Insight into Fluoride Additives to Enhance Ammonia Production from Lithium-Mediated Electrochemical Nitrogen Reduction Reaction.

Demands for green ammonia production increase due to its application as a proton carrier, and recent achievements in electrochemical Li-mediated nitrogen reduction reactions (Li-NRRs) show promising reliability. Here, it is demonstrated that F-containing additives in the electrolyte improve ammonia production by modulating the solid electrolyte interphase (SEI). It is suggested that the anionic additives with low lowest unoccupied molecular orbital levels enhance efficiency by contributing to the formation of a conductive SEI incorporated with LiF. Specifically, as little as 0.3 wt.% of BF4 - additive to the electrolyte, the Faradaic efficiency (FE) for ammonia production is enhanced by over 15% compared to an additive-free electrolyte, achieving a high yield of 161 ± 3 nmol s-1 cm-2. The BF4 - additive exhibits advantages, with decreased overpotential and improved FE, compared to its use as the bulk electrolyte. The observation of the Li3N upper layer implies that active Li-NRR catalytic cycles are occurring on the outermost SEI, and density functional theory simulations propose that an SEI incorporated with LiF facilitates energy profiles for the protonation by adjusting the binding energies of the intermediates compared to bare copper. This study unlocks the potential of additives and offers insights into the SEIs for efficient Li-NRRs.

Unlocking the Potential of Bi2S3-Derived Bi Nanoplates: Enhanced Catalytic Activity and Selectivity in Electrochemical and Photoelectrochemical CO2 Reduction to Formate.

Various electrocatalysts are extensively examined for their ability to selectively produce desired products by electrochemical CO2 reduction reaction (CO2RR). However, an efficient CO2RR electrocatalyst doesn't ensure an effective co-catalyst on the semiconductor surface for photoelectrochemical CO2RR. Herein, Bi2S3 nanorods are synthesized and electrochemically reduced to Bi nanoplates that adhere to the substrates for application in the electrochemical and photoelectrochemical CO2RR. Compared with commercial-Bi, the Bi2S3-derived Bi (S-Bi) nanoplates on carbon paper exhibit superior electrocatalytic activity and selectivity for formate (HCOO-) in the electrochemical CO2RR, achieving a Faradaic efficiency exceeding 93%, with minimal H2 production over a wide potential range. This highly selective S-Bi catalyst is being employed on the Si photocathode to investigate the behavior of electrocatalysts during photoelectrochemical CO2RR. The strong adhesion of the S-Bi nanoplates to the Si nanowire substrate and their unique catalytic properties afford exceptional activity and selectivity for HCOO- under simulated solar irradiation. The selectivity observed in electrochemical CO2RR using the S-Bi catalyst correlates with that seen in the photoelectrochemical CO2RR system. Combined pulsed potential methods and theoretical analyses reveal stabilization of the OCHO* intermediate on the S-Bi catalyst under specific conditions, which is critical for developing efficient catalysts for CO2-to-HCOO- conversion.

Exploring the role of apolipoprotein E gene promoter polymorphisms in susceptibility to normal-tension glaucoma in a Korean population.

Glaucoma, particularly primary open-angle glaucoma (POAG), poses a significant global health concern. Distinguished by intraocular pressure (IOP), POAG encompasses high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). Apolipoprotein E (APOE) is a multifaceted protein with roles in lipid metabolism, neurobiology, and neurodegenerative diseases. However, controversies persist regarding the impact of APOE single-nucleotide polymorphisms (SNPs) on open-angle glaucoma and NTG. This study aimed to identify APOE-specific SNPs influencing NTG risk. A cohort of 178 patients with NTG recruited from Uijeongbu St. Mary's Hospital and 32,858 individuals from the Korean Genome and Epidemiology Study (KoGES) cohort were included in the analysis. Genotype and haplotype analyses were performed on three promoter SNPs (rs449647, rs769446, and rs405509) and two exonic SNPs (rs429358 and rs7412) located on chromosome 19. Among the five SNPs, rs769446 genotypes exhibited significant differences between cases and controls. The minor allele C of rs769446 emerged as a protective factor against NTG. Furthermore, haplotype analysis of the five SNPs revealed that the A-T-G-T-T haplotype was a statistically significant risk factor for NTG. This study indicated an association between APOE promoter SNPs and NTG in the Korean population. Further studies are required to understand how APOE promoter SNPs contribute to NTG pathogenesis.

