Cyclin Y regulates spatial learning and memory flexibility through distinct control of the actin pathway.

Spatial learning and memory flexibility are known to require long-term potentiation (LTP) and long-term depression (LTD), respectively, on a cellular basis. We previously showed that cyclin Y (CCNY), a synapse-remodeling cyclin, is a novel actin-binding protein and an inhibitory regulator of functional and structural LTP in vitro. In this study, we report that Ccny knockout (KO) mice exhibit enhanced LTP and weak LTD at Schaffer collateral-CA1 synapses in the hippocampus. In accordance with enhanced LTP, Ccny KO mice showed improved spatial learning and memory. However, although previous studies reported that normal LTD is necessary for memory flexibility, Ccny KO mice intriguingly showed improved memory flexibility, suggesting that weak LTD could exert memory flexibility when combined with enhanced LTP. At the molecular level, CCNY modulated spatial learning and memory flexibility by distinctively affecting the cofilin-actin signaling pathway in the hippocampus. Specifically, CCNY inhibited cofilin activation by original learning, but reversed such inhibition by reversal learning. Furthermore, viral-mediated overexpression of a phosphomimetic cofilin-S3E in hippocampal CA1 regions enhanced LTP, weakened LTD, and improved spatial learning and memory flexibility, thus mirroring the phenotype of Ccny KO mice. In contrast, the overexpression of a non-phosphorylatable cofilin-S3A in hippocampal CA1 regions of Ccny KO mice reversed the synaptic plasticity, spatial learning, and memory flexibility phenotypes observed in Ccny KO mice. Altogether, our findings demonstrate that LTP and LTD cooperatively regulate memory flexibility. Moreover, CCNY suppresses LTP while facilitating LTD in the hippocampus and negatively regulates spatial learning and memory flexibility through the control of cofilin-actin signaling, proposing CCNY as a learning regulator modulating both memorizing and forgetting processes.

Myristoylation-dependent palmitoylation of cyclin Y modulates long-term potentiation and spatial learning.

Many psychiatric disorders accompany deficits in cognitive functions and synaptic plasticity, and abnormal lipid modifications of neuronal proteins are associated with their pathophysiology. Lipid modifications, including palmitoylation and myristoylation, play crucial roles in the subcellular localization and trafficking of proteins. Cyclin Y (CCNY), enriched in the postsynaptic compartment, acts as an inhibitory modulator of functional and structural long-term potentiation (LTP) in the hippocampal neurons. However, cellular and molecular mechanisms underlying CCNY-mediated inhibitory functions in the synapse remain largely unknown. Here, we report that myristoylation located CCNY to the trans-Golgi network (TGN), and subsequent palmitoylation directed the myristoylated CCNY from the TGN to the synaptic cell surface. This myristoylation-dependent palmitoylation of CCNY was required for the inhibitory role of CCNY in excitatory synaptic transmission, activity-induced dynamics of AMPA receptors and PSD-95, LTP, and spatial learning. Furthermore, spatial learning significantly reduced palmitoyl- and myristoyl-CCNY levels, indicating that spatial learning lowers the synaptic abundance of CCNY. Our findings provide mechanistic insight into how CCNY is clustered adjacent to postsynaptic sites where it could play its inhibitory roles in synaptic plasticity and spatial learning.

Shank postsynaptic scaffolding proteins in autism spectrum disorder: Mouse models and their dysfunctions in behaviors, synapses, and molecules.

Postsynaptic scaffolding proteins, which are major components of the postsynaptic density (PSD) at excitatory synapses, include Shank, PSD-95, A-kinase anchoring protein, Homer, and SAP90/PSD-95-associated protein families and play crucial roles in synaptic structure, signaling, and functions. Several genetic studies have indicated that postsynaptic scaffolding proteins contribute to the etiology of various psychiatric disorders, including neurodevelopmental disorders. Indeed, mice with mutations or deletions in specific genes encoding postsynaptic scaffolding proteins display alterations in behavioral phenotypes that are relevant to specific psychiatric disorders. Here, we review recent studies on various mutant mouse models of Shank postsynaptic scaffolding proteins associated with autism spectrum disorder, a major neurodevelopmental disorder, and discuss future directions and therapeutic strategies for the treatment of autism spectrum disorder.

Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease.

Toxic amyloid beta (Aß) species cause synaptic dysfunction and neurotoxicity in Alzheimer's disease (AD). As of yet, however, there are no reported regulators for gamma-secretase, which links a risky environment to amyloid accumulation in AD. Here, we report that pyruvate kinase M2 (PKM2) is a positive regulator of gamma-secretase under hypoxia. From a genome-wide functional screen, we identify PKM2 as a gamma-secretase activator that is highly expressed in the brains of both patients and murine models with AD. PKM2 regulates Aß production and the amount of active gamma-secretase complex by changing the gene expression of aph-1 homolog. Hypoxia induces PKM2 expression, thereby promoting gamma-secretase activity. Moreover, transgenic expression of PKM2 in 3xTg AD model mice enhances hippocampal production of Aß and exacerbates the impairment of spatial and recognition memory. Taken together, these findings indicate that PKM2 is an important gamma-secretase regulator that promotes Aß production and memory impairment under hypoxia.

SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions.

The enzyme γ-secretase generates ß-amyloid (Aß) peptides by cleaving amyloid protein precursor (APP); the aggregation of these peptides is associated with Alzheimer's disease (AD). Despite the development of various γ-secretase regulators, their clinical use is limited by coincident disruption of other γ-secretase-regulated substrates, such as Notch. Using a genome-wide functional screen of γ-secretase activity in cells and a complementary DNA expression library, we found that SERP1 is a previously unknown γ-secretase activator that stimulates Aß generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes. SERP1 interacted with a subcomplex of γ-secretase (APH1A/NCT) through its carboxyl terminus to enhance the assembly and, consequently, the activity of the γ-secretase holoenzyme complex. In response to ER stress, SERP1 preferentially recruited APP rather than Notch into the γ-secretase complex and enhanced the subcellular localization of the complex into lipid rafts, increasing Aß production. Moreover, SERP1 abundance, γ-secretase assembly, and Aß production were increased both in cells exposed to high amounts of glucose and in diabetic AD model mice. Conversely, Aß production was decreased by knocking down SERP1 in cells or in the hippocampi of mice. Compared to postmortem samples from control individuals, those from patients with AD showed increased SERP1 expression in the hippocampus and parietal lobe. Together, our findings suggest that SERP1 is an APP-biased regulator of γ-secretase function in the context of cell stress, providing a possible molecular explanation for the link between diabetes and sporadic AD.

Tailored Nanopatterning by Controlled Continuous Nanoinscribing with Tunable Shape, Depth, and Dimension.

We present that the tailored nanopatterning with tunable shape, depth, and dimension for diverse application-specific designs can be realized by utilizing controlled dynamic nanoinscribing (DNI), which can generate bur-free plastic deformation on various flexible substrates via continuous mechanical inscription of a small sliced edge of a nanopatterned mold in a compact and vacuum-free system. Systematic controlling of prime DNI processing parameters including inscribing force, temperature, and substrate feed rate can determine the nanopattern depths and their specific profiles from rounded to angular shapes as a summation of the force-driven plastic deformation and heat-driven thermal deformation. More complex nanopatterns with gradient depths and/or multidimensional profiles can also be readily created by modulating the horizontal mold edge alignment and/or combining sequential DNI strokes, which otherwise demand laborious and costly procedures. Many practical user-specific applications may benefit from this study by tailor-making the desired nanopattern structures within desired areas, including precision machine and optics components, transparent electronics and photonics, flexible sensors, and reattachable and wearable devices. We demonstrate one vivid example in which the light diffusion direction of a light-emitting diode can be tuned by application of specifically designed DNI nanopatterns.

Paramagnetic Carbon Nanosheets with Random Hole Defects and Oxygenated Functional Groups.

