VP2 residue N142 of coxsackievirus A10 is critical for the interaction with KREMEN1 receptor and neutralizing antibodies and the pathogenicity in mice.

Coxsackievirus A10 (CVA10) has recently emerged as one of the major causative agents of hand, foot, and mouth disease. CVA10 may also cause a variety of complications. No approved vaccine or drug is currently available for CVA10. The residues of CVA10 critical for viral attachment, infectivity and in vivo pathogenicity have not been identified by experiment. Here, we report the identification of CVA10 residues important for binding to cellular receptor KREMEN1. We identified VP2 N142 as a key receptor-binding residue by screening of CVA10 mutants resistant to neutralization by soluble KREMEN1 protein. The receptor-binding residue N142 is exposed on the canyon rim but highly conserved in all naturally occurring CVA10 strains, which provides a counterexample to the canyon hypothesis. Residue N142 when mutated drastically reduced receptor-binding activity, resulting in decreased viral attachment and infection in cell culture. More importantly, residue N142 when mutated reduced viral replication in limb muscle and spinal cord of infected mice, leading to lower mortality and less severe clinical symptoms. Additionally, residue N142 when mutated could decrease viral binding affinity to anti-CVA10 polyclonal antibodies and a neutralizing monoclonal antibody and render CVA10 resistant to neutralization by the anti-CVA10 antibodies. Overall, our study highlights the essential role of VP2 residue N142 of CVA10 in the interactions with KREMEN1 receptor and neutralizing antibodies and viral virulence in mice, facilitating the understanding of the molecular mechanisms of CVA10 infection and immunity. Our study also provides important information for rational development of antibody-based treatment and vaccines against CVA10 infection.

Chandipura viral glycoprotein (CNV-G) promotes Gectosome generation and enables delivery of intracellular therapeutics.

Overexpression of vesicular stomatitis virus G protein (VSV-G) elevates the secretion of EVs known as gectosomes, which contain VSV-G. Such vesicles can be engineered to deliver therapeutic macromolecules. We investigated viral glycoproteins from several viruses for their potential in gectosome production and intracellular cargo delivery. Expression of the viral glycoprotein (viral glycoprotein from the Chandipura virus [CNV-G]) from the human neurotropic pathogen Chandipura virus in 293T cells significantly augments the production of CNV-G-containing gectosomes. In comparison with VSV-G gectosomes, CNV-G gectosomes exhibit heightened selectivity toward specific cell types, including primary cells and tumor cell lines. Consistent with the differential tropism between CNV-G and VSV-G gectosomes, cellular entry of CNV-G gectosome is independent of the Low-density lipoprotein receptor, which is essential for VSV-G entry, and shows varying sensitivity to pharmacological modulators. CNV-G gectosomes efficiently deliver diverse intracellular cargos for genomic modification or responses to stimuli in vitro and in the brain of mice in vivo utilizing a split GFP and chemical-induced dimerization system. Pharmacokinetics and biodistribution analyses support CNV-G gectosomes as a versatile platform for delivering macromolecular therapeutics intracellularly.

Impact of Off-Hour Admission on In-Hospital Outcomes for Patients With Stroke Receiving Reperfusion Therapy in China.

