Physiological Role of ATPase for GABAA Receptor Resensitization

γ-Aminobutyric acid type A receptors (GABA_ARs) mediate primarily inhibitory synaptic transmission in the central nervous system. Following fast-paced activation, which provides the selective flow of mainly chloride (Cl⁻) and less bicarbonate (HCO₃⁻) ions via the pore, these receptors undergo desensitization that is paradoxically prevented by the process of their recovery, referred to as resensitization. To clarify the mechanism of resensitization, we used the cortical synaptoneurosomes from the rat brain and HEK 293FT cells. Here, we describe the effect of γ-phosphate analogues (γPAs) that mimic various states of ATP hydrolysis on GABA_AR-mediated Cl⁻ and HCO₃⁻ fluxes in response to the first and repeated application of the agonist. We found that depending on the presence of bicarbonate, opened and desensitized states of the wild or chimeric GABA_ARs had different sensitivities to γPAs. This study presents the evidence that recovery of neuronal Cl⁻ and HCO₃⁻ concentrations after desensitization is accompanied by a change in the intracellular ATP concentration via ATPase performance. The transition between the desensitization and resensitization states was linked to changes in both conformation and phosphorylation. In addition, the chimeric β3 isoform did not exhibit the desensitization of the GABA_AR-mediated Cl⁻ influx but only the resensitization. These observations lend a new physiological significance to the β3 subunit in the manifestation of GABA_AR resensitization.     

α2δ-4 and Cachd1 Proteins Are Regulators of Presynaptic Functions

The α₂δ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, α₂δ isoforms 1, 2, and 3 are strongly expressed, regulating glutamatergic synapse formation by a presynaptic mechanism. Although the α₂δ-4 isoform is predominantly found in the retina with very little expression in the brain, it was recently linked to brain functions. In contrast, Cachd1, a novel α₂δ-like protein, shows strong expression in brain, but its function in neurons is not yet known. Therefore, we aimed to investigate the presynaptic functions of α₂δ-4 and Cachd1 by expressing individual proteins in cultured hippocampal neurons. Both α₂δ-4 and Cachd1 are expressed in the presynaptic membrane and could rescue a severe synaptic defect present in triple knockout/knockdown neurons that lacked the α₂δ-1-3 isoforms (α₂δ TKO/KD). This observation suggests that presynaptic localization and the regulation of synapse formation in glutamatergic neurons is a general feature of α₂δ proteins. In contrast to this redundant presynaptic function, α₂δ-4 and Cachd1 differentially regulate the abundance of presynaptic calcium channels and the amplitude of presynaptic calcium transients. These functional differences may be caused by subtle isoform-specific differences in α₁-α₂δ protein–protein interactions, as revealed by structural homology modelling. Taken together, our study identifies both α₂δ-4 and Cachd1 as presynaptic regulators of synapse formation, differentiation, and calcium channel functions that can at least partially compensate for the loss of α₂δ-1-3. Moreover, we show that regulating glutamatergic synapse formation and differentiation is a critical and surprisingly redundant function of α₂δ and Cachd1.     

Acute and Delayed Effects of Mechanical Injury on Calcium Homeostasis and Mitochondrial Potential of Primary Neuroglial Cell Culture: Potential Causal Contributions to Post-Traumatic Syndrome

In vitro models of traumatic brain injury (TBI) help to elucidate the pathological mechanisms responsible for cell dysfunction and death. To simulate in vitro the mechanical brain trauma, primary neuroglial cultures were scratched during different periods of network formation. Fluorescence microscopy was used to measure changes in intracellular free Ca²⁺ concentration ([Ca²⁺]_i) and mitochondrial potential (ΔΨm) a few minutes later and on days 3 and 7 after scratching. An increase in [Ca²⁺]_i and a decrease in ΔΨm were observed ~10 s after the injury in cells located no further than 150–200 µm from the scratch border. Ca²⁺ entry into cells during mechanical damage of the primary neuroglial culture occurred predominantly through the NMDA-type glutamate ionotropic channels. MK801, an inhibitor of this type of glutamate receptor, prevented an acute increase in [Ca²⁺]_i in 99% of neurons. Pathological changes in calcium homeostasis persisted in the primary neuroglial culture for one week after injury. Active cell migration in the scratch area occurred on day 11 after neurotrauma and was accompanied by a decrease in the ratio of live to dead cells in the areas adjacent to the injury. Immunohistochemical staining of glial fibrillary acidic protein and β-III tubulin showed that neuronal cells migrated to the injured area earlier than glial cells, but their repair potential was insufficient for survival. Mitochondrial Ca²⁺ overload and a drop in ΔΨm may cause delayed neuronal death and thus play a key role in the development of the post-traumatic syndrome. Preventing prolonged ΔΨm depolarization may be a promising therapeutic approach to improve neuronal survival after traumatic brain injury.     

