Flattening of Lithium Plating in Carbonate Electrolytes Enabled by All-In-One Separator.

The uncontrollable dendritic growth of metallic lithium during repeated cycling in carbonate electrolytes is a crucial obstacle hindering the practical use of Li-metal batteries (LMBs). Among numerous approaches proposed to mitigate the intrinsic constraints of Li metal, the design of a functional separator is an attractive approach to effectively suppress the growth of Li dendrites because direct contact with both the Li metal surface and the electrolyte is maintained. Here, a newly designed all-in-one separator containing bifunctional CaCO3 nanoparticles (CPP separator) is proposed to achieve the flattening of Li deposits on the Li electrode. Strong interactions between the highly polar CaCO3 nanoparticles and the polar solvent reduces the ionic radius of the Li+ -solvent complex, thus increasing the Li+ transference number and leading to a reduced concentration overpotential in the electrolyte-filled separator. Furthermore, the integration of CaCO3 nanoparticles into the separator induces the spontaneous formation of mechanically-strong and lithiophilic CaLi2 at the Li/separator interface, which effectively decreases the nucleation overpotential toward Li plating. As a result, the Li deposits exhibit dendrite-free planar morphologies, thus enabling excellent cycling performance in LMBs configured with a high-Ni cathode in a carbonate electrolyte under practical operating conditions.

Counting DNA molecules on a microchannel surface for quantitative analysis.

Microscopic visualization of DNA molecules is a simple, intuitive, and powerful method. Nonetheless, DNA-molecule quantification methods that employ microscopic visualization have not been reported so far. In this study, a new quantitative approach is presented that enables the counting of individual DNA molecules that have been rendered visible by fluorescence microscopy. Toward this, a microfluidic device was employed that directed DNA molecules into microchannels and deposited the molecules onto a positively charged surface. This microfluidic device had a vertically tapered channel inlet structure that prevented the accumulation of excess DNA molecules in the channel inlet while creating a tapering flow, thereby ensuring the even distribution of the DNA molecules in the microchannels. The channel heights and the density of positive charges on the surface were optimized for analysis. The linearity of this method with respect to the determination of the concentration of DNA in solutions was subsequently determined. The limit of detection was 0.48 fg/µL, which corresponds to 64 molecules of 7.25 kbp DNA in 1 µL of sample. This quantitative approach was finally used to count two types of plasmids co-transformed in an E. coli cell; a measurement that is typically considered challenging with gel electrophoresis.

Synthesis and Evaluation of Serinolamide Derivatives as Sphingosine-1-Phosphate-1 (S1P1) Receptor Agonists.

Sphingosine-1-phosphate-1 (S1P1) receptor agonists are well-known drugs for treating multiple sclerosis (MS) caused by autoreactive lymphocytes that attack the myelin sheath. Therefore, an effective therapeutic strategy is to reduce the lymphocytes in the blood by inducing S1P1 receptor internalization. We synthesized serinolamide A, a natural product of the sea, and performed S1P1 receptor internalization assay to evaluate functionally antagonistic S1P1 receptor agonist activity. In order to synthesize derivatives with better efficacy than serinolamide A and B, new derivatives were synthesized by introducing the phenyl ring moiety of fingolimod. Among them, compounds 19 and 21 had superior S1P1 agonistic effects to serinolamide. We also confirmed that compound 19 effectively inhibited lymphocyte outflow in peripheral lymphocyte count (PLC) assay.

Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain.

Neuropathic pain is a chronic and sometimes intractable condition caused by lesions or diseases of the somatosensory nervous system. Many drugs are available but unfortunately do not provide satisfactory effects in patients, producing limited analgesia and undesirable side effects. Thus, there is an urgent need to develop new pharmaceutical agents to treat neuropathic pain. To date, highly specific agents that modulate a single target, such as receptors or ion channels, never progress to the clinic, which may reflect the diverse etiologies of neuropathic pain seen in the human patient population. Therefore, the development of multifunctional compounds exhibiting two or more pharmacological activities is an attractive strategy for addressing unmet medical needs for the treatment of neuropathic pain. To develop novel multifunctional compounds, key pharmacophores of currently used clinical pain drugs, including pregabalin, fluoxetine and serotonin analogs, were hybridized to the side chain of tianeptine, which has been used as an antidepressant. The biological activities of the hybrid analogs were evaluated at the human transporters of neurotransmitters, including serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT), as well as mu (µ) and kappa (κ) opioid receptors. The most advanced hybrid of these multifunctional compounds, 17, exhibited multiple transporter inhibitory activities for the uptake of neurotransmitters with IC50 values of 70 nM, 154 nM and 2.01 µM at hSERT, hNET and hDAT, respectively. Additionally, compound 17 showed partial agonism (EC50 = 384 nM) at the µ-opioid receptor with no influence at the κ-opioid receptor. In in vivo pain animal experiments, the multifunctional compound 17 showed significantly reduced allodynia in a spinal nerve ligation (SNL) model by intrathecal administration, indicating that multitargeted strategies in single therapy could considerably benefit patients with multifactorial diseases, such as pain.