BACKGROUND: The structure and staffing of hospitals greatly impact patient outcomes, with frequent changes occurring during nights and weekends. This retrospective cohort study assessed the impact of admission timing on in-hospital management and outcomes for patients with stroke receiving reperfusion therapy in China using data from a nationwide registry. METHODS: Data from patients receiving reperfusion therapy were extracted from the Chinese Stroke Center Alliance. Hospital admission time was categorized according to day/evening versus night and weekday versus weekend. Primary outcomes were in-hospital death or discharge against medical advice, hemorrhage transformation, early neurological deterioration, and major adverse cardiovascular events. Logistic regression was performed to compare in-hospital management performance and outcomes based on admission time categories. RESULTS: Overall, 42 381 patients received recombinant tissue-type plasminogen activator (r-tPA) therapy, and 5224 underwent endovascular treatment (EVT). Patients admitted during nighttime had a higher probability of receiving r-tPA therapy within 4.5 hours from onset or undergoing EVT within 6 hours from onset compared with those admitted during day/evening hours (adjusted odds ratio, 1.04 [95% CI, 1.01-1.08]; P=0.021; adjusted odds ratio, 1.72 [95% CI, 1.59-1.86]; P<0.001, respectively). However, no significant difference was observed between weekend and weekday admissions for either treatment. No notable differences were noted between weekends and weekdays or nighttime and daytime periods in door-to-needle time for r-tPA or door-to-puncture time for EVT initiation. Furthermore, weekend or nighttime admission did not have a significant effect on the primary outcomes of r-tPA therapy or EVT. Nevertheless, in patients undergoing EVT, a higher incidence of pneumonia was observed among those admitted at night compared with those admitted during day/evening hours (adjusted odds ratio, 1.22 [95% CI, 1.05-1.42]; P=0.011). CONCLUSIONS: Patients admitted at nighttime were more likely to receive r-tPA therapy or EVT within the time window recommended in the guidelines. However, patients receiving EVT admitted at night had an increased risk of pneumonia.

Doped Porous Carbon Spheres with Controllable Vesicle Structure: Preparation and the Effects of Pore Size on Electromagnetic Wave Absorption Properties.

This work reports on the preparation of uniform vesicle-structural carbon spheres doped with heteroatoms of N, P, and S, with the pore sizes strictly controlled by the hard templates of monodisperse submicron SiO2 spheres. The uniformly doped vesicular carbon microspheres are obtained in three steps: Stöber hydrolysis for the SiO2; in situ polymerization for the immobilization; and alkaline etching after carbonization. The size of the vesicles can be easily adjusted by regulating the particle size of the submicron SiO2 spheres, which has a significant effect on its electromagnetic wave (EMW) absorption performance. Compared with microspheres with pore sizes of 180 and 480 nm, when the vesicle aperture is 327 nm, with only 5.5 wt.% filling load and 1.9 mm thickness, the material shows the best EMW absorption behavior with the effective absorption bandwidth (EAB) covers the entire Ku band (6.32 GHz) and the minimum reflection loss (RLmin) of -36.10 dB, suggesting the optimized pore size of the microspheres can significantly improve the overall impedance matching of the material and achieve broadband wave absorption. This work paves the way for the enhancement of EMW absorption properties of porous material by optimizing the pore size of uniform apertures while maintaining their composition.

Identification of four neutralizing antigenic sites on the enterovirus D68 capsid.

IMPORTANCE: Enterovirus D68 (EV-D68) is an emerging respiratory pathogen associated with acute flaccid myelitis. Currently, no approved vaccines or antiviral drugs are available. Here, we report four functionally independent neutralizing antigenic sites (I to IV) by analyses of neutralizing monoclonal antibody (MAb)-resistant mutants. Site I is located in the VP1 BC loop near the fivefold axis. Site II resides in the VP2 EF loop, and site III is situated in VP1 C-terminus; both sites are located at the south rim of the canyon. Site IV is composed of residue in VP2 ßB strand and residues in the VP3 BC loop and resides around the threefold axis. The developed MAbs targeting the antigenic sites can inhibit viral binding to cells. These findings advance the understanding of the recognition of EV-D68 by neutralizing antibodies and viral evolution and immune escape and also have important implications for the development of novel EV-D68 vaccines.

Signature of Scramblon Effective Field Theory in Random Spin Models.

Information scrambling refers to the propagation of information throughout a quantum system. Its study not only contributes to our understanding of thermalization but also has wide implications in quantum information and black hole physics. Recent studies suggest that information scrambling in large-N systems with all-to-all interactions is mediated by collective modes called scramblons. However, a criterion for the validity of scramblon theory in a specific model is still missing. In this work, we address this issue by investigating the signature of the scramblon effective theory in random spin models with all-to-all interactions. We demonstrate that, in scenarios where the scramblon description holds, the late-time operator size distribution can be predicted from its early-time value, requiring no free parameters. As an illustration, we examine whether Brownian circuits exhibit a scramblon description and obtain a positive confirmation both analytically and numerically. Our findings provide a concrete experimental framework for unraveling the scramblon field theory in random spin models using quantum simulators.

