Carboxymethyl cellulose-based rotigotine nanocrystals-loaded hydrogel for increased transdermal delivery with alleviated skin irritation.

Transdermal rotigotine (RTG) therapy is prescribed to manage Parkinson's disease (Neupro® patch). However, its use is suffered from application site reactions. Herein, drug nanocrystalline suspension (NS)-loaded hydrogel (NS-HG) employing polysaccharides simultaneously as suspending agent and hydrogel matrix was constructed for transdermal delivery, with alleviated skin irritation. RTG-loaded NS-HG was prepared using a bead-milling technique, employing sodium carboxylmethyl cellulose (Na.CMC) as nano-suspending agent (molecular weight 90,000 g/mol) and hydrogel matrix (700,000 g/mol), respectively. NS-HG was embodied as follows: drug loading: ≤100 mg/mL; shape: rectangular crystalline; crystal size: <286.7 nm; zeta potential: -61 mV; viscosity: <2.16 Pa·s; and dissolution rate: >90 % within 15 min. Nuclear magnetic resonance analysis revealed that the anionic polymers bind to RTG nanocrystals via charge interaction, affording uniform dispersion in the matrix. Rodent transdermal absorption of RTG from NS-HG was comparable to that from microemulsions, and proportional to drug loading. Moreover, NS-HG was skin-friendly; erythema and epidermal swelling were absent after repeated application. Further, NS-HG was chemically stable; >95 % of the drug was preserved up to 4 weeks under long term (25 °C/RH60%), accelerated (40 °C/RH75%), and stress (50 °C) storage conditions. Therefore, this novel cellulose derivative-based nanoformulation presents a promising approach for effective transdermal RTG delivery with improved tolerability.

Conductive Glassy Nonconjugated Open-Shell Radical Polymer with Organosulfur Backbone for Macroscopic Conductivity.

Nonconjugated organic radicals with an open-shell radical active group exhibit unique functionality due to their radical pendant site. Compared with the previously studied doped conjugated polymers, radical polymers reveal superior processability, stability, and optical properties. Despite the success of organic radical polymer conductors based on the TEMPO radicals, it still requires potential design substitutions to meet the fundamental limits of charge transport in the radical polymer. To do so, we demonstrate that the amorphous, nonconjugated radical polymer with backbone-pendant group interaction and low glass transition temperature enables the macromolecules to have rapid charge transport in the solid state, resulting in conductivity higher than 32 S m-1. This charge transport is due to the formation of the local ordered regime with an energetically favored orientation caused by the strong coupling between the backbone and pendant group, which can significantly modulate the polymer packing with active electronic communications. The nonconjugate nature of the radical polymer maintains an optical transparency up to 98% at a 1.5 µm thick film. Thus, this effort will be a dramatically advanced model in the organic radical community for the creation of next-generation polymer conductors.

Design of High-Payload Ascorbyl Palmitate Nanosuspensions for Enhanced Skin Delivery.

A high-payload ascorbyl palmitate (AP) nanosuspension (NS) was designed to improve skin delivery following topical application. The AP-loaded NS systems were prepared using the bead-milling technique, and softly thickened into NS-loaded gel (NS-G) using hydrophilic polymers. The optimized NS-G system consisted of up to 75 mg/mL of AP, 0.5% w/v of polyoxyl-40 hydrogenated castor oil (Kolliphor® RH40) as the suspending agent, and 1.0% w/v of sodium carboxymethyl cellulose (Na.CMC 700 K) as the thickening agent, in citrate buffer (pH 4.5). The NS-G system was embodied as follows: long and flaky nanocrystals, 493.2 nm in size, -48.7 mV in zeta potential, and 2.3 cP of viscosity with a shear rate of 100 s-1. Both NS and NS-G provided rapid dissolution of the poorly water-soluble antioxidant, which was comparable to that of the microemulsion gel (ME-G) containing AP in solubilized form. In an ex vivo skin absorption study using the Franz diffusion cell mounted on porcine skin, NS-G exhibited faster absorption in skin, providing approximately 4, 3, and 1.4 times larger accumulation than that of ME-G at 3, 6, and 12 h, respectively. Therefore, the high-payload NS makes it a promising platform for skin delivery of the lipid derivative of ascorbic acid.