Functional Group-Dependent Proton Conductivity of Phosphoric Acid-Doped Ion-Pair Coordinated Polymer Electrolytes: A Molecular Dynamics Study.

Toward deployment of high-temperature polymer electrolyte membrane fuel cells (HT-PEMFCs) in our daily lives, multiple research efforts have been dedicated to develop high-performance phosphate-doped polymer electrolytes. Recently, ion-pair coordinated polymers have garnered attention for their high stability and proton conductivity. However, a comprehensive understanding of how proton transport properties are modified by the functional groups present in these polymers is still lacking. In this study, we employ molecular dynamics (MD) simulations to investigate the impact of different functional group types and conversion ratios on conductivity. We find that Grotthuss-type hopping transport predominantly governs the overall conductivity, surpassing vehicular transport by factors of 100-1000. As conductivity scales with proton concentration, we observe that less-bulky functional groups offer advantages by minimizing the volume expansion associated with increased conversion ratios. Additionally, we show that a strong ion-pair interaction between the cationic functional group and the phosphate anion disrupts the suitable intermolecular orientations required for efficient proton hopping between phosphate and phosphoric acid molecules, thereby diminishing the proton conductivity. Our study underscores the importance of optimizing the strength of ion-pair interactions to balance stability and proton conductivity, thus paving the way for the development of ion-pair coordinated polymer electrolytes with improved performance.

Recurrent pattern completion drives the neocortical representation of sensory inference.

When sensory information is incomplete or ambiguous, the brain relies on prior expectations to infer perceptual objects. Despite the centrality of this process to perception, the neural mechanism of sensory inference is not known. Illusory contours (ICs) are key tools to study sensory inference because they contain edges or objects that are implied only by their spatial context. Using cellular resolution, mesoscale two-photon calcium imaging and multi-Neuropixels recordings in the mouse visual cortex, we identified a sparse subset of neurons in the primary visual cortex (V1) and higher visual areas that respond emergently to ICs. We found that these highly selective 'IC-encoders' mediate the neural representation of IC inference. Strikingly, selective activation of these neurons using two-photon holographic optogenetics was sufficient to recreate IC representation in the rest of the V1 network, in the absence of any visual stimulus. This outlines a model in which primary sensory cortex facilitates sensory inference by selectively strengthening input patterns that match prior expectations through local, recurrent circuitry. Our data thus suggest a clear computational purpose for recurrence in the generation of holistic percepts under sensory ambiguity. More generally, selective reinforcement of top-down predictions by pattern-completing recurrent circuits in lower sensory cortices may constitute a key step in sensory inference.

Three-Dimensional Flower-like MoS2 Nanosheets Grown on Graphite as High-Performance Anode Materials for Fast-Charging Lithium-Ion Batteries.