Metabolically healthy obesity, transition from metabolic healthy to unhealthy status, and carotid atherosclerosis.

BACKGROUND: Evidence of the effects of metabolically healthy obesity (MHO) on atherosclerosis is limited; the transition effects of metabolic health and obesity phenotypes have been ignored. We examined the association between metabolic health and the transition to atherosclerosis risk across body mass index (BMI) categories in a community population. METHODS: This cross-sectional study was based on a national representative survey that included 50,885 community participants aged ≥40 years. It was conducted from 01 December 2017 to 31 December 2020, in 13 urban and 13 rural regions across Hunan China. Metabolic health was defined as meeting less than three abnormalities in blood pressure, glucose, high-density lipoprotein cholesterol, triglycerides, or waist circumference. The participants were cross-classified at baseline based on their metabolic health and obesity. In addition, the relationship between atherosclerosis and transitions in metabolic health status based on 4733 participants from baseline to the second survey after 2 years was considered. The relationship between metabolic health status and the risk of transition to Carotid atherosclerosis (CA) was assessed using logistic regression and Cox proportional hazards regression analyses. RESULTS: In this study, the mean age of the participants was 60.7 years (standard deviation [SD], 10.91), 53.0% were female, and 51.2% had CA. As compared with metabolically healthy normal weight (MHN), those with MHO phenotype (odd ratio [OR] 1.10, 95% confidence interval [CI] 1.02-1.21), metabolically unhealthy normal weight (OR 1.27, 95% CI 1.19-1.35), metabolically unhealthy overweight (OR 1.41, 95% CI 1.33-1.48), and metabolically unhealthy obese (OR 1.54, 95% CI 1.44-1.64) had higher risk for CA. However, during the follow-up of 2 years, almost 33% of the participants transitioned to a metabolically unhealthy status. As compared with stable healthy normal weight, transition from metabolically healthy to unhealthy status (hazard ratios [HR] 1.21, 95% [CI] 1.02-1.43) and stable metabolically unhealthy overweight or obesity (MUOO) (HR 1.32, 95% CI 1.17-1.48) were associated with higher risk of CA. CONCLUSIONS: In the community population, obesity remains a risk factor for CA despite metabolic health. However, the risks were highest for metabolically unhealthy status across all BMI categories. A large proportion of metabolically healthy overweight or participants with obesity converts to an unhealthy phenotype over time, which is associated with an increased risk of CA.

Theoretical Insight into Complexation Between Cyclocarbons and C60 Fullerene.

This work conducts a comprehensive theoretical study on the non-covalent complexation between cyclocarbons and C60 fullerene for the first time. The binding energy between cyclocarbons and C60 fullerene is significantly stronger than that between two C18 or two C60 fullerenes, indicating a particularly strong affinity. The cyclocarbons and C60 fullerene can spontaneously assemble into complexes in the gas phase at room temperature, and the hydrophobic effect caused by the solvent environment can promote this binding. The binding strength with C60 fullerene increases almost linearly with the increase of cyclocarbon size, and the C34@C60 dimer exhibits a perfect nano-Saturn structure. As the ring size increases, the angle between the two cyclocarbons of the 2 : 1 trimers formed by cyclocarbons and C60 fullerene gradually decreases. In C60@2 C34 trimer, the fullerene is symmetrically surrounded by two cyclocarbons. The results on the trimers formed by cyclocarbon and C60 fullerenes in a 1 : 2 ratio showed when the cyclocarbon sandwiched between two fullerenes is not quite large, the trimers exhibit an ideal dumbbell-like structure, and the presence of the first fullerene has a significant synergistic effect on the binding of the second one. The cyclocarbon greatly promotes the dimerization of fullerenes, which acted as a "molecular glue".

Aromaticity in Isoelectronic Analogues of Benzene, Carborazine and Borazine, from Electronic Structure and Magnetic Property.