[β-Glu2]TRH Is a Functional Antagonist of Thyrotropin-Releasing Hormone (TRH) in the Rodent Brain

Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH₂), in order to enable a better understanding of this peptide’s central functions, have not been identified. Using pGlu-Glu-Pro-NH₂ ([Glu²]TRH) as a lead peptide and with modification at its central residue, our studies focused on some of its analogues synthesized as potential functional antagonists of TRH in the rodent brain. Among the peptides studied, the novel isomeric analogue [β-Glu²]TRH was found to suppress the analeptic and antidepressant-like pharmacological activities of TRH without eliciting intrinsic effects in these paradigms. [β-Glu²]TRH also completely reversed TRH’s stimulation of acetylcholine turnover in the rat hippocampus without a cholinergic activity of its own, which was demonstrated through in vivo microdialysis experiments. Altogether, [β-Glu²]TRH emerged as the first selective functional antagonist of TRH’s prominent cholinergic actions, by which this endogenous peptide elicits a vast array of central effects.     

Synthesis,Characterization and Anti-Breast Cancer Activity of New 4-Aminoantipyrine-Based Heterocycles

4-Aminoantipyrine was utilized as key intermediate for the synthesis of pyrazolone derivatives bearing biologically active moieties. The newly synthesized compounds were characterized by IR, ¹H- and ¹³C-NMR spectral and microanalytical studies. The compounds were screened as anticancer agents against a human tumor breast cancer cell line MCF7, and the results showed that (Z)-4-((3-amino-5-imino-1-phenyl-1H-pyrazol-4(5H)-ylidene)methylamino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 5, 3-(4-bromophenyl) -1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 13, 1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1-Hpyrazol- 4-yl)-3-(4-iodophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 14, 3,3′-(4,4′-sulfonylbis(4,1-phenylene))bis(1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol- 4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) 16, (Z)-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-hydrazono-4-oxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 17, (Z)-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-3-phenyl-2-(2-phenylhydrazono)-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile 18, and (Z)-4-(3-amino-6-hydrazono-7-phenyl-6,7-dihydro pyrazolo[3,4-d]pyrimidin-5-yl)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 19 were the most active compounds with IC₅₀ values ranging from 30.68 to 60.72 μM compared with Doxorubicin as positive control with the IC₅₀ value 71.8 μM.     

The Dual Role of the β2-Adrenoreceptor in the Modulation of IL-17 and IFN-γ Production by T Cells in Multiple Sclerosis

Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the role of the β₂-adrenoreceptor in the norepinephrine-mediated modulation of interleukin-17 (IL-17) and interferon-γ (IFN-γ) production, which play a critical pathogenetic role in MS. CD4⁺ T cells obtained from twenty-five relapsing-remitting MS patients and sixteen healthy subjects were cultured ex vivo with norepinephrine and/or β₂-adrenoreceptor antagonist or agonist, followed by a cytokine production analysis using ELISA. Norepinephrine suppressed IL-17 and IFN-γ production by the anti-CD3/anti-CD28-microbead-stimulated CD4⁺ T cells in both groups. Blockade of the β₂-adrenoreceptor with the specific antagonist ICI 118.551 enhanced norepinephrine-mediated IL-17 suppression but decreased its inhibitory effect on IFN-γ production in MS patients. In contrast, the β₂-adrenoreceptor agonist formoterol did not influence norepinephrine’s inhibitory effect on cytokine production in both groups. The blockade of the β₂-adrenoreceptor, even in the absence of exogenous norepinephrine, suppressed IL-17 production but did not influence IFN-γ production in both groups. Conversely, β₂-adrenoreceptor activation by formoterol decreased IFN-γ production and did not affect IL-17 production in both groups. These data illustrate the inhibitory effect of norepinephrine on IL-17 and IFN-γ production by CD4⁺ T cells in MS. The inhibitory effect of norepinephrine on IFN-γ production by CD4⁺ T cells in MS could be mediated via β₂-adrenoreceptor activation.     