The demand for fast-charging lithium-ion batteries (LIBs) with long cycle life is growing rapidly due to the increasing use of electric vehicles (EVs) and energy storage systems (ESSs). Meeting this demand requires the development of advanced anode materials with improved rate capabilities and cycling stability. Graphite is a widely used anode material for LIBs due to its stable cycling performance and high reversibility. However, the sluggish kinetics and lithium plating on the graphite anode during high-rate charging conditions hinder the development of fast-charging LIBs. In this work, we report on a facile hydrothermal method to achieve three-dimensional (3D) flower-like MoS2 nanosheets grown on the surface of graphite as anode materials with high capacity and high power for LIBs. The composite of artificial graphite decorated with varying amounts of MoS2 nanosheets, denoted as MoS2@AG composites, deliver excellent rate performance and cycling stability. The 20-MoS2@AG composite exhibits high reversible cycle stability (~463 mAh g-1 at 200 mA g-1 after 100 cycles), excellent rate capability, and a stable cycle life at the high current density of 1200 mA g-1 over 300 cycles. We demonstrate that the MoS2-nanosheets-decorated graphite composites synthesized via a simple method have significant potential for the development of fast-charging LIBs with improved rate capabilities and interfacial kinetics.

Isolation of a polyethylene-degrading bacterium, Acinetobacter guillouiae, using a novel screening method based on a redox indicator.

Plastic, a polymer synthesized from petrochemicals, is used worldwide. However, natural degradation of plastic is difficult, causing environmental pollution, with microplastics posing a serious threat to human health. In this study, we aimed to use a new screening method based on the oxidation-reduction indicator, 2,6-dichlorophenolindophenol, to isolate a polyethylene-degrading bacterium, Acinetobacter guillouiae, from insect larvae. Plastic-degrading strains are identified by the color change in the redox indicator from blue to colorless as plastic metabolism occurs. Polyethylene biodegradation by A. guillouiae was verified through weight loss, surface erosion, physiological evidence, and chemical changes on the plastic surface. In addition, we analyzed the characteristics of hydrocarbon metabolism in polyethylene-degrading bacteria. Results suggested that alkane hydroxylation and alcohol dehydrogenation were key steps in polyethylene degradation. This novel screening method will pave the way for high-throughput screening of polyethylene-degrading microorganisms and extending its application to other types of plastics may potentially address plastic pollution.

Probing inter-areal computations with a cellular resolution two-photon holographic mesoscope.

Brain computation depends on intricately connected yet highly distributed neural networks. Due to the absence of the requisite technologies, causally testing fundamental hypotheses on the nature of inter-areal processing have remained largely out-of-each. Here we developed the first two photon holographic mesoscope, a system capable of simultaneously reading and writing neural activity patterns with single cell resolution across large regions of the brain. We demonstrate the precise photo-activation of spatial and temporal sequences of neurons in one brain area while reading out the downstream effect in several other regions. Investigators can use this new platform to understand feed-forward and feed-back processing in distributed neural circuits with single cell precision for the first time.

Safety Assessment of Starch Nanoparticles as an Emulsifier in Human Skin Cells, 3D Cultured Artificial Skin, and Human Skin.

Emulsion systems are widely used in various industries, including the cosmetic, pharmaceutical, and food industries, because they require emulsifiers to stabilize the inherently unstable contact between oil and water. Although emulsifiers are included in many products, excessive use of emulsifiers destroys skin barriers and causes contact dermatitis. Accordingly, the consumer demand for cosmetic products made from natural ingredients with biocompatibility and biodegradability has increased. Starch in the form of solid nanosized particles is considered an attractive emulsifier that forms and stabilizes Pickering emulsion. Chemical modification of nanosized starch via acid hydrolysis can effectively provide higher emulsion stability. However, typical acid hydrolysis limits the industrial application of starch due to its high time consumption and low recovery. In previous studies, the effects of starch nanoparticles (SNPs) prepared by treatment with acidic dry heat, which overcomes these limitations, on the formation and stability of Pickering emulsions were reported. In this study, we evaluated the safety of SNPs in skin cell lines, 3D cultured skin, and human skin. We found that the cytotoxicity of SNPs in both HaCaT cells and HDF cells could be controlled by neutralization. We also observed that SNPs did not induce structural abnormalities on 3D cultured skin and did not permeate across micropig skin tissue or human skin membranes. Furthermore, patches loaded with SNPs were found to belong in the "No irritation" category because they did not cause any irritation when placed on human skin. Overall, the study results suggest that SNPs can be used as a safe emulsifier in various industries, including in cosmetics.