Carborazine (B2C2N2H6) and borazine (B3N3H6) are isoelectronic analogues of benzene (C6H6). The aromatic character of borazine have basically reached a consensus after a long period of controversy, but the related properties of carborazine are even rarely reported. In this work, we systematically investigated the geometric structure, charge distribution, frontier molecular orbital characteristics, bonding, electronic delocalization, magnetic shielding effect, and induced ring current of carborazine and borazine, and compared the studied characteristics with those of benzene to determine the aromatic character of the two analogues. The combination of multiple properties shows that although they are isoelectronic, carborazine is evidently aromatic, while borazine only exhibits rather weak aromaticity. The C atom acting as a connecting bridge between B and N atoms in carborazine reduces the electronegativity difference on the molecular backbone and enhances the electronic delocalization over the conjugated path, which is the essence of the distinct disparity of aromaticity between carborazine and borazine.

Strong Electronic Interaction Enables Enhanced Solar-Driven CO2 Reduction into Selective CH4 on SrTiO3 with Photodeposited Pt2+ Sites.

Targeting selective CO2 photoreduction into CH4 remains a challenge due to the sluggish reaction kinetics and poor hydrogenation ability of the unstable intermediate. Here, the active Pt2+ sites were photodeposited on the SrTiO3 photocatalyst, which was well demonstrated to manipulate the CH4 product selectivity. The results showed that SrTiO3 mainly yielded the CO (6.98 µmol g-1) product with poor CH4 (0.17 µmol g-1). With the Pt2+ modification, 100% CH4 selectivity could be obtained with an optimized yield rate of 8.07 µmol g-1. The prominent enhancement resulted from the following roles: (1) the strong electronic interaction between the Pt2+ cocatalyst and SrTiO3 could prompt efficient separation of the photoelectron-hole pairs. (2) The Pt2+ sites were active to capture and activate inert CO2 into HCO3- and CO32- species and allowed fast *COOH formation with the lowered reaction barrier. (3) Compared with SrTiO3, the formed *CO species could be captured tightly on the Pt2+ cocatalyst surface for generating the *CH2 intermediate by the following electron-proton coupling reaction, thus leading to the CH4 product with 100% selectivity.

Finer Particle Size Distribution and Potential Higher Toxicity of Elemental Carbon and Polycyclic Aromatic Hydrocarbons Emitted by Ships after Fuel Oil Quality Improvement.

Ship emissions are a significant source of air pollution, and the primary policy to control is fuel oil quality improvement. However, the impact of this policy on particle size distribution and composition characteristics remains unclear. Measurements were conducted on nine different vessels (ocean-going vessels, coastal cargo ships, and inland cargo ships) to determine the impact of fuel upgrading (S < 0.1% m/m marine gas oil (MGO) vs S < 0.5% m/m heavy fuel oil (HFO)) on elemental carbon (EC) and polycyclic aromatic hydrocarbons (PAHs) emitted by ships. (1) Fuel improvement significantly reduced EC and PAH emission, by 31 ± 25 and 45 ± 38%, respectively. However, particle size distributions showed a trend toward finer particles, with the peak size decreasing from DP = 0.38-0.60 µm (HFO) to DP = 0.15-0.25 µm (MGO), and the emission factor of DP < 100 nm increased. (2) Changes in emission characteristics led to an increase in the toxicity of ultrafine particulate matter. (3) Ship types and engine conditions affected the EC and PAH particle size distributions. Inland ships have a more concentrated particle size distribution. Higher loads result in higher emissions. (4) The composition and engine conditions of fuel oils jointly affected pollutant formation mechanisms. MGO and HFO exhibited opposite EC emissions when emitting the same level of PAHs.

METTL3-mediated m6A modification enhances ZDHHC16 expression in nonsmall- cell lung cancer patients, attenuating ferroptosis by suppressing CREB ubiquitination.

