Loss of adipose TET proteins enhances ß-adrenergic responses and protects against obesity by epigenetic regulation of ß3-AR expression.

ß-adrenergic receptor (ß-AR) signaling plays predominant roles in modulating energy expenditure by triggering lipolysis and thermogenesis in adipose tissue, thereby conferring obesity resistance. Obesity is associated with diminished ß3-adrenergic receptor (ß3-AR) expression and decreased ß-adrenergic responses, but the molecular mechanism coupling nutrient overload to catecholamine resistance remains poorly defined. Ten-eleven translocation (TET) proteins are dioxygenases that alter the methylation status of DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further oxidized derivatives. Here, we show that TET proteins are pivotal epigenetic suppressors of ß3-AR expression in adipocytes, thereby attenuating the responsiveness to ß-adrenergic stimulation. Deletion of all three Tet genes in adipocytes led to increased ß3-AR expression and thereby enhanced the downstream ß-adrenergic responses, including lipolysis, thermogenic gene induction, oxidative metabolism, and fat browning in vitro and in vivo. In mouse adipose tissues, Tet expression was elevated after mice ate a high-fat diet. Mice with adipose-specific ablation of all TET proteins maintained higher levels of ß3-AR in both white and brown adipose tissues and remained sensitive to ß-AR stimuli under high-fat diet challenge, leading to augmented energy expenditure and decreased fat accumulation. Consequently, they exhibited improved cold tolerance and were substantially protected from diet-induced obesity, inflammation, and metabolic complications, including insulin resistance and hyperlipidemia. Mechanistically, TET proteins directly repressed ß3-AR transcription, mainly in an enzymatic activity-independent manner, and involved the recruitment of histone deacetylases to increase deacetylation of its promoter. Thus, the TET-histone deacetylase-ß3-AR axis could be targeted to treat obesity and related metabolic diseases.

Combinatorial Effect of Tricomponent Dual-Rim Nanoring Building Blocks: Label-Free SERS Detection of Biomolecules.

Detecting weakly adsorbing molecules via label-free surface-enhanced Raman scattering (SERS) has presented a significant challenge. To address this issue, we propose a novel approach for creating tricomponent SERS substrates using dual-rim nanorings (DRNs) made of Au, Ag, and CuO, each possessing distinct functionalities. Our method involves depositing different metals on Pt nanoring skeletons to obtain each nanoring with varying surface compositions while maintaining a similar size and shape. Next, the mixture of these nanorings is transferred into a monolayer assembly with homogeneous intermixing on a solid substrate. The surface of the CuO DRNs has dangling bonds (Cu2+) that facilitate the strong adsorption of carboxylates through the formation of chelating bonds, while the combination of Au and Ag DRNs significantly enhances the SERS signal intensity through a strong coupling effect. Notably, the tricomponent assemblies enable the successful SERS-based analysis of biomolecules such as amino acids, proteins, nucleobases, and nucleotides.

Three-Dimensional Au Octahedral Nanoheptamers: Single-Particle and Bulk Near-Field Focusing for Surface-Enhanced Raman Scattering.

Herein, we present a synthetic approach to fabricate Au nanoheptamers composed of six individual Au nanospheres interconnected through thin metal bridges arranged in an octahedral configuration. The resulting structures envelop central Au nanospheres, producing Au nanosphere heptamers with an open architectural arrangement. Importantly, the initial Pt coating of the Au nanospheres is a crucial step for protecting the inner Au nanospheres during multiple reactions. As-synthesized Au nanoheptamers exhibit multiple hot spots formed by nanogaps between nanospheres, resulting in strong electromagnetic near-fields. Additionally, we conducted surface-enhanced Raman-scattering-based detection of a chemical warfare agent simulant in the gas phase and achieved a limit of detection of 100 ppb, which is 3 orders lower than that achieved using Au nanospheres and Au nanohexamers. This pseudocore-shell nanostructure represents a significant advancement in the realm of complex nanoparticle synthesis, moving the field one step closer to sophisticated nanoparticle engineering.

Metal Fluorides Passivate II-VI and III-V Quantum Dots.