Effect of fatty acid chain length on physicochemical properties of starch nanocomposites obtained via nanoprecipitation.

To evaluate the effect of elaborate difference in the hydrophobicity of core material on encapsulation process and physicochemical properties of the composites, composites of starch and FA with various chain lengths (C:12-22) were prepared via nanoprecipitation. X-ray diffraction analyses revealed that all composites had a Vh-amylose crystalline unit cell, but the chain length of FA did not induce a clear change in crystallinity or the hydrodynamic mean diameter of the composites. As the chain length of FA increased from 12 to 22, FA content in the composites increased from 1.69 to 14.85 mg/g composite. The absorption analyses of Rose Bengal on the composite surfaces revealed that their hydrophobicity increased with increasing chain length of FA. The incorporation of FA enhanced the emulsification activity of the composites, and this result revealed that the composites could be applied as an emulsification agent. For longer FA, composite storage stability increased, but the release of FA by in vitro digestion was delayed.

Interfacial Strain-Modulated Nanospherical Ni2 P by Heteronuclei-Mediated Growth on Ti3 C2 Tx MXene for Efficient Hydrogen Evolution.

Interface modulation of nickel phosphide (Ni2 P) to produce an optimal catalytic activation barrier has been considered a promising approach to enhance the hydrogen production activity via water splitting. Herein, heteronuclei-mediated in situ growth of hollow Ni2 P nanospheres on a surface defect-engineered titanium carbide (Ti3 C2 Tx ) MXene showing high electrochemical activity for the hydrogen evolution reaction (HER) is demonstrated. The heteronucleation drives intrinsic strain in hexagonal Ni2 P with an observable distortion at the Ni2 P@Ti3 C2 Tx MXene heterointerface, which leads to charge redistribution and improved charge transfer at the interface between the two components. The strain at the Ni2 P@Ti3 C2 Tx MXene heterointerface significantly boosts the electrochemical catalytic activities and stability toward HER in an acidic medium via a combination between experimental results and theoretical calculations. In a 0.5 m H2 SO4 electrolyte, the Ni2 P@Ti3 C2 Tx MXene hybrid shows excellent HER catalytic performance, requiring an overpotential of 123.6 mV to achieve 10 mA cm-2 with a Tafel slope of 39 mV dec-1 and impressive durability over 24 h operation. This approach presents a significant potential to rationally design advanced catalysts coupled with 2D materials and transition metal-based compounds for state-of-the-art high efficiency energy conversions.

Microvasculature Dropout and Development of Normal Tension Glaucoma in Glaucoma Suspects: The Normal Tension Glaucoma Suspect Cohort Study.

PURPOSE: To investigate the contribution of vessel parameters to identify normal tension glaucoma (NTG) suspects at risk of NTG development. DESIGN: Multicenter prospective cohort study. SUBJECTS: A total of 307 eyes of 307 NTG suspects having intraocular pressure within the normal range; a suspicious optic disc, but without definite localized retinal nerve fiber layer (RNFL) defects; and a normal visual field (VF). METHODS: To measure laminar vessel density (VD), the VD was measured in the intradisc region from images of the deep vascular layers of optical coherence tomography angiography (OCT-A). Conversion to NTG was defined either by a new localized RNFL defect in the superotemporal or inferotemporal region, or the presence of a glaucomatous VF defect on 2 consecutive tests according to the pattern deviation plots. MAIN OUTCOME MEASURE: Conversion to NTG. RESULTS: In total, 73 (23.8%) of the 307 NTG suspects converted to NTG during the follow-up period of 59.84 ± 12.44 months. Detection rate of microvasculature dropout (MvD) was significantly higher in NTG suspects who progressed to NTG (50.7%) than in those who did not (6.4%; P < .001). The macular deep VD (P = .006) and laminar deep VD (P = .004) were significantly lower in NTG suspects who progressed to NTG. The presence of MvD (P < .001) and lower laminar deep VD (P = .006) were significantly associated with NTG conversion. CONCLUSIONS: NTG suspects with baseline MvD or a lower laminar deep VD on OCT-A had a higher risk of conversion.