Ordered graphitic carbon nanosheets (GCNs) were, for the first time, synthesized by the direct condensation of multifunctional phenylacetyl building blocks (monomers) in the presence of phosphorous pentoxide. The GCNs had highly ordered structures with random hole defects and oxygenated functional groups, showing paramagnetism. The results of combined structural and magnetic analyses indicate that the hole defects and functional groups are associated with the appearance and stabilization of unpaired spins. DFT calculations further suggest that the emergence of stabilized spin moments near the edge groups necessitates the presence of functionalized carbon atoms around the hole defects. That is, both hole defects and oxygenated functional groups are essential ingredients for the generation and stabilization of spins in GCNs.

Oxidative Dehydrogenation of Ethylbenzene into Styrene by Fe-Graphitic Catalysts.

Carbon-based catalysts have attracted much attention for the dehydrogenation (DH) of organic molecules, due to their rich active sites, high conversion efficiency, and selectivity. However, because of their poor stability at high operation temperature and relatively high cost, their practical applications have been limited. Here, we report a simple ball-milling-induced mechanochemical reaction which can introduce iron (Fe) and different functional groups (mostly stable aromatic C═O after heat-treatment) along the edges of graphitic nanoplatelets. The resulting Fe-graphitic nanoplatelets (Fe-XGnPs, X = H, C, N, or V) provide active sites for the oxidative dehydrogenation (ODH) of ethylbenzene into styrene. Among them, Fe-NGnPs (X = N) displayed the highest performance for styrene production at low temperature (∼11.13 mmol g-1 h-1, 450 °C) with high selectivity and durability.

Direct Synthesis of a Covalent Triazine-Based Framework from Aromatic Amides.

There have been extensive efforts to synthesize crystalline covalent triazine-based frameworks (CTFs) for practical applications and to realize their potential. The phosphorus pentoxide (P2 O5 )-catalyzed direct condensation of aromatic amide instead of aromatic nitrile to form triazine rings. P2 O5 -catalyzed condensation was applied on terephthalamide to construct a covalent triazine-based framework (pCTF-1). This approach yielded highly crystalline pCTF-1 with high specific surface area (2034.1 m2 g-1 ). At low pressure, the pCTF-1 showed high CO2 (21.9 wt % at 273 K) and H2 (1.75 wt % at 77 K) uptake capacities. The direct formation of a triazine-based COF was also confirmed by model reactions, with the P2 O5 -catalyzed condensation reaction of both benzamide and benzonitrile to form 1,3,5-triphenyl-2,4,6-triazine in high yield.

A Robust 3D Cage-like Ultramicroporous Network Structure with High Gas-Uptake Capacity.

A three-dimensional (3D) cage-like organic network (3D-CON) structure synthesized by the straightforward condensation of building blocks designed with gas adsorption properties is presented. The 3D-CON can be prepared using an easy but powerful route, which is essential for commercial scale-up. The resulting fused aromatic 3D-CON exhibited a high Brunauer-Emmett-Teller (BET) specific surface area of up to 2247 m2 g-1 . More importantly, the 3D-CON displayed outstanding low pressure hydrogen (H2 , 2.64 wt %, 1.0 bar and 77 K), methane (CH4 , 2.4 wt %, 1.0 bar and 273 K), and carbon dioxide (CO2 , 26.7 wt %, 1.0 bar and 273 K) uptake with a high isosteric heat of adsorption (H2 , 8.10 kJ mol-1 ; CH4 , 18.72 kJ mol-1 ; CO2 , 31.87 kJ mol-1 ). These values are among the best reported for organic networks with high thermal stability (ca. 600 °C).

Defect-Free Encapsulation of Fe0 in 2D Fused Organic Networks as a Durable Oxygen Reduction Electrocatalyst.

Because they provide lower cost but comparable activity to precious platinum (Pt)-based catalysts, nonprecious iron (Fe)-based materials, such as Fe/Fe3C and Fe-N-C, have gained considerable attention as electrocatalysts for the oxygen reduction reaction (ORR). However, their practical application is hindered by their poor stability, which is attributed to the defective protection of extremely unstable Fe nanoparticles. Here, we introduce a synthesis strategy for a stable Fe-based electrocatalyst, which was realized by defect-free encapsulation of Fe nanoparticles using a two-dimensional (2D) phenazine-based fused aromatic porous organic network (Aza-PON). The resulting Fe@Aza-PON catalyst showed electrocatalytic activity (half-wave potential, 0.839 V; Tafel slope, 60 mV decade-1) comparable to commercial Pt on activated carbon (Pt/C, 0.826 V and 90 mV decade-1). More importantly, the Fe@Aza-PON displayed outstanding stability (zero current loss even after 100 000 cycles) and tolerance against contamination (methanol and CO poisoning). In a hybrid Li-air battery test, the Fe@Aza-PON demonstrated performance superior to Pt/C.