Novel rivaroxaban-loaded microsphere systems with different surface microstructure for enhanced oral bioavailability.

This study compares rivaroxaban-loaded polymeric microsphere systems with three types of surface microstructure. Three types of polymeric microspheres loaded with rivaroxaban were fabricated using a spray-drying technique: solvent-evaporated, surface-attached, and solvent-wet microspheres, depending on whether the drug and additives used are soluble in the solvent. The solvent-evaporated and surface-attached microspheres had a rivaroxaban/polyvinylpyrrolidone/sodium lauryl sulfate (SLS) weight ratio of 1/0.25/2.2, and the solvent-wetted microspheres contained rivaroxaban/polyvinyl alcohol/SLS in equal weight ratio (1/0.25/2). The physicochemical properties of the microspheres were evaluated using scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and particle size distribution analysis. The aqueous solubility and dissolution rate of rivaroxaban in the three types of microspheres were compared to those of the drug powder. The solvent-evaporated, surface-attached, and solvent-wetted microspheres were approximately 208, 140, and 172 times as soluble as the drug powder, and the final dissolution rate (120 min) was approximately 5, 2, and 4 times that of the drug powder, respectively. In addition, the oral bioavailability increased by approximately 2, 1.3, and 1.6 times compared to that of the drug powder (area under drug concentration-time curve: 2101.3 ± 314.8, 1325.2 ± 333.3, and 1664.0 ± 102.6 h·ng/mL, respectively). Finally, the solvent-evaporated microspheres showed the greatest improvement (solvent evaporating microspheres > solvent wetted microspheres > surface-attached microspheres ≥ drug powder). Therefore, the solvent-evaporated microspheres may represent a novel oral dosage form that improves the oral bioavailability of rivaroxaban, a poorly soluble drug.

Enhanced Oral Bioavailability of Rivaroxaban-Loaded Microspheres by Optimizing the Polymer and Surfactant Based on Molecular Interaction Mechanisms.

This study aimed to develop microspheres using water-soluble carriers and surfactants to improve the solubility, dissolution, and oral bioavailability of rivaroxaban (RXB). RXB-loaded microspheres with optimal carrier (poly(vinylpyrrolidone) K30, PVP) and surfactant (sodium lauryl sulfate (SLS)) ratios were prepared. 1H NMR and Fourier transform infrared (FTIR) analyses showed that drug-excipient and excipient-excipient interactions affected RXB solubility, dissolution, and oral absorption. Therefore, molecular interactions between RXB, PVP, and SLS played an important role in improving RXB solubility, dissolution, and oral bioavailability. Formulations IV and VIII, containing optimized RXB/PVP/SLS ratios (1:0.25:2 and 1:1:2, w/w/w), had significantly improved solubility by approximately 160- and 86-fold, respectively, compared to RXB powder, with the final dissolution rates improved by approximately 4.5- and 3.4-fold, respectively, compared to those of RXB powder at 120 min. Moreover, the oral bioavailability of RXB was improved by 2.4- and 1.7-fold, respectively, compared to that of RXB powder. Formulation IV showed the highest improvement in oral bioavailability compared to RXB powder (AUC, 2400.8 ± 237.1 vs 1002.0 ± 82.3 h·ng/mL). Finally, the microspheres developed in this study successfully improved the solubility, dissolution rate, and bioavailability of RXB, suggesting that formulation optimization with the optimal drug-to-excipient ratio can lead to successful formulation development.

Manufacture of antibacterial carbon fiber-reinforced plastics (CFRP) using imine-based epoxy vitrimer for medical application.