Highly Selective Electrocatalytic Oxidation of Amines to Nitriles Assisted by Water Oxidation on Metal-Doped α-Ni(OH)2.

Selective oxidation to synthesize nitriles is critical for feedstock manufacturing in the chemical industry. Current strategies typically involve substitutions of alkyl halides with toxic cyanides or the use of strong oxidation reagents (oxygen or peroxide) under ammoxidation/oxidation conditions, setting considerable challenges in energy efficiency, sustainability, and production safety. Herein, we demonstrate a facile, green, and safe electrocatalytic route for selective oxidation of amines to nitriles under ambient conditions, assisted by the anodic water oxidation on metal-doped α-Ni(OH)2 (a typical oxygen evolution reaction catalyst). By controlling the balance between co-adsorption of the amine molecule and hydroxyls on the catalyst surface, we demonstrate that Mn doping significantly promotes the subsequent chemical oxidation of amines, resulting in Faradaic efficiencies of 96% for nitriles under ≥99% conversion. This anodic oxidation is further coupled with cathodic hydrogen evolution for overall atomic economy and additional green energy production.

Impact of cardiovascular comorbidity on increased neutrophil-lymphocyte ratio in pseudoexfoliation syndrome.

BACKGROUND: The purpose of this study was to compare neutrophil-to-lymphocyte ratios (NLRs) of patients with pseudoexfoliation syndrome (PEX) according to the presence of cardiovascular disease (CVD) with those without CVD as controls. METHODS: A total of 197 participants (97 patients with PEX and 100 participants without PEX regarded as the control group) were included in this retrospective study. The PEX group was divided into 2 subgroups, PEX with CVD (group 1) and PEX without CVD (group 2). NLRs were then compared to those of the control group. RESULTS: The incidence of CVD was significantly (P = .015) higher in the PEX group than in the control group. NLR was significantly higher in the group 1 and group 2 compared with that of the control group (P = .048 and P = .002, respectively). In the PEX group, group 1 showed higher NLR than group 2 (P = .023). CONCLUSION: Although the PEX group showed a higher incidence of CVD, the NLR was higher in the PEX group regardless of cardiovascular comorbidity than that in the control group.

Association of Polymorphisms at the SIX1/SIX6 Locus With Normal Tension Glaucoma in a Korean Population.

PRCIS: We demonstrated that SIX1/SIX6 locus polymorphism (rs10483727 and rs33912345) was significantly associated with a genetic susceptibility to NTG in a Korean population. More studies are needed to investigate whether the SIX1/SIX6 locus is associated with NTG among various ethnic populations. PURPOSE: Several previous studies have reported that the relevance of the SIX1/SIX6 locus to open angle glaucoma (OAG) in various ethnic populations. However, definitions of OAG patients were different among those studies. The relevance of the SIX1/SIX6 locus to normal tension glaucoma (NTG) in a Korean population remains uncertain. Therefore, the purpose of this study was to investigate the relationship of the SIX1/SIX6 locus with NTG in a Korean cohort. METHOD: Patients with NTG and ethnically matched healthy controls were recruited from eye clinics in Korea (210 cases and 117 controls). Four polymorphisms (rs33912345, rs12436579, rs2179970, and rs10483727) of the SIX1/SIX6 locus were genotyped for 327 subjects using a TaqMan single nucleotide polymorphism genotyping assay. RESULTS: The rs33912345 polymorphism was significantly correlated with NTG in the recessive model [odds ratio (OR): 0.265; 95% confidence interval (CI): 0.078-0.898, P =0.033], but not in the allelic and dominant models (both P >0.05). The SNP rs10483727 was significantly associated with NTG in the allelic model (OR: 0.674; 95% CI: 0.464-0.979, P =0.038) and the recessive model (OR: 0.187; 95% CI: 0.058-0.602, P =0.005). Genetic association analysis of SNP rs12436579 and rs2179970 revealed no significant difference in genotype distribution between NTG cases and controls in the allelic, dominant, or recessive models (all P >0.05). CONCLUSION: The current study found that SIX1-SIX6 locus rs10483727 and rs33912345 polymorphisms were significantly associated with NTG risk in the Korean population.