At present, the early diagnosis and treatment of non-small cell lung cancer (NSCLC) is still an urgent problem to be solved worldwide, including in China. The present work investigated the possible protective effect of ZDHHC16 in cell proliferation and metastasis of NSCLC and explored its possible mechanisms. ZDHHC16 expression level in patients with Non-Small-Cell Lung Cancer was up-regulation. ZDHHC16 gene is stabilized by m6A methylation. ZDHHC16 gene reduced ferroptosis of NSCLC by the rehabilitation of the mitochondrial structure. ZDHHC16 promoted CREB expression through the inhibition of CREB Ubiquitination. Confocal microscopy showed that ZDHHC16 reduced the CREB expression of NSCLC. ZDHHC16 up-regulation reduced CREB Ubiquitination, and down-regulation of ZDHHC16 promoted CREB Ubiquitination of NSCLC. CREB Agonists reduced the effects of ZDHHC16 on ferroptosis, not affecting the Warburg effect of NSCLC. CREB inhibitor reduced the effects of si-ZDHHC16 on ferroptosis, not affecting the Warburg effect of NSCLC. METTL3-mediated m6A modification increases ZDHHC16 stability. Our study revealed that the m6A-forming enzyme METTL3 upregulates ZDHHC16 expression in NSCLC patients, leading to the reduction of ferroptosis by inhibiting CREB ubiquitination.

Uranium extraction from seawater: material design, emerging technologies and marine engineering.

Uranium extraction from seawater (UES), a potential approach to securing the long-term uranium supply and sustainability of nuclear energy, has experienced significant progress in the past decade. Promising adsorbents with record-high capacities have been developed by diverse innovative synthetic strategies, and scale-up marine field tests have been put forward by several countries. However, significant challenges remain in terms of the adsorbents' properties in complex marine environments, deployment methods, and the economic viability of current UES systems. This review presents an up-to-date overview of the latest advancements in the UES field, highlighting new insights into the mechanistic basis of UES and the methodologies towards the function-oriented development of uranium adsorbents with high adsorption capacity, selectivity, biofouling resistance, and durability. A distinctive emphasis is placed on emerging electrochemical and photochemical strategies that have been employed to develop efficient UES systems. The most recent achievements in marine tests by the major countries are summarized. Challenges and perspectives related to the fundamental, technical, and engineering aspects of UES are discussed. This review is envisaged to inspire innovative ideas and bring technical solutions towards the development of technically and economically viable UES systems.

Care stressors and perceived stress among family caregivers of Chinese older adults with disabilities: The mediation effect of resilience.

OBJECTIVES: Guided by the Stress Process Model, this study examined the mediating effect of resilience on the relationship between care stressors and perceived caregiving stress. METHODS: Data were based on 234 older adults with disabilities and their caregivers from 6 urban districts and 6 rural counties from Jinan, China. Descriptive analysis, analysis of variance, ordinary least squares regression, and mediation analysis were performed. RESULTS: Perceived stress among family caregivers of Chinese older adults with disabilities was affected by the physical and mental health of both themselves and the care recipients, as well as care intensity and financial difficulties. Resilience played a partial mediating role in the associations among three stressors (i.e. older adults' disability levels, number of chronic diseases, and caregivers' self-reported mental) and perceived caregiving stress. CONCLUSIONS: Enhanced resilience aids caregivers' adaptation to their roles, suggesting the need for societal, spiritual, emotional, and behavioral resilience training.

Emission and optical characteristics of brown carbon in size-segregated particles from three types of Chinese ships.

Brown carbon (BrC) is one of the important light absorption substances that have high light absorption ability under short wavelength light. However, limit studies have focused on the BrC emission from ships. In this study, size-segregated particulate matters (PM) were collected from three different types of ships, light absorption characteristics and size distribution of methanol-soluble BrC and water-soluble BrC in PM from ship exhausts were investigated. Results showed that four-stroke low-power diesel fishing boat (4-LDF) had the highest mass concentrations of methanol-soluble organic carbon (MSOC) and water-soluble organic carbon (WSOC), followed by 2-stroke high-power heavy-fuel-oil vessel (2-HHV), and four-stroke high-power marine-diesel vessel (4-HMV). While 2-HHV had obviously higher light absorption coefficients of methanol-soluble BrC (Abs365,M) and water-soluble BrC (Abs365,W) in unit weight of PM than the other two types of ships. The tested ships presented comparable or higher absorption efficiency of BrC in water extracts (MAE365,W) compared with other BrC emission sources. Majority of BrC was concentrated in fine particles, and the particle size distributions of both Abs365,M and Abs365,W showed bimodal patterns, peaking at 0.43-0.65 µm and 4.7-5.8 µm, respectively. However, different particle size distributions were found for MAE365,M between diesel and heavy fuel oil ships. Besides, different wavelength dependence in particles with different size were also detected. Ship exhaust could be confirmed as a non-ignorable BrC emission source, and complex influencing factor could affect the light absorption characteristics of ship emissions. Particle size should also be considered when light absorption ability of BrC was evaluated.