An antibacterial carbon fiber-reinforced plastics (CFRP) was manufactured based on a vitrimer containing imine groups. A liquid curing agent was prepared to include an imine group in the matrix, and was synthesized without a simple mixing reaction and any purification process. The vitrimer used as the matrix for CFRP was prepared by reacting a commercial epoxy with a synthesized curing agent. The structural and thermal properties of the vitrimer were determined by Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). In addition, the temperature-dependent behavior of the vitrimer was characterized by stress relaxation, reshaping, and shape memory experiments. The mechanical properties of composites fabricated using vitrimer were fully analyzed by tensile, flexural, short-beam strength, and Izod impact tests and had mechanical properties similar to reference material. Moreover, both the vitrimer and the vitrimer composites showed excellent antibacterial activity against Staphylococcus aureus and Escherichia coil due to the imine group inside the vitrimer. Therefore, vitrimer composites have potential for applications requiring antimicrobial properties, such as medical devices.

Performance of cut-offs adjusted with positive control band intensity in line-blot assays for myositis-specific antibodies.

The diagnostic performance of band intensity (BI) cut-offs, adjusted by a positive control band (PCB) in a line-blot assay (LBA) for myositis-related autoantibodies (MRAs) is investigated. Sera from 153 idiopathic inflammatory myositis (IIM) patients with available immunoprecipitation assay (IPA) data and 79 healthy controls were tested using the EUROLINE panel. Strips were evaluated for BI using the EUROLineScan software, and the coefficient of variation (CV) was calculated. Sensitivity and specificity, area under the curve (AUC), and the Youden's index (YI) were estimated at non-adjusted or PCB-adjusted cut-off values. Kappa statistics were calculated for IPA and LBA. Although inter-assay CV for PCB BI was 3.9%, CV was 12.9% in all samples, and a significant correlation was found between BIs of PCB and seven MRAs (all P < 0.05). At adjusted BI (aBI) > 10, the negative conversion rate of myositis-specific autoantibody (MSA)-positivity at BI > 10 was 11.5% in controls and 1.3% in patients. The specificity, AUC, and YI for MSAs at aBI > 10 or > 20 were higher than those at non-adjusted cut-off values. Additionally, AUC (0.720), YI (0.440), and the prevalence of MRAs with kappa > 0.60 (58.3%) were the highest at aBI > 20. The overall sensitivity and specificity for MSAs were 50.3% and 93.7% at aBI > 20, respectively, and 59.5% and 65.8% with BI > 10, respectively. The diagnostic performance of LBA can be improved using PCB-adjusted BIs. aBI > 20 is the optimal cut-off for IIM diagnosis using the EUROLINE LBA panel.

Intrinsic Defects and Their Role in the Phase Transition of Na-Ion Anode Na2Ti3O7.

The development of high-power anode materials for Na-ion batteries is one of the primary obstacles due to the growing demands for their use in the smart grid. Despite the appealingly low cost and non-toxicity, Na2Ti3O7 suffers from low electrical conductivity and poor structural stability, which restricts its use in high-power applications. Viable approaches for overcoming these drawbacks reported to date are aliovalent doping and hydrogenation/hydrothermal treatments, both of which are closely intertwined with native defects. There is still a lack of knowledge, however, of the intrinsic defect chemistry of Na2Ti3O7, which impairs the rational design of high-power titanate anodes. Here, we report hybrid density functional theory calculations of the native defect chemistry of Na2Ti3O7. The defect calculations show that the insulating properties of Na2Ti3O7 arise from the Na and O Schottky disorder that act as major charge compensators. Under high-temperature hydrogenation treatment, these Schottky pairs of Na and O vacancies become dominant defects in Na2Ti3O7, triggering the spontaneous partial phase transition to Na2Ti6O13 and improving the electrical conductivity of the composite anode. Our findings provide an explanation on the interplay between intrinsic defects, structural phase transitions, and electrical conductivity, which can aid understanding of the properties of composite materials obtained from phase transitions.

