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Vancomycin and norvancomycin have diminished antibacterial efficacy due to acquired or intrinsic resistance from mutations in the terminal dipeptide of lipid II in Gram-positive bacteria or failure to penetrate into the periplasm in Gram-negative bacteria. Herein, we rationally designed and synthesized a series of vancomycin analogues bearing single amine or guanidine functionality, altering various linkers and modification sites, to combat the resistance. Extensive antibacterial screening was performed to delineate a comprehensive SAR. Many derivatives revitalized the activity in vitro, exhibiting a 4-128-fold or 2-16-fold enhancement against the acquired or intrinsic resistance with lower toxicity. Significantly, the optimal compound 4g demonstrated greater pharmacokinetic and pharmacodynamic profiles. Further studies uncovered additional independent and synergistic mechanisms for 4g , including the enhanced membrane activity and augmented inhibition of peptidoglycan biosynthesis via increased lipid II binding, highlighting its potential as a future lead candidate to replenish the glycopeptide antibiotic arsenal.

The activation of nitrogen (N 2 ) is vital for sustainable ammonia production and nitrogen fixation technologies. This study employs density functional theory (DFT) to investigate the nitrogen activation and reduction capabilities of Group VIII single-atom catalysts anchored on MoS 2 . Among these, osmium anchored on MoS 2 (Os@MoS 2 ) emerged as the most promising catalyst, exhibiting the highest N 2 activation and the lowest nitrogen reduction reaction (NRR) overpotential (0.624 V). A pronounced "electron drift" effect was observed for Os@MoS 2 , leading to significant charge redistribution that weakens the N ≡ N triple bond, facilitating its activation. The N-N dissociation energy barrier at the *N-NH 2 intermediate was calculated to be only 0.82 eV, confirming Os@MoS 2 's superior catalytic efficiency. Detailed analyses, including electrostatic potential maps, electron localization functions, spin density, and charge transfer, revealed the pivotal role of orbital interactions in driving N 2 activation. Interestingly, the trends in adsorbed N 2 bond energies and NRR overpotentials showed a consistent diagonal pattern across the Group VIII catalysts, emphasizing the importance of electronic and geometric factors. This work offers valuable insights into nitrogen activation mechanisms and provides a framework for designing efficient catalysts, highlighting Os@MoS 2 's potential in sustainable ammonia synthesis.

Tubular structures exist broadly in biological systems and exhibit important functions including mediating cellular communications. The construction of artificial analogues in living cells would provide a new strategy for chemotherapy. In this report, a kind of supramolecular channel has been constructed within intercellular gaps by mimicking the assembly process and structure of natural gap junctional channels, which consist of hydrophobic tubular modules located in the adjacent cell membranes and hydrophilic modules within the extracellular space. The assembly of the channels was driven by electrostatic interactions. The channels could inhibit tumor cell invasion by preventing cell migration.

Single-molecule localization microscopy (SMLM) requires high-intensity laser irradiation, typically exceeding kW/cm 2 , to yield a sufficient photon count. However, this intense visible light exposure incurs substantial cellular toxicity, hindering its use in living cells. Here, we developed a class of near-infrared (NIR) spontaneously blinking fluorophores for SMLM. These NIR fluorophores are a combination of rhodamine spirolactams and merocyanine derivatives, where the rhodamine spirolactam component converts between a bright and dark state based on pH-dependent spirocyclization and merocyanine derivatives shift the excitation wavelength into the infrared. Single-molecule characterizations demonstrated their potential for SMLM. At a moderate power density of 3.93 kW/cm 2 , these probes exhibit duty cycle as low as 0.18% and an emission rate as high as 26,700 photons/s. Phototoxicity assessment under single-molecule imaging conditions reveals that NIR illumination (721 nm) minimizes harm to living cells. Employing these NIR fluorophores, we successfully captured time-lapse super-resolution tracking of mitochondria at a Fourier ring correlation (FRC) resolution of 69.4 nm and reconstructed the ultrastructures of endoplasmic reticulum (ER) in living cells.

Municipal solid waste (MSW) management systems play a crucial role in greenhouse gas (GHG) emissions in China. Although the government has implemented many policies to improve the MSW management system, the impact of these improvements on city-level GHG emission reduction remains largely unexplored. This study conducted a comprehensive analysis of both direct and downstream GHG emissions from the MSW sector, encompassing sanitary landfill, dump, incineration, and biological treatment, across 352 Chinese cities from 2001 to 2021 by adopting inventory methods recommended by the Intergovernmental Panel on Climate Change (IPCC). The results reveal that (1) GHG emissions from the MSW sector in China peaked at 70.6 Tg of CO 2 equiv in 2018, followed by a significant decline to 47.6 Tg of CO 2 equiv in 2021, (2) cities with the highest GHG emission reduction benefits in the MSW sector were historical emission hotspots over the past 2 decades, and (3) with the potential achievement of zero-landfilling policy by 2030, an additional reduction of 203.7 Tg of CO 2 equiv is projected, with the emission reduction focus toward cities in South China (21.9%), Northeast China (17.8%), and Southwest China (17.3%). This study highlights that, even without explicit emission reduction targets for the MSW sector, the improvements of this sector have significantly reduced GHG emissions in China.