Quantum dots (QDs) with metal fluoride surface ligands were prepared via reaction with anhydrous oleylammonium fluoride. Carboxylate terminated II-VI QDs underwent carboxylate for fluoride exchange, while InP QDs underwent photochemical acidolysis yielding oleylamine, PH3, and InF3. The final photoluminescence quantum yield (PLQY) reached 83% for InP and near unity for core-shell QDs. Core-only CdS QDs showed dramatic improvements in PLQY, but only after exposure to air. Following etching, the InP QDs were bound by oleylamine ligands that were characterized by the frequency and breadth of the corresponding ν(N-H) bands in the infrared absorption spectrum. The fluoride content (1.6-9.2 nm-2) was measured by titration with chlorotrimethylsilane and compared with the oleylamine content (2.3-5.1 nm-2) supporting the formation of densely covered surfaces. The influence of metal fluoride adsorption on the air stability of QDs is discussed.

Plasmonic Annular Nanotrenches with 1 nm Nanogaps for Detection of SARS-CoV-2 Using SERS-Based Immunoassay.

This study represents the synthesis of a novel class of nanoparticles denoted as annular Au nanotrenches (AANTs). AANTs are engineered to possess embedded, narrow circular nanogaps with dimensions of approximately 1 nm, facilitating near-field focusing for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via a surface-enhanced Raman scattering (SERS)-based immunoassay. Notably, AANTs exhibited an exceedingly low limit of detection (LOD) of 1 fg/mL for SARS-CoV-2 spike glycoproteins, surpassing the commercially available enzyme-linked immunosorbent assay (ELISA) by 6 orders of magnitude (1 ng/mL from ELISA). To assess the real-world applicability, a study was conducted on 50 clinical samples using an SERS-based immunoassay with AANTs. The results revealed a sensitivity of 96% and a selectivity of 100%, demonstrating the significantly enhanced sensing capabilities of the proposed approach in comparison to ELISA and commercial lateral flow assay kits.

Plasmonic Dodecahedral-Walled Elongated Nanoframes for Surface-Enhanced Raman Spectroscopy.

Here, elongated pseudohollow nanoframes composed of four rectangular plates enclosing the sides and two open-frame ends with four ridges pointing at the tips for near-field focusing are reported. The side facets act as light-collecting domains and transfer the collected light to the sharp tips for near-field focusing. The nanoframes are hollow inside, allowing the gaseous analyte to penetrate through the entire architecture and enabling efficient detection of gaseous analytes when combined with Raman spectroscopy. The resulting nanostructures are named Au dodecahedral-walled nanoframes. Synthesis of the nanoframes involves shape transformation of Au nanorods with round tips to produce Au-elongated dodecahedra, followed by facet-selective Pt growth, etching of the inner Au, and regrowth steps. The close-packed assembly of Au dodecahedral-walled nanoframes exhibits an attomolar limit of detection toward benzenethiol. This significant enhancement in SERS is attributed to the presence of a flat solid terrace for a large surface area, sharp edges and vertices for strong electromagnetic near-field collection, and open frames for effective analyte transport and capture. Moreover, nanoframes are applied to detect chemical warfare agents, specifically mustard gas simulants, and 20 times higher sensitivity is achieved compared to their solid counterparts.

Multiple Stepwise Synthetic Pathways toward Complex Plasmonic 2D and 3D Nanoframes for Generation of Electromagnetic Hot Zones in a Single Entity.