Identification of 2,4-Di-tert-butylphenol as a Novel Agonist for Insect Odorant Receptors.

Odorant molecules interact with odorant receptors (ORs) lining the pores on the surface of the sensilla on an insect's antennae and maxillary palps. This interaction triggers an electrical signal that is transmitted to the insect's nervous system, thereby influencing its behavior. Orco, an OR coreceptor, is crucial for olfactory transduction, as it possesses a conserved sequence across the insect lineage. In this study, we focused on 2,4-di-tert-butylphenol (DTBP), a single substance present in acetic acid bacteria culture media. We applied DTBP to oocytes expressing various Drosophila melanogaster odor receptors and performed electrophysiology experiments. After confirming the activation of DTBP on the receptor, the binding site was confirmed through point mutations. Our findings confirmed that DTBP interacts with the insect Orco subunit. The 2-heptanone, octanol, and 2-hexanol were not activated for the Orco homomeric channel, but DTBP was activated, and the EC50 value was 13.4 ± 3.0 µM. Point mutations were performed and among them, when the W146 residue changed to alanine, the Emax value was changed from 1.0 ± 0 in the wild type to 0.0 ± 0 in the mutant type, and all activity was decreased. Specifically, DTBP interacted with the W146 residue of the Orco subunit, and the activation manner was concentration-dependent and voltage-independent. This molecular-level analysis provides the basis for novel strategies to minimize pest damage. DTBP, with its specific binding to the Orco subunit, shows promise as a potential pest controller that can exclusively target insects.

Effect of Dispersion Medium on Pharmacokinetic Profile of Rotigotine Crystalline Suspension following Subcutaneous Injection.

Rotigotine (RTG) is prescribed as a once-daily transdermal patch for managing early Parkinson's disease (PD), which presents issues such as skin irritation and poor patient adherence. Therefore, the aims of the present study were to formulate aqueous and oily vehicle-based RTG crystalline suspensions for prolonged delivery and to compare their pharmacokinetic profiles and the local behaviors of RTG crystals. RTG-loaded aqueous (AS) and oil suspensions (OS) were fabricated using bead-milling technology (100 mg/mL as RTG), employing carboxymethyl cellulose and sesame oil as suspending agent and oily vehicle, respectively. RTG AS and OS exhibited comparable physical properties in terms of particle size (about 800−900 nm), crystallinity, and dissolution profile, despite higher drug solubility in OS than AS (19.6 and 0.07 mg/mL, respectively). However, AS and OS exhibited markedly distinctive local distribution and inflammatory responses at the injection site, which further promoted different pharmacokinetic patterns following subcutaneous injection in rats. With OS, no drug aggregates were observed with prolonged persistence of the Sudan III-stained oily vehicle at the injection site. In contrast, with AS injection, drug clusters > 7 mm were formed, followed by an enclosure with macrophages and a fibroblastic band. Accordingly, AS exhibited a protracted pharmacokinetic profile over 3 weeks, with prolonged elimination half-life. The local inflammatory response caused by AS injection was almost alleviated after 3 weeks post-dosing. Based on these findings, we conclude that RTG AS system can be a platform to design sophisticated long-acting delivery systems with extended dosing intervals to manage PD.

Mitochondrial double-stranded RNAs as a pivotal mediator in the pathogenesis of SjÓ§gren's syndrome.