Regulating the Solvation Structure in Polymer Electrolytes for High-Voltage Lithium Metal Batteries.

Solid polymer electrolytes are promising electrolytes for safe and high-energy-density lithium metal batteries. However, traditional ether-based polymer electrolytes are limited by their low lithium-ion conductivity and narrow electrochemical window because of the well-defined and intimated Li+-oxygen binding topologies in the solvation structure. Herein, we proposed a new strategy to reduce the Li+-polymer interaction and strengthen the anion-polymer interaction by combining strong Li+-O (ether) interactions, weak Li+-O (ester) interactions with steric hindrance in polymer electrolytes. In this way, a polymer electrolyte with a high lithium ion transference number (0.80) and anion-rich solvation structure is obtained. This polymer electrolyte possesses a wide electrochemical window (5.5 V versus Li/Li+) and compatibility with both Li metal anode and high-voltage NCM cathode. Li||LiNi0.5Co0.2Mn0.3O2 full cells with middle-high active material areal loading (~7.5 mg cm-2) can stably cycle at 4.5 V. This work provides new insight into the design of polymer electrolytes for high-energy-density lithium metal batteries through the regulation of ion-dipole interactions.

Open-Cage Fullerene as a Macrocyclic Ligand for Na, Pt, and Rh Metal Complexes.

An open-cage [60]fullerene derivative was prepared through Malaprade oxidation of a vicinal triol moiety as the key step. Above the 17-membered orifice, there is one carboxyl group. Three ketone carbonyl groups and one lactone carbonyl group are located on the rim of the orifice. The carboxylic and carbonyl oxygen atoms around the orifice act as strong polydentate ligands for a sodium ion. These oxygen atoms also react with [Rh(CO)2Cl]2 to form various isomeric rhodium complexes with comparable stability. The fullerene C═C bond on the rim of the orifice forms a stable platinum complex when treated with Pt(PPh3)4. Single crystal X-ray diffraction data reveal that one of the carboxylic oxygen atoms above the orifice forms a H-bond with the water molecule trapped in the cage.

The atherogenic index of plasma and carotid atherosclerosis in a community population: a population-based cohort study in China.

BACKGROUND: The atherogenic index of plasma (AIP) is an important alternative metabolic biomarker of atherosclerosis and cardiovascular diseases. Nevertheless, the correlation between the AIP and carotid atherosclerosis is unknown among the general population. METHODS: A total of 52,380 community residents, aged ≥ 40 years who underwentcervical vascular ultrasound from December 2017 to December 2020 in Hunan China, were selected for retrospective analysis. The AIP was calculated as a logarithmically converted ratio of triglycerides (TG) to high-density lipoprotein-cholesterol (HDL-C). The participants were divided into AIP quartile groups (Q1-Q4). Logistic regression models and restricted cubic spline analyses were used to examine the association of the AIP with carotid atherosclerosis. Stratified analyses were applied to control for confounding factors. The incremental predictive value of the AIP was further assessed. RESULTS: After adjusting for traditional risk factors, an increased AIP was associated with a higher rate of carotid atherosclerosis (CA), increased carotid intima-media thickness (CIMT), and plaques [odds ratio, OR (95% confidence interval, CI): 1.06 (1.04, 1.08), 1.07 (1.05, 1.09), and 1.04 (1.02, 1.06) per 1-SD increase in the AIP, respectively]. Compared with those participants in the quartile 1 group, those in the quartile 4 group had a greater risk of CA [OR 1.18, 95% CI (1.12, 1.25)], increased CIMT [OR 1.20, 95% CI (1.13, 1.26)], and plaques [OR 1.13, 95% CI (1.06, 1.19)]. However, we did not observe an association between the AIP and stenosis [0.97 (0.77, 1.23), p for trend = 0.758]. Restricted cubic spline analyses also showed a cumulative increase in the risk of CA, increased CIMT, and plaques but not stenosis severity (> 50%) with an increase of the AIP. Subgroup analyses showed that a more significant association between the AIP and the prevalence of increased CA was detected in younger subjects (aged < 60 years) with a body mass index (BMI) of ≥ 24 and fewer comorbidities. Additionally, the AIP provided incremental predictive capacity over established risk factors for CA, as shown by an improvement in the net reclassification index (NRI) and integrated discrimination index (IDI) (all P < 0.05). CONCLUSIONS: An elevated AIP in a community-based population is associated with a higher rate of CA. the AIP could serve as a potential biomarker for CA risk assessment.