ConspectusRational design of nanocrystals with high controllability via wet chemistry is of critical importance in all areas of nanoscience and nanotechnology research. Specifically, morphologically complex plasmonic nanoparticles have received considerable attention because light-matter interactions are strongly associated with the size and shape of nanoparticles. Among many types of nanostructures, plasmonic nanoframes (NFs) with controllable structural intricacy could be excellent candidates as strong light-entrappers with inner voids as well as high surface area, leading to highly effective interaction with light and analytes compared to their solid counterparts. However, so far studies on single-rim-based NFs have suffered from insufficient near-field focusing capability due to their structural simplicity (e.g., a single rim or NF molded from simple platonic solids), which necessitates a conceptually new NF architecture. If one considers a stereoscopic nanostructure with dual, triple, and multiple resonant intra-nanogaps on each crystallographic facet of nanocrystals, unprecedented physicochemical properties could be expected. Realizing such complex multiple NFs with intraparticle surface plasmon coupling via localized surface plasmon resonance is very challenging due to the lack of synthetic strategic principles with systematic structural control, all of which require a deep understanding of surface chemistry. Moreover, realizing those complex architectures with high homogeneity in size and shape via a bottom-up method where diverse particle interactions are involved is more challenging. Although there have been several reports on NFs used for catalysis, techniques for production of structurally complex NFs with high uniformity and an understanding of the correlation between such complexity in a single plasmonic entity and electromagnetic near-field focusing have remained highly elusive.In this Account, we will summarize and highlight the rational synthetic pathways for the design of complex two-dimensional (2D) and three-dimensional (3D) NFs with unique inner rim structures and characterize their optical properties. This systematic strategy is based on publications from our group during the last 10 years. First, we will introduce a chemical step of shape transformation of triangular Au nanoplates to circular and hexagonal plates, which are used as sacrificial layers for the formation of NFs. Then, we will describe the methods on how to synthesize monorim-based plasmonic NFs using Pt scaffolds with different shapes and correlate with their electromagnetic near-field. Then, we will describe a multiple stepwise synthetic method for the formation of 2D complex NFs wherein different starting Au nanocrystals evolved from systematic shape transformation are used to produce circular, triangular, hexagonal, crescent, and Y-shaped inner hot zones. Then, we will discuss how one can synthesize NFs with multiple rims wherein rims with different diameters are concentrically connected, by exploiting chemical toolkits such as eccentric and concentric growth of Au, borrowing the concept of total synthesis that is frequently adopted in organic chemistry. We then introduce dual-rim-faceted NFs and frame-in-frame 3D matryoshka NF geometries via well-faceted growth of Au with high control of intra-nanogaps. Finally, and importantly, we will provide examples of more advanced hierarchical NF architectures produced by controlling geometrical shapes of nanoparticles, number of rims, and different components, leading to the expansion of the NF library.

Development of an In-Pipe Inspection Robot for Large-Diameter Water Pipes.

This paper describes the development of an in-pipe inspection robot system designed for large-diameter water pipes. The robot is equipped with a Magnetic Flux Leakage (MFL) sensor module. The robot system is intended for pipes with diameters ranging from 900 mm to 1200 mm. The structure of the in-pipe inspection robot consists of the front and rear driving parts, with the inspection module located centrally. The robot is powered by 22 motors, including eight wheels with motors positioned at both the bottom and the top for propulsion. To ensure that the robot's center aligns with that of the pipeline during operation, lifting units have been incorporated. The robot is equipped with cameras and LiDAR sensors at the front and rear to monitor the internal environment of the pipeline. Pipeline inspection is conducted using the MFL inspection modules, and the robot's driving mechanism is designed to execute spiral maneuvers while maintaining contact with the pipeline surface during rotation. The in-pipe inspection robot is configured with wireless communication modules and batteries, allowing for wireless operation. Following its development, the inspection robot underwent driving experiments in actual pipelines to validate its performance. The field test bed used for these experiments is approximately 1 km in length. Results from the driving experiments on the field test bed confirmed the robot's ability to navigate various curvatures and obstacles within the pipeline. It is posited that the use of the developed in-pipe inspection robot can reduce economic costs and enhance the safety of inspectors when examining aging pipes.

Plasmonic Double-Walled Nanoframes with Face-to-Face Nanogaps for Strong SERS Activity.

A synthesis method for plasmonic double-walled nanoframes was developed, where single-walled truncated octahedral nanoframes with (111) open facets and (100) solid flat planes are nested in a core-shell manner. By applying multiple chemical toolkits to Au cuboctahedrons as a starting template, Au double-walled nanoframes with controllable face-to-face nanogaps were successfully synthesized in high homogeneity in size and shape. Importantly, when the gap distance between inner and outer flat walled frames became closer, augmentation of electromagnetic near-field focusing was achieved, leading to generation of hot-zones, which was verified by surface-enhanced Raman spectroscopy. The unique optical property of Au double-walled nanoframes with high structural intricacy was carefully investigated and the SERS substrates comprising Au double-walled nanoframes with the narrowest nanogaps exhibited much improved near-field enhancement toward strongly and/or weakly adsorbing analytes, allowing for gas phase detection in chemical warfare agents, which is a huge challenge in early warning systems.