Changing Microspatial Patterns of Sulfate-Reducing Microorganisms (SRM) during Cycling of Marine Stromatolite Mats

Microspatial arrangements of sulfate-reducing microorganisms (SRM) in surface microbial mats (~1.5 mm) forming open marine stromatolites were investigated. Previous research revealed three different mat types associated with these stromatolites, each with a unique petrographic signature. Here we focused on comparing “non-lithifying” (Type-1) and “lithifying” (Type-2) mats. Our results revealed three major trends: (1) Molecular typing using the dsrA probe revealed a shift in the SRM community composition between Type-1 and Type-2 mats. Fluorescence in-situ hybridization (FISH) coupled to confocal scanning-laser microscopy (CSLM)-based image analyses, and ³⁵SO₄ ²⁻-silver foil patterns showed that SRM were present in surfaces of both mat types, but in significantly (p < 0.05) higher abundances in Type-2 mats. Over 85% of SRM cells in the top 0.5 mm of Type-2 mats were contained in a dense 130 μm thick horizontal layer comprised of clusters of varying sizes; (2) Microspatial mapping revealed that locations of SRM and CaCO₃ precipitation were significantly correlated (p < 0.05); (3) Extracts from Type-2 mats contained acylhomoserine-lactones (C4-, C6-, oxo-C6 C7-, C8-, C10-, C12-, C14-AHLs) involved in cell-cell communication. Similar AHLs were produced by SRM mat-isolates. These trends suggest that development of a microspatially-organized SRM community is closely-associated with the hallmark transition of stromatolite surface mats from a non-lithifying to a lithifying state.     

Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice

Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[¹¹C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1^(−/−) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (k_elim) was calculated from time–activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.     

C18:1 Methyl Ester Metathesis in [bmim][X] Type Ionic Liquids

The efficacy of [bmim][X] ionic liquids (ILs) (X = PF₆⁻, BF₄⁻ and NTf₂⁻) as reaction media for methyl oleate metathesis was compared with that of conventional organic solvents (PhCl, PhMe, DCM and DCE) using the well-defined first and second generation Grubbs precatalysts, RuCl₂(PCy₃)(L)(=CHPh) (L = PCy₃ or H₂IMes). Best catalytic performance, with excellent selectivity (>98%) at moderate reaction temperatures, was achieved in [bmim][X] ILs compared to conventional solvents. The effects of anion, reaction temperature, solvent polarity, solvent viscosity, and ligand-anion interaction on the reaction are also addressed.     

Insulin Diminishes Superoxide Increase in Cytosol and Mitochondria of Cultured Cortical Neurons Treated with Toxic Glutamate

Glutamate excitotoxicity is involved in the pathogenesis of many disorders, including stroke, traumatic brain injury, and Alzheimer’s disease, for which central insulin resistance is a comorbid condition. Neurotoxicity of glutamate (Glu) is primarily associated with hyperactivation of the ionotropic N-methyl-D-aspartate receptors (NMDARs), causing a sustained increase in intracellular free calcium concentration ([Ca²⁺]_i) and synchronous mitochondrial depolarization and an increase in intracellular superoxide anion radical (O₂^–•) production. Recently, we found that insulin protects neurons against excitotoxicity by decreasing the delayed calcium deregulation (DCD). However, the role of insulin in O₂^–• production in excitotoxicity still needs to be clarified. The present study aims to investigate insulin’s effects on glutamate-evoked O₂^–• generation and DCD using the fluorescent indicators dihydroethidium, MitoSOX Red, and Fura-FF in cortical neurons. We found a linear correlation between [Ca²⁺]_i and [O₂^–•] in primary cultures of the rat neuron exposed to Glu, with insulin significantly reducing the production of intracellular and mitochondrial O₂^–• in the primary cultures of the rat neuron. MK 801, an inhibitor of NMDAR-gated Ca²⁺ influx, completely abrogated the glutamate effects in both the presence and absence of insulin. In experiments in sister cultures, insulin diminished neuronal death and O₂ consumption rate (OCR).     