METTL3-mediated m6A RNA methylation induces the differentiation of lung resident mesenchymal stem cells into myofibroblasts via the miR-21/PTEN pathway.

BACKGROUND: The accumulation of myofibroblasts is the key pathological feature of pulmonary fibrosis (PF). Aberrant differentiation of lung-resident mesenchymal stem cells (LR-MSCs) has been identified as a critical source of myofibroblasts, but the molecular mechanisms underlying this process remain largely unknown. In recent years, N6-methyladenosine (m6A) RNA modification has been implicated in fibrosis development across diverse organs; however, its specific role in promoting the differentiation of LR-MSCs into myofibroblasts in PF is not well defined. METHODS: In this study, we examined the levels of m6A RNA methylation and the expression of its regulatory enzymes in both TGF-ß1-treated LR-MSCs and fibrotic mouse lung tissues. The downstream target genes of m6A and their related pathways were identified according to a literature review, bioinformatic analysis and experimental verification. We also assessed the expression levels of myofibroblast markers in treated LR-MSCs and confirmed the involvement of the above-described pathway in the aberrant differentiation direction of LR-MSCs under TGF-ß1 stimulation by overexpressing or knocking down key genes within the pathway. RESULTS: Our results revealed that METTL3-mediated m6A RNA methylation was significantly upregulated in both TGF-ß1-treated LR-MSCs and fibrotic mouse lung tissues. This process directly led to the aberrant differentiation of LR-MSCs into myofibroblasts by targeting the miR-21/PTEN pathway. Moreover, inhibition of METTL3 or miR-21 and overexpression of PTEN could rescue this abnormal differentiation. CONCLUSION: Our study demonstrated that m6A RNA methylation induced aberrant LR-MSC differentiation into myofibroblasts via the METTL3/miR-21/PTEN signaling pathway. We indicated a novel mechanism to promote PF progression. Targeting METTL3-mediated m6A RNA methylation and its downstream targets may present innovative therapeutic approaches for the prevention and treatment of PF.

Electronic Structure and Aromaticity of an Unusual Cyclo[18]carbon Precursor, C18 Br6.

Herein, the electronic structure and bonding character of the stable cyclo[18]carbon (C18 ) precursor, C18 Br6 , are thoroughly characterized by molecular orbital (MO), density of states (DOS), bond order (BO), and interaction region indicator (IRI) analyses. The delocalization characters of out-of-plane and in-plane π-electrons (labeled as πout - and πin -electrons, respectively) in bonding regions were examined using localized orbital locator (LOL) and electron localization function (ELF). The aromaticity was investigated, studying the molecular magnetic response to external magnetic field by computing the magnetically induced current density (Jind ), iso-chemical shielding surface (ICSS), anisotropy of the induced current density (AICD), and the induced magnetic field (Bind ). All these analyses indicate that C18 Br6 is a globally aromatic species with lower aromaticity than C18 , and the blocking of in-plane π-conjugation (labeled as πin -conjugation) by the presence of -Br substituents in it is the underlying cause for the weakening of molecular aromaticity.