Plasmonic-Magnetic Active Nanorheology for Intracellular Viscosity.

We demonstrate active plasmonic systems where plasmonic signals are repeatedly modulated by changing the orientation of nanoprobes under an external magnetic field, which is a prerequisite for in situ active nanorheology in intracellular viscosity measurements. Au/Ni/Au nanorods act as "nanotransmitters", which transmit the mechanical motion of nanorods to an electromagnetic radiation signal as a periodic sine function. This fluctuating optical response is transduced to frequency peaks via Fourier transform surface plasmon resonance (FTSPR). As a driving frequency of the external magnetic field applied to the Au/Ni/Au nanorods increases and reaches above a critical threshold, there is a transition from the synchronous motion of nanorods to asynchronous responses, leading to the disappearance of the FTSPR peak, which allows us to measure the local viscosity of the complex fluids. Using this ensemble-based method with plasmonic functional nanomaterials, we measure the intracellular viscosity of cancer cells and normal cells in a reliable and reproducible manner.

Au Octahedral Nanosponges: 3D Plasmonic Nanolenses for Near-Field Focusing.

Here, we report the synthesis of three-dimensional plasmonic nanolenses for strong near-field focusing. The nanolens exhibits a distinctive structural arrangement composed of nanoporous sponge-like networks within their interior. We denote these novel nanoparticles as "Au octahedral nanosponges" (Au Oh NSs). Employing a carefully planned multistep synthetic approach with Au octahedra serving as sacrificial templates, we successfully synthesized Au Oh NSs in solution. The porous domains resembling sponges contributed to enhanced scattering and absorption of incident light within metal ligaments. This optical energy was subsequently transferred to the nanospheres at the vertex, where near-field focusing was maximized. We named this observed enhancement a "lightning-sphere effect". Using single particle-by-particle surface-enhanced Raman scattering (SERS), we optimized the morphological dimensions of the spheres and porous domains to achieve the most effective near-field focusing. In the context of bulk SERS measurements targeting weakly adsorbing analytes (2-chloroethyl phenyl sulfide) in the gas phase, we achieved a low detection limit of 10 ppb. For nonadsorbing species (dimethyl methyl phosphonate), utilization of hybrid SERS substrates consisting of Au Oh NSs and metal-organic frameworks as gas-adsorbing intermediate layers was highly effective for successful SERS detection.

Multi-Layered PtAu Nanoframes and Their Light-Enhanced Electrocatalytic Activity via Plasmonic Hot Spots.

Here, the rational design of complex PtAu double nanoframes (DNFs) for plasmon-enhanced electrocatalytic activity toward the methanol oxidation reaction (MOR) is reported. The synthetic strategy for the DNFs consists of on-demand multiple synthetic chemical toolkits, including well-faceted Au growth, rim-on selective Pt deposition, and selective Au etching steps. DNFs are synthesized by utilizing Au truncated octahedrons (TOh) as a starting template. The outer octahedral (Oh) nanoframes (NFs) nest the inner TOh NFs, eventually forming DNFs with a tunable intra-nanogap distance. Residual Au adatoms on Pt skeletons act as light entrappers and produce plasmonic hot spots between inner and outer frames through localized surface plasmon resonance (LSPR) coupling, which promotes enhanced electrocatalytic activity for the MOR. Importantly, the correlation between the gap-induced hot carriers and electrocatalytic activity is evaluated. The highest catalytic activity is achieved when the gap is the narrowest. To further harness their light-trapping capability, hierarchically structured triple NFs (TNFs) are synthesized, wherein three NFs are entangled in a single entity with a high density of hot regions, exhibiting superior electrocatalytic activity toward the MOR with a sixfold larger current density under light irradiation compared to the dark conditions.

Plasmonic Cyclic Au Nanosphere Hexamers.