Galectin-3 Contributes to the Inhibitory Effect of lα,25-(OH)2D3 on Osteoclastogenesis

The active form of vitamin D, 1α,25-(OH)₂D₃, not only promotes intestinal calcium absorption, but also regulates the formation of osteoclasts (OCs) and their capacity for bone mineral dissolution. Gal-3 is a newly discovered bone metabolic regulator involved in the proliferation, differentiation, and apoptosis of various cells. However, the role of galectin-3 (gal-3) in OC formation and the regulatory effects of 1α,25-(OH)₂D₃ have yet to be explored. To confirm whether gal-3 contributes to the regulatory effects of 1α,25-(OH)₂D₃ on osteoclastogenesis, osteoclast precursors (OCPs) were induced by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL). TRAP staining and bone resorption analyses were used to verify the formation and activation of OCs. qPCR, Western blotting, co-immunoprecipitation, and immunofluorescence assays were used to detect gene and protein expression. The regulatory effects of gal-3 in OC formation after treatment with 1α,25-(OH)₂D₃ were evaluated using gal-3 siRNA. The results showed that 1α,25-(OH)₂D₃ significantly increased gal-3 expression and inhibited OC formation and bone resorption. Expression levels of OC-related genes and proteins, matrix metalloproteinase 9 (MMP-9), nuclear factor of activated T cells 1 (NFATc1), and cathepsin K (Ctsk) were also inhibited by 1α,25-(OH)₂D₃. Gal-3 knockdown attenuated the inhibitory effects of 1α,25-(OH)₂D₃ on OC formation, activation, and gene and protein expression. In addition, gal-3 was co-localized with the vitamin D receptor (VDR). These data suggest that gal-3 contributes to the osteoclastogenesis inhibitory effect of lα,25-(OH)₂D₃, which is involved in bone and calcium homeostasis.     

Extracellular Prolidase (PEPD) Induces Anabolic Processes through EGFR, β1-integrin,and IGF-1R Signaling Pathways in an Experimental Model of Wounded Fibroblasts

The role of prolidase (PEPD) as a ligand of the epidermal growth factor receptor (EGFR) was studied in an experimental model of wound healing in cultured fibroblasts. The cells were treated with PEPD (1–100 nM) and analysis of cell viability, proliferation, migration, collagen biosynthesis, PEPD activity, and the expressions of EGFR, insulin-like growth factor 1 (IGF-1), and β₁-integrin receptor including downstream signaling proteins were performed. It has been found that PEPD stimulated proliferation and migration of fibroblasts via activation of the EGFR-downstream PI3K/Akt/mTOR signaling pathway. Simultaneously, PEPD stimulated the expression of β₁-integrin and IGF-1 receptors and proteins downstream to these receptors such as FAK, Grb2, and ERK1/2. Collagen biosynthesis was increased in control and “wounded” fibroblasts under PEPD treatment. The data suggest that PEPD-induced EGFR signaling may serve as a new attempt to therapy wound healing.     

GABAA Receptor Modulators with a Pyrazolo[1,5-a]quinazoline Core: Synthesis,Molecular Modelling Studies and Electrophysiological Assays

As a continuation of our study in the GABA_A receptor modulators field, we report the design and synthesis of new 8-chloropyrazolo[1,5-a]quinazoline derivatives. Molecular docking studies and the evaluation of the ‘Proximity Frequencies’ (exploiting our reported model) were performed on all the final compounds (3, 4, 6a–c, 7a,b, 8, 9, 12a–c, 13a,b, 14–19) to predict their profile on the α1β2γ2-GABA_AR subtype. Furthermore, to verify whether the information coming from this virtual model was valid and, at the same time, to complete the study on this series, we evaluated the effects of compounds (1–100 µM) on the modulation of GABA_A receptor function through electrophysiological techniques on recombinant α1β2γ2L-GABA_A receptors expressed in Xenopus laevis oocytes. The matching between the virtual prediction and the electrophysiological tests makes our model a useful tool for the study of GABA_A receptor modulators.     

