ABSTRACT
Dendritic spine development is crucial for the establishment of excitatory synaptic connectivity and functional neural circuits. Alterations in spine morphology and density have been associated with multiple neurological disorders. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. However, the role of DIP2A in the brain remains largely unknown. In this study, we found that deletion of Dip2a in mice induced defects in spine morphogenesis along with thin postsynaptic density (PSD), and reduced synaptic transmission of pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin. Furthermore, Dip2a knockout (KO) mice exhibited autism-like behaviors, including excessive repetitive behaviors and defects in social novelty. Importantly, acetylation mimetic cortactin restored the impaired synaptic transmission and ameliorated repetitive behaviors in these mice. Altogether, our findings establish an initial link between DIP2A gene variations in autism spectrum disorder (ASD) and highlight the contribution of synaptic protein acetylation to synaptic processing.
Subject(s)
Acetyl Coenzyme A/genetics , Autism Spectrum Disorder/genetics , Cortactin/genetics , Dendritic Spines/metabolism , Morphogenesis/genetics , Nuclear Proteins/genetics , Protein Processing, Post-Translational , Acetyl Coenzyme A/deficiency , Acetylation , Amino Acid Motifs , Animals , Animals, Newborn , Autism Spectrum Disorder/metabolism , Autism Spectrum Disorder/physiopathology , Binding Sites , Cortactin/metabolism , Dendritic Spines/ultrastructure , Disease Models, Animal , Embryo, Mammalian , Gene Expression Regulation, Developmental , Genetic Complementation Test , Mice , Mice, Knockout , Nuclear Proteins/deficiency , Post-Synaptic Density/metabolism , Post-Synaptic Density/ultrastructure , Protein Binding , Protein Interaction Domains and Motifs , Pyramidal Cells/metabolism , Pyramidal Cells/ultrastructure , Synaptic TransmissionABSTRACT
This endeavor demonstrates a two-channel spatial division multiplexed (SDM) system and combines it with an all-optical four-level pulse amplitude modulation (PAM4) scheme to quadruple the data rate and presents the experimental setup, system model, as well as key results. The system initially introduces spatial reuse of optical frequencies in a single-core multimode optical fiber by transmitting two SDM channels, where both operate at 1310 nm. It then complements the two SDM channels with an all-optical PAM4 scheme to enable 2 bits/symbol and 40 Gbps optical transport while using only 10 Gbps sources. Since all sources operate at the same wavelength, it effectively achieves PAM16 efficiencies at the given wavelength. The system accomplishes these results without the use of dedicated PAM4 chipsets.
ABSTRACT
ß-site APP-cleaving enzyme 1 (BACE1) initiates amyloid precursor protein (APP) cleavage and ß-amyloid (Aß) production, a critical step in the pathogenesis of Alzheimer's disease (AD). It is thus of considerable interest to investigate how BACE1 activity is regulated. BACE1 has its maximal activity at acidic pH and GFP variant-pHluorin-displays pH dependence. In light of these observations, we generated three tandem fluorescence-tagged BACE1 fusion proteins, named pHluorin-BACE1-mCherry, BACE1-mCherry-pHluorin and BACE1-mCherry-EGFP. Comparing the fluorescence characteristics of these proteins in response to intracellular pH changes induced by chloroquine or bafilomycin A1, we found that pHluorin-BACE1-mCherry is a better pH sensor for BACE1 because its fluorescence intensity responds to pH changes more dramatically and more quickly. Additionally, we found that (pro)renin receptor (PRR), a subunit of the v-ATPase complex, which is critical for maintaining vesicular pH, regulates pHluorin's fluorescence and BACE1 activity in pHluorin-BACE1-mCherry expressing cells. Finally, we found that the expression of Swedish mutant APP (APPswe) suppresses pHluorin fluorescence in pHluorin-BACE1-mCherry expressing cells in culture and in vivo, implicating APPswe not only as a substrate but also as an activator of BACE1. Taken together, these results suggest that the pHluorin-BACE1-mCherry fusion protein may serve as a useful tool for visualizing active/inactive BACE1 in culture and in vivo.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Green Fluorescent Proteins/metabolism , Luminescent Proteins/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Cell Line, Tumor , Chloroquine/pharmacology , Female , Fluorescence , HEK293 Cells , Humans , Hydrogen-Ion Concentration/drug effects , Macrolides/pharmacology , Male , Mice , Receptors, Cell Surface/metabolism , Transfection , Vacuolar Proton-Translocating ATPases/metabolism , Red Fluorescent ProteinABSTRACT