SjÓ§gren's syndrome (SS) is a systemic autoimmune disease that targets the exocrine glands, resulting in impaired saliva and tear secretion. To date, type I interferons (I-IFNs) are increasingly recognized as pivotal mediators in SS, but their endogenous drivers have not been elucidated. Here, we investigate the role of mitochondrial double-stranded RNAs (mt-dsRNAs) in regulating I-IFNs and other glandular phenotypes of SS. We find that mt-dsRNAs are elevated in the saliva and tears of SS patients (n = 73 for saliva and n = 16 for tears) and in salivary glands of non-obese diabetic mice with salivary dysfunction. Using the in-house-developed 3D culture of immortalized human salivary gland cells, we show that stimulation by exogenous dsRNAs increase mt-dsRNAs, activate the innate immune system, trigger I-IFNs, and promote glandular phenotypes. These responses are mediated via the Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT) pathway. Indeed, a small chemical inhibitor of JAK1 attenuates mtRNA elevation and immune activation. We further show that muscarinic receptor ligand acetylcholine ameliorates autoimmune characteristics by preventing mt-dsRNA-mediated immune activation. Last, direct suppression of mt-dsRNAs reverses the glandular phenotypes of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation in the pathogenesis of SS and suggests mt-dsRNAs as propagators of a pseudo-viral signal in the SS target tissue.

Analysis of prognostic factors through survival rate analysis of oral squamous cell carcinoma patients treated at the National Cancer Center: 20 years of experience.

Objectives: This study aimed to analyze the clinicopathological prognostic factors affecting the survival of patients with oral squamous cell carcinoma (OSCC). Materials and Methods: A retrospective study was conducted on patients with OSCC who received treatment at the Oral Oncology Clinic of the National Cancer Center (NCC) from June 2001 to December 2020. The patients' sex, age, primary site, T stage, node metastasis, TNM staging, perineural invasion (PNI), lymphovascular invasion (LVI), differentiation, surgical resection margin, smoking, and drinking habits were investigated to analyze risk factors. For the univariate analysis, a Kaplan-Meier survival analysis and log-rank test were used. Additionally, for the multivariable analysis, a Cox proportional hazard model analysis was used. For both analyses, statistical significance was considered when P<0.05. Results: During the investigation period, 407 patients were received surgical treatment at the NCC. Their overall survival rate (OS) for five years was 70.7%, and the disease-free survival rate (DFS) was 60.6%. The multivariable analysis revealed that node metastasis, PNI, and differentiation were significantly associated with poor OS. For DFS, PNI and differentiation were associated with poor survival rates. Conclusion: In patients with OSCC, cervical node metastasis, PNI, and differentiation should be considered important prognostic factors for postoperative survival.

Design of Montelukast Nanocrystalline Suspension for Parenteral Prolonged Delivery.

Background: Montelukast (MTK), a representative leukotriene receptor antagonist, is currently being investigated as a potential candidate for treating Alzheimer's disease. For potent and effective dosing in elderly patients, a parenteral prolonged delivery system is favored, with improved medication adherence with reduced dosage frequency. Purpose: This study aimed to design a nanocrystalline suspension (NS)-based MTK prolonged delivery system and evaluate its pharmacokinetics profile and local tolerability following subcutaneous administration. Methods: To decelerate the dissolution rate, the amorphous MTK raw material was transformed into a crystalline state using a solvent-mediated transformation method and subsequently formulated into NS using a bead-milling technique. The MTK NSs were characterized by morphology, particle size, crystallinity, and in vitro dissolution profiles. The pharmacokinetic profile and local tolerability at the injection site following subcutaneous injection of MTK suspension were evaluated in rats. Results: Microscopic and physical characterization revealed that the amorphous MTK powder was lucratively transformed into a crystalline form in acidic media (pH 4). MTK crystalline suspensions with different diameters (200 nm, 500 nm, and 3 µm) were uniformly prepared using bead-milling technology, employing polysorbate 80 as suspending agent. Prepared crystalline suspensions exhibited analogous crystallinity (melting point, 150°C) and size-dependent in vitro dissolution profiles. MTK NSs with particle sizes of 200 nm and 500 nm provided a protracted pharmacokinetic profile for up to 4 weeks in rats, with a higher maximum drug concentration in plasma than the 3 µm-sized injectable suspensions. Histopathological examination revealed that MTK NS caused chronic granulomatous inflammation at the injection site, which resolved after 4 weeks. Conclusion: The MTK parenteral NS delivery system is expected to be a valuable tool for treating Alzheimer's disease with extended dose intervals.