Low-temperature growth of highly crystalline β-Ga2O3 nanowires by solid-source chemical vapor deposition

Growing Ga₂O₃ dielectric materials at a moderately low temperature is important for the further development of high-mobility III-V semiconductor-based nanoelectronics. Here, β-Ga₂O₃ nanowires are successfully synthesized at a relatively low temperature of 610°C by solid-source chemical vapor deposition employing GaAs powders as the source material, which is in a distinct contrast to the typical synthesis temperature of above 1,000°C as reported by other methods. In this work, the prepared β-Ga₂O₃ nanowires are mainly composed of Ga and O elements with an atomic ratio of approximately 2:3. Importantly, they are highly crystalline in the monoclinic structure with varied growth orientations in low-index planes. The bandgap of the β-Ga₂O₃ nanowires is determined to be 251 nm (approximately 4.94 eV), in good accordance with the literature. Also, electrical characterization reveals that the individual nanowire has a resistivity of up to 8.5 × 10⁷ Ω cm, when fabricated in the configuration of parallel arrays, further indicating the promise of growing these highly insulating Ga₂O₃ materials in this III-V nanowire-compatible growth condition.

PACS

77.55.D; 61.46.Km; 78.40.Fy     

Structure of N-Terminal Sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser of Aβ-Peptide with Phospholipase A2 from Venom of Andaman Cobra Sub-Species Naja naja sagittifera at 2.0 ? Resolution

Alzheimer’s disease (AD) is one of the most significant social and health burdens of the present century. Plaques formed by extracellular deposits of amyloid β (Aβ) are the prime player of AD’s neuropathology. Studies have implicated the varied role of phospholipase A₂ (PLA₂) in brain where it contributes to neuronal growth and inflammatory response. Overall contour and chemical nature of the substrate-binding channel in the low molecular weight PLA₂s are similar. This study involves the reductionist fragment-based approach to understand the structure adopted by N-terminal fragment of Alzheimer’s Aβ peptide in its complex with PLA₂. In the current communication, we report the structure determined by X-ray crystallography of N-terminal sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser (DAEFRHDS) of Aβ-peptide with a Group I PLA₂ purified from venom of Andaman Cobra sub-species Naja naja sagittifera at 2.0 Å resolution (Protein Data Bank (PDB) Code: 3JQ5). This is probably the first attempt to structurally establish interaction between amyloid-β peptide fragment and hydrophobic substrate binding site of PLA₂ involving H bond and van der Waals interactions. We speculate that higher affinity between Aβ and PLA₂ has the therapeutic potential of decreasing the Aβ–Aβ interaction, thereby reducing the amyloid aggregation and plaque formation in AD.     

Research into the Bioengineering of a Novel α-Conotoxin from the Milked Venom of Conus obscurus

The marine cone snail produces one of the fastest prey strikes in the animal kingdom. It injects highly efficacious venom, often causing prey paralysis and death within seconds. Each snail has hundreds of conotoxins, which serve as a source for discovering and utilizing novel analgesic peptide therapeutics. In this study, we discovered, isolated, and synthesized a novel α3/5-conotoxins derived from the milked venom of Conus obscurus (α-conotoxin OI) and identified the presence of α-conotoxin SI-like sequence previously found in the venom of Conus striatus. Five synthetic analogs of the native α-conotoxin OI were generated. These analogs incorporated single residue or double residue mutations. Three synthetic post-translational modifications (PTMs) were synthetically incorporated into these analogs: N-terminal truncation, proline hydroxylation, and tryptophan bromination. The native α-conotoxin OI demonstrated nanomolar potency in Poecilia reticulata and Homo sapiens muscle-type nicotinic acetylcholine receptor (nAChR) isoforms. Moreover, the synthetic α-[P9K] conotoxin OI displayed enhanced potency in both bioassays, ranging from a 2.85 (LD₅₀) to 18.4 (IC₅₀) fold increase in comparative bioactivity. The successful incorporation of PTMs, with retention of both potency and nAChR isoform selectivity, ultimately pushes new boundaries of peptide bioengineering and the generation of novel α-conotoxin-like sequences.     