Rational design of plasmonic colloidal assemblies via bottom-up synthesis is challenging but would show unprecedented optical properties that strongly relate to the assembly's shape and spatial arrangement. Herein, the synthesis of plasmonic cyclic Au nanosphere hexamers (PCHs) is reported, wherein six Au nanospheres (Au NSs) are connected via thin metal ligaments. By tuning Au reduction, six dangling Au NSs are interconnected with a core hexagon nanoplate (NPL). Then, Pt atoms are selectively deposited on the edges of the spheres. After etching of the core, necklace-like nanostructures of Pt framework are obtained. Deposition of Au is followed, leading to PCHs in high yield (≈90%). Notably, PCHs exhibit the combinatorial plasmonic characteristics of individual Au NSs and the in-plane coupling of the six linked Au NSs. They yield highly uniform, reproducible, and polarization-independent single-particle surface-enhanced Raman scattering signals, which are attributed to the 2-dimensional isotropic alignment of the Au NSs. Those are applied to a SERS-based immunoassay as quantitative and qualitative single particle SERS nanoprobes. This assay shows a low limit-of-detection, down to 100 pm, which is orders of magnitude lower than those based on Au NSs, and one order of magnitude lower than an assay using analogous particles of smooth Au nanorings.

Correction: A probabilistic model for the ultradian timing of REM sleep in mice.

[This corrects the article DOI: 10.1371/journal.pcbi.1009316.].

Ring-in-a-Triangle Nanoframes: Integrating with Intra- and Interhotspots for Highly Amplified Near-Field Focusing.

The development of a stepwise synthetic strategy for Au ring-in-a-triangle nanoframes with a high degree of structural solidity is essential to the advancement of highly amplified near-field focusing. This strategy leads to the formation of an inscribed nanoring in a triangular metal frame with stability to withstand elevated temperatures and an oxidizing environment, which is critical for successful single-particle surface-enhanced Raman scattering (SERS). The existence of inscribed nanorings plays an important role in enhancing the so-called "lightning rod effect," whereby the electromagnetic near-field enhancement occurs on the highly curved curvature of a metallic interface. We evaluated the corresponding single-particle SERS as a function of the thickness of the rims and then constructed two-dimensional (2D) bulk SERS substrates, wherein an ensemble of hotspots exists. The synergic contribution from both inter- and intrahotspots allowed the outstanding linearity of the calibration curve and the lowest limit of detection, ∼10-18 M for the analyte concentration.

Formation of the N≡N Triple Bond from Reductive Coupling of a Paramagnetic Diruthenium Nitrido Compound.

Construction of nitrogen-nitrogen triple bonds via homocoupling of metal nitrides is an important fundamental reaction relevant to a potential Nitrogen Economy. Here, we report that room temperature photolysis of Ru2(chp)4N3 (chp- = 2-chloro-6-hydroxypyridinate) in CH2Cl2 produces N2 via reductive coupling of Ru2(chp)4N nitrido species. Computational analysis reveals that the nitride coupling transition state (TS) features an out-of-plane "zigzag" geometry instead of the anticipated planar zigzag TS. However, with intentional exclusion of dispersion correction, the planar zigzag TS geometry can also be found. Both the out-of-plane and planar zigzag TS geometries feature two important types of orbital interactions: (1) donor-acceptor interactions involving intermolecular donation of a nitride lone pair into an empty Ru-N π* orbital and (2) Ru-N π to Ru-N π* interactions derived from coupling of nitridyl radicals. The relative importance of these two interactions is quantified both at and after the TS. Our analysis shows that both interactions are important for the formation of the N-N σ bond, while radical coupling interactions dominate the formation of N-N π bonds. Comparison is made to isoelectronic Ru2-oxo compounds. Formation of an O-O bond via bimolecular oxo coupling is not observed experimentally and is calculated to have a much higher TS energy. The major difference between the nitrido and oxo systems stems from an extremely large driving force, ∼-500 kJ/mol, for N-N coupling vs a more modest driving force for O-O coupling, -40 to -140 kJ/mol.

All-Hot-Spot Bulk Surface-Enhanced Raman Scattering (SERS) Substrates: Attomolar Detection of Adsorbates with Designer Plasmonic Nanoparticles.