Mitochondrial double-stranded RNAs govern the stress response in chondrocytes to promote osteoarthritis development.

Protein kinase R (PKR) is an immune response protein that becomes activated by double-stranded RNAs (dsRNAs). PKR overactivation is associated with degenerative diseases with inflammation, including osteoarthritis (OA), but the dsRNA activator remains largely unknown. Here, we find that mitochondrial dsRNA (mt-dsRNA) expression and its cytosolic efflux are facilitated in chondrocytes under OA-eliciting conditions, leading to innate immune activation. Moreover, mt-dsRNAs are released to the extracellular space and activate Toll-like receptor 3 at the plasma membrane. Elevated levels of mt-dsRNAs in the synovial fluids and damaged cartilage of OA patients and in the cartilage of surgery-induced OA mice further support our data. Importantly, autophagy prevents PKR activation and protects chondrocytes from mitochondrial stress partly by removing cytosolic mtRNAs. Our study provides a comprehensive understanding of innate immune activation by mt-dsRNAs during stress responses that underlie the development of OA and suggests mt-dsRNAs as a potential target for chondroprotective intervention.

Treatment outcomes and prognostic factors in oral tongue cancer: a 20-year retrospective study at the National Cancer Center, South Korea.

Objectives: This study aimed to analyze the treatment outcomes and to evaluate the clinicopathological prognostic factors of oral tongue cancer. Patients and. Methods: We retrospectively analyzed treatment results and prognostic factors in 205 patients with oral tongue squamous cell carcinoma who were admitted to the National Cancer Center, South Korea, between January 2001 and December 2020. The patients were treated with surgery and postoperative, definitive radiotherapy (RT) or chemoradiotherapy (CRT). Results: Eighteen patients (8.8%) were treated with curative RT or CRT, while the rest (91.2%) were treated with surgery with or without postoperative RT or CRT. The median follow-up period was 30 months (range, 0-234 months). The 5-year overall survival (OS) and 5-year disease-free survival (DFS) were 72% and 63%, respectively. Multivariate analysis revealed that a positive neck nodal status (N1, N2-3) was significantly associated with poorer 5-year OS and DFS, while perineural invasion was associated with poorer 5-year DFS. Conclusion: Cervical metastasis and perineural invasion are significant prognostic predictors, and combination treatments are necessary for improving OS and DFS in patients with these factors.

Graphene-Based Intrinsically Stretchable 2D-Contact Electrodes for Highly Efficient Organic Light-Emitting Diodes.

Intrinsically stretchable organic light-emitting diodes (ISOLEDs) are becoming essential components of wearable electronics. However, the efficiencies of ISOLEDs have been highly inferior compared with their rigid counterparts, which is due to the lack of ideal stretchable electrode materials that can overcome the poor charge injection at 1D metallic nanowire/organic interfaces. Herein, highly efficient ISOLEDs that use graphene-based 2D-contact stretchable electrodes (TCSEs) that incorporate a graphene layer on top of embedded metallic nanowires are demonstrated. The graphene layer modifies the work function, promotes charge spreading, and impedes inward diffusion of oxygen and moisture. The work function (WF) of 3.57 eV is achieved by forming a strong interfacial dipole after deposition of a newly designed conjugated polyelectrolyte with crown ether and anionic sulfonate groups on TCSE; this is the lowest value ever reported among ISOLEDs, which overcomes the existing problem of very poor electron injection in ISOLEDs. Subsequent pressure-controlled lamination yields a highly efficient fluorescent ISOLED with an unprecedently high current efficiency of 20.3 cd A-1 , which even exceeds that of an otherwise-identical rigid counterpart. Lastly, a 3 inch five-by-five passive matrix ISOLED is demonstrated using convex stretching. This work can provide a rational protocol for designing intrinsically stretchable high-efficiency optoelectronic devices with favorable interfacial electronic structures.