An efficient synthesis of the C20-C46 segment of phorboxazole B is described. The key steps involved Hg(OAc)(2)/I(2)-induced cyclization to construct the cis-tetrahydropyran moiety, the coupling of the metalated 2-methyloxazole 7 with lactone 6, and Julia olefination to furnish the conjugated diene moiety.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxazoles/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Molecular Structure , Oxazoles/chemistryABSTRACT
Lithium transitionmetal (Fe, Mn, Co, Ni) silicate cathode materials are new promising substituting cathode materials for lithium ion batteries. They had caught the researchers' eyes in the past several years. Nowadays, there are growing interests for silicate cathode materials in the field of lithium ion batteries. Among the silicate cathode materials, Li2FeSiO4 is the most promising cathode materials because of its high structure stability, high reversible capacity, high electronic conductivity and the abundant resource of iron and silicon. Although Li2MnSiO4 and Li2CoSiO4 have much higher theoretic specific capacity than Li2FeSiO4, they all have inferior electrochemical behaviours due to different reasons. There are only calculation results about Li2NiSiO4 till now. This brief critical review firstly discussed some papers about the first-principle calculation of Li2MSiO4 (M=Fe, Mn, Co Ni), and then collects and discusses relevant papers and recent patents about the fabrication, structure, particle size and electrochemical performance of nano/micro Li2MSiO4 (M=Fe, Mn, Co Ni) and their composites. Finally, the future challenges of Li2FeSiO4 are also discussed.
Subject(s)
Electric Power Supplies , Lithium/chemistry , Nanostructures/chemistry , Silicates/chemistry , Transition Elements/chemistry , Electrochemical Techniques , Electrodes , Patents as TopicABSTRACT
As the vital part of lithium ion batteries, conductive additives play important roles in the electrochemical performance of lithium ion batteries. They construct a conductive percolation network to increase and keep the electronic conductivity of electrode, enabling it charge and discharge faster. In addition, conductive additives absorb and retain electrolyte, allowing an intimate contact between the lithium ions and active materials. Carbon nanomaterials are carbon black, Super P, acetylene black, carbon nanofibers, and carbon nanotubes, which all have superior properties such as low weight, high chemical inertia and high specific surface area. They are the ideal conductive additives for lithium ion batteries. This review will discuss some registered patents and relevant papers about the carbon nanomaterials that are used as conductive additives in cathode or anode to improve the electrochemical performance of lithium ion batteries.
Subject(s)
Electric Power Supplies , Lithium/chemistry , Nanotechnology/methods , Nanotubes, Carbon/chemistry , Patents as Topic , Electrodes , Models, Chemical , Soot/chemistryABSTRACT
An efficient and highly convergent total synthesis of the potent antitumor agent phorboxazole B has been achieved. The synthetic strategy of this synthesis features: 1) a highly efficient substrate-controlled hydrogenation to construct the functionalized cis-tetrahydropyrane unit; 2) iterative crotyl addition to synthesize the segment that contains alternating hydroxyl and methyl substituents; 3) Hg(OAc)2/I2-induced cyclization to establish the cis-tetrahydropyrane moiety; 4) 1,3-asymmetric induction in the Mukaiyama aldol reaction to afford the stereogenic centers at C9 and C3; and 5) the exploration of the Still-Gennari olefination reaction to complete the macrolide ring of phorboxazoloe B.