Mediating the effects of depression in the relationship between university students' attitude toward suicide, frustrated interpersonal needs, and non-suicidal self-injury during the COVID-19 pandemic.

OBJECTIVE: The study aimed to examine the relationship on attitudes toward suicide, frustrated interpersonal needs, and non-suicidal self-injury (NSSI) of the university students. METHODS: The participants included 175 university students. Data were analyzed using the SPSS PROCESS macro (Model 4). RESULTS: Depression showed a fully mediating effect on the relationship between one's attitude toward suicide and NSSI behaviors. Furthermore, depression showed a full mediating impact on the relationship between frustrated interpersonal needs and NSSI behaviors. CONCLUSIONS: These findings indicate that suicidal attitudes and frustrated interpersonal needs should be considered significant factors for developing NSSI preventions and intervention among university students.

Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis.

The sphingosine-1-phosphate-1 (S1P1) receptor agonists have great potential for the treatment of multiple sclerosis (MS) because they can inhibit lymphocyte egress through receptor internalization. We designed and synthesized triazole and isoxazoline derivatives to discover a novel S1P1 agonist for MS treatment. Of the two scaffolds, the isoxazoline derivative was determined to have excellent in vitro efficacy and drug-like properties. Among them, compound 21l was found to have superior drug-like properties as well as excellent in vitro efficacies (EC50 = 7.03 nM in ß-arrestin recruitment and EC50 = 11.8 nM in internalization). We also confirmed that 21l effectively inhibited lymphocyte egress in the peripheral lymphocyte count test and significantly improved the clinical score in the experimental autoimmune encephalitis MS mouse model.

Imbalanced Data Classification via Cooperative Interaction Between Classifier and Generator.

Learning classifiers with imbalanced data can be strongly biased toward the majority class. To address this issue, several methods have been proposed using generative adversarial networks (GANs). Existing GAN-based methods, however, do not effectively utilize the relationship between a classifier and a generator. This article proposes a novel three-player structure consisting of a discriminator, a generator, and a classifier, along with decision boundary regularization. Our method is distinctive in which the generator is trained in cooperation with the classifier to provide minority samples that gradually expand the minority decision region, improving performance for imbalanced data classification. The proposed method outperforms the existing methods on real data sets as well as synthetic imbalanced data sets.

Optimization and Evaluation of Novel Antifungal Agents for the Treatment of Fungal Infection.

Due to the increased morbidity and mortality by fungal infections and the emergence of severe antifungal resistance, there is an urgent need for new antifungal agents. Here, we screened for antifungal activity in our in-house library through the minimum inhibitory concentration test and derived two hit compounds with moderate antifungal activities. The hit compounds' antifungal activities and drug-like properties were optimized by substituting various aryl ring, alkyl chain, and methyl groups. Among the optimized compounds, 22h was the most promising candidate with good drug-like properties and exhibited potent fast-acting fungicidal antifungal effects against various fungal pathogens and synergistic antifungal activities with some known antifungal drugs. Additionally, 22h was further confirmed to disturb fungal cell wall integrity by activating multiple cell wall integrity pathways. Furthermore, 22h exerted significant antifungal efficacy in both the subcutaneous infection mouse model and ex vivo human nail infection model.

KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson's Disease.

Monoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson's disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.

Development and optimization of halogenated vinyl sulfones as Nrf2 activators for the treatment of Parkinson's disease.

The Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a pivotal role in the cellular defense system against oxidative stress by inducing antioxidant and anti-inflammatory effects. We previously developed Nrf2 activators that potentially protect the death of dopaminergic (DAergic) neuronal cells against oxidative stress in Parkinson's disease (PD). In this study, we designed and synthesized a class of halogenated vinyl sulfones by inserting halogens and pyridine to maximize Nrf2 activation efficacy. Among the synthesized compounds, (E)-3-chloro-2-(2-((2-chlorophenyl)sulfonyl)vinyl)pyridine (9d) significantly exhibited potent Nrf2 activating efficacy (9d: EC50 = 26 nM) at least 10-fold compared with the previous developed compounds (1 and 2). Furthermore, treating with 9d remarkably increased Nrf2 nuclear translocation and Nrf2 protein levels in microglial BV-2 cells. 9d was shown to induce the expression of antioxidant response genes HO-1, GCLC, GCLM, and SOD-1 at both the mRNA and protein levels and suppress proinflammatory cytokines and enzymes. Also, 9d remarkably protected DAergic neurons and restored the PD-associated motor dysfunction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model.

Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti-inflammatory properties in Parkinson's disease animal model.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by abnormal movement, including slowed movements, shuffling gait, lack of balance, and tremor. Oxidative stress has been shown to play a decisive role in dopaminergic neuronal cell death in PD. The nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling pathway provides the main defense system against oxidative stress by inducing the expression of antioxidant enzyme genes. Direct interference in the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an effective strategy for Nrf2 activation. Therefore, we searched for novel Nrf2 activators that can disrupt Nrf2-Keap1 interaction by using a virtual screening approach and identified a potent Nrf2 activator, KKPA4026. KKPA4026 was confirmed to induce the expression of the Nrf2-dependent antioxidant enzymes heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase regulatory subunit, and NAD(P)H:quinone oxidoreductase 1 in BV-2 cells. Furthermore, KKPA4026 showed anti-inflammatory effects in an Nrf2-dependent manner. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, KKPA4026 effectively attenuated PD-associated behavioral deficits and protected dopaminergic neurons. In summary, we identified KKPA4026 as a novel Nrf2 activator and suggested that Nrf2 activation through interference with the Nrf2-Keap1 interaction may be effective for PD treatment.

Discovery of Novel Biased Opioid Receptor Ligands through Structure-Based Pharmacophore Virtual Screening and Experiment.

Gi -protein-biased agonists with minimal ß-arrestin recruitment represent opportunities to overcome the serious adverse effects of human mu opioid receptor (µ-OR) agonists and developing alternative and safe treatments for pain. In order to discover novel non-morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in-house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel µ-OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R-group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new Gi -protein-biased compound, 1-{5-(3-chlorophenyl)-7,8-dimethoxy-3-[4-(methylsulfonyl)benzyl]-3H-pyrazolo[3,4-c]isoquinolin-1-yl}-N,N-dimethylmethanamine, showed an EC50 value of 179 nm against the µ-OR. This resulted in significant pain relief for mice in the phase II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G-protein-coupled receptors.

High Efficiency Flip Chip-Based UV Emitter with Indium Tin Oxide Nano Grains/Al Reflector and Periodic Microhole Arrays.

We propose a high efficiency flip chip-based ultraviolet (UV) emitter with aluminum (Al) reflector that includes indium tin oxide (ITO) nano grains for current injection between the Al and p-AlGaN layer. Al has attracted attention as a reflector for high efficiency UV emitters because of its high reflectance in the UV region. To improve the efficiency of UV emitter, we generated periodic microhole arrays on the p-AlGaN layer, which serve as a scattering center in the flip chip structure and enhance the light extraction efficiency. The light output power of the fabricated flip chip-based UV emitter with ITO nano grains/Al reflector and microhole arrays on the p-AlGaN layer is significantly improved by 72% and 45% at an injection current of 20 mA, compared to that of UV emitter with only Al reflector and ITO nano grains/Al reflector.

Transparent Conductive Electrodes of ß-Ga2O3/Ag/ß-Ga2O3 Multilayer for Ultraviolet Emitters.

We investigated the optical and electrical properties of a ß-Ga2O3/Ag/ß-Ga2O3 multilayer transparent conductive electrode deposited on an α-Al2O3 (0001) substrate. For the deposition of a continuous Ag layer, we preliminarily performed anultraviolet-ozone pretreatment of the Ga2O3 bottom layer. To obtain a stable ß-phase of Ga2O3, the ß-Ga2O3/Ag/ß-Ga2O3 multilayer was annealed at 700 °C under N2 atmosphere. The transmittance and sheet resistance of the ß-Ga2O3/Ag/ß-Ga2O3 multilayer were critically affected by the surface morphology and thickness of the Ag interlayer. The multilayer with optimized thicknesses (ß-Ga2O3 top layer: 30 nm; Ag interlayer: 12 nm; ß-Ga2O3 bottom layer: 60 nm) exhibited a resistance of 8.48 Ωsq-1, an average optical transmittance of 87.16% in the ultraviolet wavelength range from 300 to 350 nm, and a figure of merit of 29.81 × 10-3 Ω-1.

Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease.

Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50 = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.

1H NMR toxicometabolomics following cisplatin-induced nephrotoxicity in male rats.