Building a Korean morphological analyzer using two Korean BERT models.

A morphological analyzer plays an essential role in identifying functional suffixes of Korean words. The analyzer input and output differ from each other in their length and strings, which can be dealt with by an encoder-decoder architecture. We adopt a Transformer architecture, which is an encoder-decoder architecture with self-attention rather than a recurrent connection, to implement a Korean morphological analyzer. Bidirectional Encoder Representations from Transformers (BERT) is one of the most popular pretrained representation models; it can present an encoded sequence of input words, considering contextual information. We initialize both the Transformer encoder and decoder with two types of Korean BERT, one of which is pretrained with a raw corpus, and the other is pretrained with a morphologically analyzed dataset. Therefore, implementing a Korean morphological analyzer based on Transformer is a fine-tuning process with a relatively small corpus. A series of experiments proved that parameter initialization using pretrained models can alleviate the chronic problem of a lack of training data and reduce the time required for training. In addition, we can determine the number of layers required for the encoder and decoder to optimize the performance of a Korean morphological analyzer.

Enabling 100C Fast-Charging Bulk Bi Anodes for Na-Ion Batteries.

It is challenging to develop alloying anodes with ultrafast charging and large energy storage using bulk anode materials because of the difficulty of carrier-ion diffusion and fragmentation of the active electrode material. Herein, a rational strategy is reported to design bulk Bi anodes for Na-ion batteries that feature ultrafast charging, long cyclability, and large energy storage without using expensive nanomaterials and surface modifications. It is found that bulk Bi particles gradually transform into a porous nanostructure during cycling in a glyme-based electrolyte, whereas the resultant structure stores Na ions by forming phases with high Na diffusivity. These features allow the anodes to exhibit unprecedented electrochemical properties; the developed Na-Bi half-cell delivers 379 mA h g-1 (97% of that measured at 1C) at 7.7 A g-1 (20C) during 3500 cycles. It also retained 94% and 93% of the capacity measured at 1C even at extremely fast-charging rates of 80C and 100C, respectively. The structural origins of the measured properties are verified by experiments and first-principles calculations. The findings of this study not only broaden understanding of the underlying mechanisms of fast-charging anodes, but also provide basic guidelines for searching battery anodes that simultaneously exhibit high capacities, fast kinetics, and long cycling stabilities.

Extracellular pyruvate kinase M2 promotes osteoclastogenesis and is associated with radiographic progression in early rheumatoid arthritis.

Extracellular PKM2 (exPKM2) levels have been reported to be increased in several cancers and inflammatory diseases, including rheumatoid arthritis (RA). This study aimed to investigate the association of circulating exPKM2 levels with radiographic progression in RA patients and the effect of exPKM2 on osteoclastogenesis. Plasma and synovial fluid exPKM2 levels were significantly elevated in RA patients. Plasma exPKM2 levels were correlated with RA disease activity and were an independent predictor for radiographic progression in RA patients with a disease duration of ≤ 12 months. CD14+ monocytes but not RA fibroblast-like synoviocytes secreted PKM2 upon stimulation with inflammatory mediators. Recombinant PKM2 (rPKM2) increased the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells and resorption pit in osteoclast precursors, dose-dependently, even in the absence of receptor activator of nuclear factor-kappa B ligand (RANKL). rPKM2 treatment upregulated the expression of dendrocyte-expressed seven transmembrane protein (DC-STAMP) and MMP-9 via the ERK pathway. Although rPKM2 did not directly bind to RAW264.7 cells, extracellular application of pyruvate, the end-product of PKM2, showed effects similar to those seen in rPKM2-induced osteoclastogenesis. These results suggest that exPKM2 is a potential regulator of RA-related joint damage and a novel biomarker for subsequent radiographic progression in patients with early-stage RA.