Forming a three-dimensional porous organic network via solid-state explosion of organic single crystals.

Solid-state reaction of organic molecules holds a considerable advantage over liquid-phase processes in the manufacturing industry. However, the research progress in exploring this benefit is largely staggering, which leaves few liquid-phase systems to work with. Here, we show a synthetic protocol for the formation of a three-dimensional porous organic network via solid-state explosion of organic single crystals. The explosive reaction is realized by the Bergman reaction (cycloaromatization) of three enediyne groups on 2,3,6,7,14,15-hexaethynyl-9,10-dihydro-9,10-[1,2]benzenoanthracene. The origin of the explosion is systematically studied using single-crystal X-ray diffraction and differential scanning calorimetry, along with high-speed camera and density functional theory calculations. The results suggest that the solid-state explosion is triggered by an abrupt change in lattice energy induced by release of primer molecules in the 2,3,6,7,14,15-hexaethynyl-9,10-dihydro-9,10-[1,2]benzenoanthracene crystal lattice.

Macroporous Inverse Opal-like MoxC with Incorporated Mo Vacancies for Significantly Enhanced Hydrogen Evolution.

The hydrogen evolution reaction (HER) is one of the most important pathways for producing pure and clean hydrogen. Although platinum (Pt) is the most efficient HER electrocatalyst, its practical application is significantly hindered by high-cost and scarcity. In this work, an MoxC with incorporated Mo vacancies and macroporous inverse opal-like (IOL) structure (MoxC-IOL) was synthesized and studied as a low-cost efficient HER electrocatalyst. The macroporous IOL structure was controllably fabricated using a facile-hard template strategy. As a result of the combined benefits of the Mo vacancies and structural advantages, including appropriate hydrogen binding energy, large exposed surface, robust IOL structure and fast mass/charge transport, the synthesized MoxC-IOL exhibited significantly enhanced HER electrocatalytic performance with good stability, with performance comparable or superior to Pt wire in both acidic and alkaline solutions.

Phosphorylated CAV1 activates autophagy through an interaction with BECN1 under oxidative stress.

CAV1/Caveolin1, an integral membrane protein, is involved in caveolae function and cellular signaling pathways. Here, we report that CAV1 is a positive regulator of autophagy under oxidative stress and cerebral ischemic injury. Treatment with hydrogen peroxide enhanced autophagy flux and caused the localization of BECN1 to the mitochondria, whereas these changes were impaired in the absence of CAV1. Among many autophagy signals, only LC3 foci formation in response to hydrogen peroxide was abolished by CAV1 deficiency. Under oxidative stress, CAV1 interacted with a complex of BECN1/VPS34 through its scaffolding domain, and this interaction facilitated autophagosome formation. Interestingly, the phosphorylation of CAV1 at tyrosine-14 was essential for the interaction with BECN1 and their localization to the mitochondria, and the activation of autophagy in response to hydrogen peroxide. In addition, the expression of a phosphatase PTPN1 reduced the phosphorylation of CAV1 and inhibited autophagy. Further, compared to that in wild-type mice, autophagy was impaired and cerebral infarct damage was aggravated in the brain of Cav1 knockout mice. These results suggest that the phosphorylated CAV1 functions to activate autophagy through binding to the BECN1/VPS34 complex under oxidative stress and to protect against ischemic damage.

An efficient and pH-universal ruthenium-based catalyst for the hydrogen evolution reaction.