Cisplatin (CP) is an anti-cancer drug used for treatment of solid tumors, but the major adverse effect is drug-induced nephrotoxicity. The current study aimed to determine biomarkers that might predict nephrotoxicity induced by CP using serum or urinary proton nuclear magnetic resonance (1H NMR) spectral data in male Sprague-Dawley (S-D) rats. CP (0, 0.5 or 5 mg/kg) was intraperitoneally (i.p.) administered for single dose. Animals were sacrificed 2 days (D2) or 8 days (D8) after administration of CP in order to perform analysis of serum biochemistries and histopathologic examination. Urine samples were collected every 24 hr from pre-treatment to sacrifice. Serum and urinary 1H NMR spectral data revealed apparent differential clustering between control and CP-treated groups as evidenced by principal component analysis (PCA) and orthogonal projections to latent structures-discriminant analysis (OPLS-DA) in global and targeted profiling. The concentrations of endogenous serum metabolites, alanine, betaine, glucose, glutamine, lactate, and leucine were significantly increased on D2. Urinary concentrations of alanine, glucose, glycine, guanidinoacetate, acetate, and lactate were significantly elevated on D2 or D8, whereas concentrations of urinary metabolites, citrate and hippurate were significantly decreased on D2 or D8. The correlation of serum and urinary 1H NMR OPLS-DA with serum biochemistry and renal histopathologic changes suggests that 1H NMR urinalysis may be used to reliably predict or screen CP-induced nephrotoxicity. Data suggest that these altered endogenous metabolites might serve as specific biomarkers for CP-induced nephrotoxicity.

Optimization of Vinyl Sulfone Derivatives as Potent Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Parkinson's Disease Therapy.

We previously developed a novel series of vinyl sulfones as nuclear factor erythroid 2-related factor 2 (Nrf2) activators with therapeutic potential for Parkinson's disease (PD). However, the previously developed lead compound (1) exhibited undesirable druglike properties. Here, we optimized vinyl sulfones by introducing nitrogen heterocycles to improve druglike properties. Among the synthesized compounds, 17e was the most promising drug candidate with good druglike properties. Compound 17e showed superior effects on Nrf2 activation in cell-based assays compared to compound 1 (17e: half-maximal effective concentration (EC50) = 346 nM; 1: EC50 = 530 nM). Compound 17e was further confirmed to induce expression of Nrf2-dependent antioxidant enzymes at both mRNA and protein levels. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD, 17e significantly attenuated loss of tyrosine hydroxylase-immunopositive dopaminergic neurons, suppressed microglial activation, and alleviated PD-associated motor dysfunction. Thus, 17e is a novel Nrf2 activator with excellent druglike properties and represents a potential therapeutic candidate for PD.

Wide Bandgap Transparent Conducting Electrode of FTO/Ag/FTO Structure for Ultraviolet Light-Emitting Diodes.

We investigated the effect of the Ag interlayer thickness on the structural, electrical and optical properties of FTO/Ag/FTO structures designed for use in wide bandgap transparent conducting electrodes. The top and bottom FTO layers were deposited on α-Al2O3 (0001) substrates via RF magnetron sputtering at 300 °C and Ag interlayers were deposited using an e-beam evaporator system. We optimized the figure of merit by changing the thickness of the inserted Ag interlayer from 10 nm to 14 nm, achieving a maximum value of 2.46 × 10-3 Ω-1 and a resistivity of 6.4 × 10-4 Ω · cm using an FTO (70 nm)/Ag (14 nm)/FTO (40 nm) structure. Furthermore, the average optical transmittance in the deep UV range (300 to 330 nm) was 82.8%.

Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy.

Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC50: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAO-B inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson's disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.

Magnetic resonance metabolic profiling of estrogen receptor-positive breast cancer: correlation with currently used molecular markers.

Estrogen receptor (ER)-positive breast cancers overall have a good prognosis, however, some patients suffer relapses and do not respond to endocrine therapy. The purpose of this study was to determine whether there are any correlations between high-resolution magic angle spinning (HR-MAS) magnetic resonance spectroscopy (MRS) metabolic profiles of core needle biopsy (CNB) specimens and the molecular markers currently used in patients with ER-positive breast cancers. The metabolic profiling of CNB samples from 62 ER-positive cancers was performed by HR-MAS MRS. Metabolic profiles were compared according to human epidermal growth factor receptor 2 (HER2) and Ki-67 status, and luminal type, using the Mann-Whitney test. Multivariate analysis was performed with orthogonal projections to latent structure-discriminant analysis (OPLS-DA). In univariate analysis, the HER2-positive group was shown to have higher levels of glycine and glutamate, compared to the HER2-negative group (P<0.01, and P <0.01, respectively). The high Ki-67 group showed higher levels of glutamate than the low Ki-67 group without statistical significance. Luminal B cancers showed higher levels of glycine (P=0.01) than luminal A cancers. In multivariate analysis, the OPLS-DA models built with HR-MAS MR metabolic profiles showed visible discrimination between the subgroups according to HER2 and Ki-67 status, and luminal type. This study showed that the metabolic profiles of CNB samples assessed by HR-MAS MRS can be used to detect potential prognostic biomarkers as well as to understand the difference in metabolic mechanism among subtypes of ER-positive breast cancer.