Peroxymonosulfate activation by black TiO2 nanotube arrays under solar light: Switching the activation mechanism and enhancing catalytic activity and stability.

Black TiO2 nanotube arrays (black TNAs) suffer from the low activity and deactivation for peroxymonosulfate (PMS) activation, which limit their application in the oxidative destruction of organic pollutants in water. Here, we report an efficient, environmentally benign, and cost-effective method to enhance the catalytic activity and prevent the deactivation of black TNAs in PMS activation by utilizing solar energy. Optical absorption and electrochemical analysis and density functional theory calculations demonstrated that abundant oxygen vacancies (estimated to be 26%) on the black TNAs surface markedly improved solar light absorption and electrical conductivity and played a critical role as a catalytic active site for PMS activation. As a result, the solar light-irradiated black TNAs/PMS system exhibited the higher phenol degradation rate (k = 0.0488 min-1) and total organic carbon (TOC) removal efficiency (~70%) compared to other TNAs systems. These results were ascribed to the switching of the reaction mechanism from non-radical mechanism to radical-involved. Black TNAs oxidized organic pollutants by mediating electron transfer from organics to PMS in the dark (i.e., a non-radical pathway). On the other hand, PMS activation under solar light irradiation involved the production of highly reactive sulfate and hydroxyl radicals (i.e., radical pathway), markedly improving the degradation and mineralization of organics. Additionally, the solar light-irradiated black TNAs showed relative pH-independence for PMS activation and durable catalytic performance without the loss of activity during the repetitive reaction cycles.

Discovery of new ERRγ agonists regulating dopaminergic neuronal phenotype in SH-SY5Y cells.

The discovery of small molecules that regulate specific neuronal phenotypes is important for the development of new therapeutic candidates for neurological diseases. Estrogen-related receptor γ (ERRγ), an orphan nuclear receptor widely expressed in the central nervous system (CNS), is closely related to the regulation of neuronal metabolism and differentiation. We previously reported that upregulation of ERRγ could enhance dopaminergic neuronal phenotypes in the neuroblastoma cell line, SH-SY5Y. In this study, we designed and synthesized a series of new ERRγ agonists using the X-ray crystal structure of the GSK4716-bound ERRγ complex and known synthetic ligands. Our new ERRγ agonists exhibited increased transcriptional activities of ERRγ. In addition, our molecular docking results supported the experimental findings for ERRγ agonistic activity of the potent analogue, 5d. Importantly, 5d not only enhanced the expression of dopaminergic neuronal-specific molecules, TH and DAT but also activated the relevant signaling events, such as the CREB-mediated signaling pathway. The results of the present study may provide useful clues for the development of novel ERRγ agonists for neurological diseases related to the dopaminergic nervous system.

Thalamocortical Mechanisms Regulating the Relationship between Transient Beta Events and Human Tactile Perception.