The hydrogen evolution reaction (HER) is a crucial step in electrochemical water splitting and demands an efficient, durable and cheap catalyst if it is to succeed in real applications. For an energy-efficient HER, a catalyst must be able to trigger proton reduction with minimal overpotential and have fast kinetics. The most efficient catalysts in acidic media are platinum-based, as the strength of the Pt-H bond is associated with the fastest reaction rate for the HER. The use of platinum, however, raises issues linked to cost and stability in non-acidic media. Recently, non-precious-metal-based catalysts have been reported, but these are susceptible to acid corrosion and are typically much inferior to Pt-based catalysts, exhibiting higher overpotentials and lower stability. As a cheaper alternative to platinum, ruthenium possesses a similar bond strength with hydrogen (∼65 kcal mol-1), but has never been studied as a viable alternative for a HER catalyst. Here, we report a Ru-based catalyst for the HER that can operate both in acidic and alkaline media. Our catalyst is made of Ru nanoparticles dispersed within a nitrogenated holey two-dimensional carbon structure (Ru@C2N). The Ru@C2N electrocatalyst exhibits high turnover frequencies at 25 mV (0.67 H2 s-1 in 0.5 M H2SO4 solution; 0.75 H2 s-1 in 1.0 M KOH solution) and small overpotentials at 10 mA cm-2 (13.5 mV in 0.5 M H2SO4 solution; 17.0 mV in 1.0 M KOH solution) as well as superior stability in both acidic and alkaline media. These performances are comparable to, or even better than, the Pt/C catalyst for the HER.

Edge-selenated graphene nanoplatelets as durable metal-free catalysts for iodine reduction reaction in dye-sensitized solar cells.

Metal-free carbon-based electrocatalysts for dye-sensitized solar cells (DSSCs) are sufficiently active in Co(II)/Co(III) electrolytes but are not satisfactory in the most commonly used iodide/triiodide (I(-)/I3 (-)) electrolytes. Thus, developing active and stable metal-free electrocatalysts in both electrolytes is one of the most important issues in DSSC research. We report the synthesis of edge-selenated graphene nanoplatelets (SeGnPs) prepared by a simple mechanochemical reaction between graphite and selenium (Se) powders, and their application to the counter electrode (CE) for DSSCs in both I(-)/I3 (-) and Co(II)/Co(III) electrolytes. The edge-selective doping and the preservation of the pristine graphene basal plane in the SeGnPs were confirmed by various analytical techniques, including atomic-resolution transmission electron microscopy. Tested as the DSSC CE in both Co(bpy)3 (2+/3+) (bpy = 2,2'-bipyridine) and I(-)/I3 (-) electrolytes, the SeGnP-CEs exhibited outstanding electrocatalytic performance with ultimately high stability. The SeGnP-CE-based DSSCs displayed a higher photovoltaic performance than did the Pt-CE-based DSSCs in both SM315 sensitizer with Co(bpy)3 (2+/3+) and N719 sensitizer with I(-)/I3 (-) electrolytes. Furthermore, the I3 (-) reduction mechanism, which has not been fully understood in carbon-based CE materials to date, was clarified by an electrochemical kinetics study combined with density functional theory and nonequilibrium Green's function calculations.

Two-dimensional polyaniline (C3N) from carbonized organic single crystals in solid state.

The formation of 2D polyaniline (PANI) has attracted considerable interest due to its expected electronic and optoelectronic properties. Although PANI was discovered over 150 y ago, obtaining an atomically well-defined 2D PANI framework has been a longstanding challenge. Here, we describe the synthesis of 2D PANI via the direct pyrolysis of hexaaminobenzene trihydrochloride single crystals in solid state. The 2D PANI consists of three phenyl rings sharing six nitrogen atoms, and its structural unit has the empirical formula of C3N. The topological and electronic structures of the 2D PANI were revealed by scanning tunneling microscopy and scanning tunneling spectroscopy combined with a first-principle density functional theory calculation. The electronic properties of pristine 2D PANI films (undoped) showed ambipolar behaviors with a Dirac point of -37 V and an average conductivity of 0.72 S/cm. After doping with hydrochloric acid, the conductivity jumped to 1.41 × 10(3) S/cm, which is the highest value for doped PANI reported to date. Although the structure of 2D PANI is analogous to graphene, it contains uniformly distributed nitrogen atoms for multifunctionality; hence, we anticipate that 2D PANI has strong potential, from wet chemistry to device applications, beyond linear PANI and other 2D materials.

