mineral oil fluorescence spectroscopy detection system is a hot issue of the online real-time monitoring system. The de-noising method of the lifting wavelet transform (LWT) in the application of mineral oil fluorescence spectrum is proposed. Compared with traditional discrete wavelet transform (DWT), this wavelet transform method decomposes the existing wavelet filter module into the basic construction modules and steps to complete the transform with simplicity and a fast speed. There are characteristics of low computational complexity, in situ operation and the easy implement in the denoising process of mineral oil fluorescence spectra. The LWT can effectively solve the problems in these respects. The three methods of LWT, DWT and EMD are applied to the fluorescence spectra of 0# diesel oil, 97# gasoline and kerosene. The indicators evaluating de-noising effect such as the Signal-to-Noise Ratio (SNR), Mean Squared Error (MSE) and Normalied Correlation Coefficient (NCC) of the three kinds of mineral oil in the fluorescence spectra denoising prove the effectiveness of the lifting scheme wavelet transform in the application of mineral oil fluorescence spectrum. Meanwhile, the lifting scheme transform can improve the flexibility of structure and operation simplicity that makes the de-noising time reduced by 62%, validating the speediness of the de-noising method of the LWT in the application of mineral oil fluorescence spectrum and it is suitable for mineral oil fast de-noising processing system in real time.

[The Fluorescence Detection of Oil Pollutants Based on Self-Weighted Alternating Trilinear Decomposition].

The oil pollutants detector is designed in this paper. The pulse xenon lamp is used as light source; the step type multi-mode pure silica fiber is chosen to transmit the excitation and emission light. The asymmetric Czemy-Turner light path of high precision grating monochromator is adopted. The detector is applied to determine the fluorescence spectrum of diesel, gasoline and kerosene. The optimal excitation /emission wavelengths are: 290/330 nm (diesel)，270/300 nm (gasoline) and 280/330 nm (kerosene). The detection limits are: diesel (0.025 mg·L-1), gasoline (0.042 mg·L-1) and kerosene(0.054 mg·L-1). The relative errors are: diesel(2.55%), gasoline(2.06%) and kerosene(1.71%). Experiment results show that the designed detector has high accuracy of measurement. The different concentration of diesel, gasoline and kerosene mixed solution is configured, and three dimensional fluorescence spectra being measured. The self-weighted alternating trilinear decomposition is adopted to decompose the spectrum data. The predicted concentration and recovery rate show that self-weighted alternating trilinear decomposition has high resolution for mixed oil substance.