Transient neocortical events with high spectral power in the 15-29 Hz beta band are among the most reliable predictors of sensory perception. Prestimulus beta event rates in primary somatosensory cortex correlate with sensory suppression, most effectively 100-300 ms before stimulus onset. However, the neural mechanisms underlying this perceptual association are unknown. We combined human magnetoencephalography (MEG) measurements with biophysical neural modeling to test potential cellular and circuit mechanisms that underlie observed correlations between prestimulus beta events and tactile detection. Extending prior studies, we found that simulated bursts from higher-order, nonlemniscal thalamus were sufficient to drive beta event generation and to recruit slow supragranular inhibition acting on a 300 ms timescale to suppress sensory information. Further analysis showed that the same beta-generating mechanism can lead to facilitated perception for a brief period when beta events occur simultaneously with tactile stimulation before inhibition is recruited. These findings were supported by close agreement between model-derived predictions and empirical MEG data. The postevent suppressive mechanism explains an array of studies that associate beta with decreased processing, whereas the during-event facilitatory mechanism may demand a reinterpretation of the role of beta events in the context of coincident timing.

Lack of association between SIX1/SIX6 locus polymorphisms and pseudoexfoliation syndrome in a population from the Republic of Korea.

Previous studies have reported the association of the SIX1/SIX6 locus with open-angle glaucoma in various ethnic populations. However, the relevance of the SIX1/SIX6 locus to pseudoexfoliation syndrome (XFS) appears uncertain at present. Thus, we investigated the relationship between polymorphisms in the SIX1/SIX6 locus and XFS in a Korean XFS cohort. A total of 246 participants comprising 167 unrelated Korean patients with XFS and 79 ethnically matched control subjects were recruited. Four polymorphisms of the SIX1/SIX6 locus (rs33912345, rs12436579, rs2179970, and rs10483727) were genotyped using a TaqMan® allelic discrimination assay. Genotypic and allelic associations were analyzed using logistic regression. The minor allele frequency (MAF) of rs33912345 was found to be 0.287 and 0.247 in the XFS cases and controls, respectively, and the MAF of rs12436579 was found to be 0.383 and 0.361 in the XFS cases and control subjects, respectively. The MAF of rs2179970 was found to be 0.090 and 0.095 in the XFS cases and control subjects, respectively, and the MAF of rs10483727 was found to be 0.293 and 0.253 in the XFS cases and control subjects, respectively. Genetic association analysis of 4 SIX1/SIX6 locus single nucleotide polymorphisms (SNPs) revealed no significant difference in genotype distribution between the XFS cases and control subjects in the allelic, dominant, or recessive models (all, P > .05). The current study suggested that SIX1/SIX6 locus polymorphisms (rs33912345, rs12436579, rs2179970, and rs10483727) may not be associated with a genetic susceptibility to XFS in a Korean cohort.

Concise syntheses and anti-inflammatory effects of isocorniculatolide B and corniculatolide B and C.

The first total syntheses of isocorniculatolide B, corniculatolide B, and corniculatolide C, consisting of isomeric corniculatolide skeletons, have been accomplished in a divergent manner. The key features of the synthesis involve the construction of diaryl ether linkages by nucleophilic aromatic substitution, installation of a C14-substituted alkyl side chain via a sequence of Baeyer-Villiger reaction and Claisen rearrangement, and efficient construction of corniculatolide and isocorniculatolide frameworks, including 17-membered (exterior) macrolactone skeletons from a versatile diaryl ether intermediate by Mitsunobu macrolactonization. Moreover, we prepared the structural congeners of isomeric corniculatolides via diverted total synthesis approach including desmethyl analogues and related dimeric macrolides. The anti-inflammatory activities of the synthesized natural products, analogues and synthetic intermediates were also investigated. In particular, corniculatolide B significantly inhibited the protein expression of COX-2 and the mRNA expressions of TNF-α, IL-1ß and IL-6 by inhibiting of NF-κB signaling in intestinal epithelial cells induced by lipopolysaccharide treatment. It also significantly inhibited the promoter activity and the phosphorylation of subunits p50 and p65 of NF-κB to the same extent as Bay 11-7082, a potent IκB kinase inhibitor. These results suggest that corniculatolide B might have therapeutic potential in inflammatory bowel disease via NF-κB signaling pathway.