Unusually Stable Triazine-based Organic Superstructures.

Solid-state reactions have been rapidly gaining popularity in organic chemistry owing to their simplicity, efficiency, and selectivity compared to liquid-phase reactions. Herein, we describe the formation of superstructures through the solid-state reaction of an organic single-crystal. The superstructure of 5,5',5''-(1,3,5-triazine-2,4,6-triyl)triisophthalonitrile (TIPN) can be formed by cyclotrimerization of 1,3,5-tricyanobenzene (TCB) single crystals. The TIPN superstructure was confirmed by single crystal X-ray diffraction and visualized by transmission electron microscopy. The superstructure has hexagonally packed 1-dimensional (1D) channels along the crystal axis. Furthermore, the superstructure arises from interdigitated nitrile interactions in the crystal lattice, and thus has electron-beam tolerance and very high thermal stability.

Dual-specificity phosphatase 26 (DUSP26) stimulates Aß42 generation by promoting amyloid precursor protein axonal transport during hypoxia.

Amyloid beta peptide (Aß) is a pathological hallmark of Alzheimer's disease (AD) and is generated through the sequential cleavage of amyloid precursor protein (APP) by ß- and γ-secretases. Hypoxia is a known risk factor for AD and stimulates Aß generation by γ-secretase; however, the underlying mechanisms remain unclear. In this study, we showed that dual-specificity phosphatase 26 (DUSP26) regulates Aß generation through changes in subcellular localization of the γ-secretase complex and its substrate C99 under hypoxic conditions. DUSP26 was identified as a novel γ-secretase regulator from a genome-wide functional screen using a cDNA expression library. The phosphatase activity of DUSP26 was required for the increase in Aß42 generation through γ-secretase, but this regulation did not affect the amount of the γ-secretase complex. Interestingly, DUSP26 induced the accumulation of C99 in the axons by stimulating anterograde transport of C99-positive vesicles. Additionally, DUSP26 induced c-Jun N-terminal kinase (JNK) activation for APP processing and axonal transport of C99. Under hypoxic conditions, DUSP26 expression levels were elevated together with JNK activation, and treatment with JNK inhibitor SP600125, or the DUSP26 inhibitor NSC-87877, reduced hypoxia-induced Aß generation by diminishing vesicle trafficking of C99 to the axons. Finally, we observed enhanced DUSP26 expression and JNK activation in the hippocampus of AD patients. Our results suggest that DUSP26 mediates hypoxia-induced Aß generation through JNK activation, revealing a new regulator of γ-secretase-mediated APP processing under hypoxic conditions. We propose the role of phosphatase dual-specificity phosphatase 26 (DUSP26) in the selective regulation of Aß42 production in neuronal cells under hypoxic stress. Induction of DUSP26 causes JNK-dependent shift in the subcellular localization of γ-secretase and C99 from the cell body to axons for Aß42 generation. These findings provide a new strategy for developing new therapeutic targets to arrest AD progression.

Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model.

In neurodegenerative diseases like AD, tau forms neurofibrillary tangles, composed of tau protein. In the AD brain, activated caspases cleave tau at the 421th Asp, generating a caspase-cleaved form of tau, TauC3. Although TauC3 is known to assemble rapidly into filaments in vitro, a role of TauC3 in vivo remains unclear. Here, we generated a transgenic mouse expressing human TauC3 using a neuron-specific promoter. In this mouse, we found that human TauC3 was expressed in the hippocampus and cortex. Interestingly, TauC3 mice showed drastic learning and spatial memory deficits and reduced synaptic density at a young age (2-3months). Notably, tau oligomers as well as tau aggregates were found in TauC3 mice showing memory deficits. Further, i.p. or i.c.v. injection with methylene blue or Congo red, inhibitors of tau aggregation in vitro, and i.p. injection with rapamycin significantly reduced the amounts of tau oligomers in the hippocampus, rescued spine density, and attenuated memory impairment in TauC3 mice. Together, these results suggest that TauC3 facilitates early memory impairment in transgenic mice accompanied with tau oligomer formation, providing insight into the role of TauC3 in the AD pathogenesis associated with tau oligomers and a useful AD model to test drug candidates.