TGF-β1 Protection against Aβ1–42-Induced Neuroinflammation and Neurodegeneration in Rats

Transforming growth factor (TGF)-β1, a cytokine that can be expressed in the brain, is a key regulator of the brain’s responses to injury and inflammation. Alzheimer’s disease (AD), the most common neurodegenerative disorder, involves inflammatory processes in the brain in addition to the hallmarks, amyloid-β (Aβ) plaques and neurofibrillary tangles. Recently, we have shown that T-helper (Th) 17 cells, a subpopulation of CD4⁺ T-cells with high proinflammation, also participate in the brain inflammatory process of AD. However, it is poorly known whether TGF-β1 ameliorates the lymphocyte-mediated neuroinflammation and, thereby, alleviates neurodegeneration in AD. Herein, we administered TGF-β1 via the intracerebroventricle (ICV) in AD model rats, by Aβ_1–42 injection in both sides of the hippocampus, to show the neuroprotection of TGF-β1. The TGF-β1 administration after the Aβ_1–42 injection ameliorated cognitive deficit and neuronal loss and apoptosis, reduced amyloid precursor protein (APP) expression, elevated protein phosphatase (PP)2A expression, attenuated glial activation and alleviated the imbalance of the pro-inflammatory/anti-inflammatory responses of T-lymphocytes, compared to the Aβ_1–42 injection alone. These findings demonstrate that TGF-β1 provides protection against AD neurodegeneration and suggest that the TGF-β1 neuroprotection is implemented by the alleviation of glial and T-cell-mediated neuroinflammation.     

A new NiCuCu Ni complex containing doubly end-on azido bridged dicopper(II) and macrocyclic nickel(II) complex ancillary ligands: Synthesis, structure and magnetism

[Cu₂(NiL)₂(N₃)₄] was synthesized by combining “complex as ligand” approach and “pure bridging ligand” approach (H₂L = dimethyl 5,6,7,8,15,16-hexahydro-15-methyl-6,7-dioxodibenzo[1,4,8,11]tetraazacyclotetradecine-13,18-dicarboxylate). The two Cu^II ions are bridged by two end-on azido ligands. ππ and oxamido–carbonyl interactions link the molecules into 1D supramolecular chains. Ferromagnetic interactions exist between the two Cu^II ions.     

Comparison of resistive switching characteristics using copper and aluminum electrodes on GeOx/W cross-point memories

Comparison of resistive switching memory characteristics using copper (Cu) and aluminum (Al) electrodes on GeO_x/W cross-points has been reported under low current compliances (CCs) of 1 nA to 50 μA. The cross-point memory devices are observed by high-resolution transmission electron microscopy (HRTEM). Improved memory characteristics are observed for the Cu/GeO_x/W structures as compared to the Al/GeO_x/W cross-points owing to AlO_x formation at the Al/GeO_x interface. The RESET current increases with the increase of the CCs varying from 1 nA to 50 μA for the Cu electrode devices, while the RESET current is high (>1 mA) and independent of CCs varying from 1 nA to 500 μA for the Al electrode devices. An extra formation voltage is needed for the Al/GeO_x/W devices, while a low operation voltage of ±2 V is needed for the Cu/GeO_x/W cross-point devices. Repeatable bipolar resistive switching characteristics of the Cu/GeO_x/W cross-point memory devices are observed with CC varying from 1 nA to 50 μA, and unipolar resistive switching is observed with CC >100 μA. High resistance ratios of 10² to 10⁴ for the bipolar mode (CCs of 1 nA to 50 μA) and approximately 10⁸ for the unipolar mode are obtained for the Cu/GeO_x/W cross-points. In addition, repeatable switching cycles and data retention of 10³ s are observed under a low current of 1 nA for future low-power, high-density, nonvolatile, nanoscale memory applications.     

Enhanced resistive switching memory characteristics and mechanism using a Ti nanolayer at the W/TaOx interface

Enhanced resistive memory characteristics with 10,000 consecutive direct current switching cycles, long read pulse endurance of >10⁵ cycles, and good data retention of >10⁴ s with a good resistance ratio of >10² at 85°C are obtained using a Ti nanolayer to form a W/TiO_x/TaO_x/W structure under a low current operation of 80 μA, while few switching cycles are observed for W/TaO_x/W structure under a higher current compliance >300 μA. The low resistance state decreases with increasing current compliances from 10 to 100 μA, and the device could be operated at a low RESET current of 23 μA. A small device size of 150 × 150 nm² is observed by transmission electron microscopy. The presence of oxygen-deficient TaO_x nanofilament in a W/TiO_x/TaO_x/W structure after switching is investigated by Auger electron spectroscopy. Oxygen ion (negative charge) migration is found to lead to filament formation/rupture, and it is controlled by Ti nanolayer at the W/TaO_x interface. Conducting nanofilament diameter is estimated to be 3 nm by a new method, indicating a high memory density of approximately equal to 100 Tbit/in.².