Here we report a synthetic pathway toward Au truncated octahedral dual-rim nanoframes wherein two functional facets are formed including (1) eight hot nanogaps formed by hexagonal nanoframes embracing core circular nanorings for near-field focusing and (2) six flat squares that facilitate the formation of well-ordered arrays of nanoframes through self-assembly. The existence of intra-nanogaps in a single entity enables strong electromagnetic near-field focusing, allowing single-particle surface-enhanced Raman spectroscopy. Then, we built "all-hot-spot bulk SERS substrates" with those entities, wherein the presence of truncated terraces with high homogeneity in size and shape facilitate spontaneous self-assembly into a highly ordered and uniform superlattice, exhibiting a limit of detection of attomolar concentrations toward 2-naphthalenethiol, which is 6 orders lower than that of monorim counterparts. The observed low limit of detection originates from the combined synergic effect from both inter- and intraparticle coupling in a superlattice, which we dubbed "all-hot-spot bulk SERS substrates".

Pepsinogens and Gastrin Demonstrate Low Discrimination for Gastric Precancerous Lesions in a Multi-Ethnic United States Cohort.

Early identification of gastric precancerous lesions, including atrophic gastritis (AG) and intestinal metaplasia (IM), may improve gastric cancer detection and prevention. Because AG and IM are generally asymptomatic, many of the estimated 15 million Americans who carry these lesions remain undiagnosed.1 AG and IM are associated with either active or prior Helicobacter pylori (Hp) infection. Hp infection leads to perturbations in the serum concentration of gastric hormones pepsinogen I (PGI), pepsinogen II, the pepsinogen I/II ratio (PGR), gastrin-17 (G-17), and Hp IgG.2,3 In East Asia and other regions with high burden of Hp infection and gastric cancer, these biomarkers have been used as screening tools for AG and IM.4 However, there exists limited data on the sensitivity and discrimination of these serologic markers in low-Hp-prevalence populations, such as the United States.

The risk of diffuse-type gastric cancer following diagnosis with gastric precancerous lesions: a systematic review and meta-analysis.

PURPOSE: Gastric cancers are classified as diffuse-type (DTGC) or intestinal-type (ITGC). DTGCs have distinct clinical and histopathologic features, and carry a worse overall prognosis compared to ITGCs. Atrophic gastritis (AG) and intestinal metaplasia (IM) are known precursors to ITGC. It is unknown if AG and IM increase risk for DTGC. METHODS: We performed a systematic review to identify studies reporting on the association of AG/IM and DTGC. We extracted the odds ratio (OR) of the association from studies, and performed pool analysis. Subgroup analysis was performed on studies reporting histologic severity (using operative link systems) to assess if histologic severity of AG/IM was associated with higher risk. RESULTS: We identified six case-control and eight cohort studies for inclusion. Both AG (pooled OR = 1.9, 95% CI 1.5 to 2.4, p < 0.001) and IM (pooled OR = 2.3, 95% CI 1.9 to 2.9, p < 0.001) demonstrated an association with DTGC. High AG severity was associated with increased risk for DTGC compared to low AG severity (OR = 1.7, 95% CI 1.2 to 2.3, p = 0.002). Similarly, high IM severity was associated with increased risk compared to low IM severity (OR = 1.9, 95% CI 1.3 to 2.7, p = 0.001). CONCLUSION: Both AG and IM are associated with DTGC. Increasing histologic severity of both AG and IM increases risk for DTGC. There may exist a common pathway between ITGC and some DTGCs mediated through mucosal precursor lesions. These data may inform future strategies of cancer risk attenuation and control.

Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling.

Synergistic activation of inflammatory cytokine genes by interferon-γ (IFN-γ) and Toll-like receptor (TLR) signaling is important for innate immunity and inflammatory disease pathogenesis. Enhancement of TLR signaling, a previously proposed mechanism, is insufficient to explain strong synergistic activation of cytokine production in human macrophages. Rather, we found that IFN-γ induced sustained occupancy of transcription factors STAT1, IRF-1, and associated histone acetylation at promoters and enhancers at the TNF, IL6, and IL12B loci. This priming of chromatin did not activate transcription but greatly increased and prolonged recruitment of TLR4-induced transcription factors and RNA polymerase II to gene promoters and enhancers. Priming sensitized cytokine transcription to suppression by Jak inhibitors. Genome-wide analysis revealed pervasive priming of regulatory elements by IFN-γ and linked coordinate priming of promoters and enhancers with synergistic induction of transcription. Our results provide a synergy mechanism whereby IFN-γ creates a primed chromatin environment to augment TLR-induced gene transcription.