The glutathione S -transferases (GSTs) are important detoxifying enzymes in insects. Our previous studies found that the susceptibility of Chilo suppressalis to abamectin was significantly increased when the CsGST activity was inhibited by glutathione (GSH) depletory. In this study, the potential detoxification mechanisms of CsGSTs to abamectin were explored. Six CsGSTs of C. suppressalis were expressed in vitro . Enzymatic kinetic parameters including K m and V max of recombinant CsGSTs were determined, and results showed that all of the six CsGSTs were catalytically active and displaying glutathione transferase activity. Insecticide inhibitions revealed that a low concentration of abamectin could effectively inhibit the activities of CsGSTs including CsGSTd1, CsGSTe4, CsGSTo2, CsGSTs3, and CsGSTu1. However, the in vitro metabolism assay found that the six CsGSTs could not metabolize abamectin directly. Additionally, the glutathione transferase activity of CsGSTs in C. suppressalis was significantly increased post-treatment with abamectin. Comprehensive analysis of the results in present and our previous studies demonstrated that CsGSTs play an important role in detoxification of abamectin by catalyzing the conjugation of GSH to abamectin in C. suppressalis , and the high binding affinities of CsGSTd1, CsGSTe4, CsGSTo2, CsGSTs3, and CsGSTu1 with abamectin might also suggest the involvement of CsGSTs in detoxification of abamectin via the noncatalytic passive binding and sequestration instead of direct metabolism. These studies are helpful to better understand the detoxification mechanisms of GSTs in insects.

The separation of xenon/krypton gas mixtures is a valuable but challenging endeavor in the gas industry due to their similar physical characteristics and closely sized molecules. To address this, we investigated the effectiveness of the hydrate-based gas separation method for mixed Xe-Kr gas via molecular dynamics (MD) simulations. The formation process of hydrates facilitates the encapsulation of guest molecules within hydrate cages, offering a potential strategy for gas separation. Higher temperatures and pressures are advantageous for accelerating the hydrate growth rate. The final occupancy of guest molecules and empty cages within 5 12 , 5 12 6 4 , and all hydrate cages were thoroughly examined. An increase in the pressure and temperature enhanced the occupancy rates of Xe in both 5 12 and 5 12 6 4 cages, whereas elevated pressure alone improved the occupancy of Kr in 5 12 6 4 cages. However, the impact of temperature and pressure on Kr occupancy within 5 12 cages was found to be minimal. Elevated temperature and pressure resulted in a reduced occupancy of empty cages. Predominantly, 5 12 6 4 cages were occupied by Xe, whereas Kr showed a propensity to occupy the 5 12 cages. With increasing simulated pressure, the final occupancy of Xe molecules in all cages rose from 0.37 to 0.41 for simulations at 260 K, while the final occupancy of empty cages decreased from 0.24 to 0.2., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The mitogen-activated protein kinase-interacting protein kinases (MNKs) are the only kinases known to phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at Ser209, which plays a significant role in cap-dependent translation. Dysregulation of the MNK/eIF4E axis has been found in various solid tumors and hematological malignancies, including diffuse large B-cell lymphoma (DLBCL). Herein, structure-activity relationship studies and docking models determined that 20j exhibits excellent MNK1/2 inhibitory activity, stability, and hERG safety. 20j exhibits strong and broad antiproliferative activity against different cancer cell lines, especially GCB-DLBCL DOHH2. 20j suppresses the phosphorylation of eIF4E in Hela cells (IC 50 = 90.5 nM) and downregulates the phosphorylation of eIF4E and 4E-BP1 in A549 cells. In vivo studies first revealed that ibrutinib enhances the antitumor effect of 20j without side effects in a DOHH2 xenograft model. This study provided a solid foundation for the future development of a MNK inhibitor for GCB-DLBCL treatment.

Hampered by their susceptibility to nucleophilic attack and chemical bleaching, electron-deficient squaraine dyes have long been considered unsuitable for biological imaging. This study unveils a surprising twist: in aqueous environments, bleaching is not irreversible but rather a reversible spontaneous quenching process. Leveraging this new discovery, we introduce a novel deep-red squaraine probe tailored for live-cell super-resolution imaging. This probe enables single-molecule localization microscopy (SMLM) under physiological conditions without harmful additives or intense lasers and exhibits spontaneous blinking orchestrated by biological nucleophiles, such as glutathione or hydroxide anion. With a low duty cycle (∼0.1%) and high-emission rate (∼6 × 10 4 photons/s under 400 W/cm 2 ), the squaraine probe surpasses the benchmark Cy5 dye by 4-fold and Si-rhodamine by a factor of 1.7 times. Live-cell SMLM with the probe reveals intricate structural details of cell membranes, which demonstrates the high potential of squaraine dyes for next-generation super-resolution imaging.

It is an urgent need to tackle the global crisis of multidrug-resistant bacterial infections. We report here an innovative strategy for large-scale screening of new antibacterial agents using a whole bacteria-based DNA-encoded library (DEL) of vancomycin derivatives via peripheral modifications. A bacterial binding affinity assay was established to select the modification fragments in high-affinity compounds. The optimal resynthesized derivatives demonstrated excellently enhanced activity against various resistant bacterial strains and provided useful structures for vancomycin derivatization. This work presents the new concept in a natural product-templated DEL and in antibiotic discovery through bacterial affinity screening, which promotes the fight against drug-resistant bacteria.

The lepidopteran-specific RNAi efficiency-related nuclease (REase) has been shown to contribute to double-strand RNA (dsRNA) degradation in several lepidopteran insects. However, little is known about its regulatory mechanism. In this study, we identified and characterized SfREase in Spodoptera frugiperda . The exposure of the third-instar larvae to dsEGFP and high temperature led to the upregulation of SfREase, whereas starvation treatment resulted in the downregulation of SfREase . Further experiments revealed that dsRNA degraded more slowly in the hemolymph or midgut fluid extracted from dsSfREase-injected or dsSfREase-ingested larvae compared with those from dsEGFP-treated larvae, and the recombinant SfREase degraded dsRNA in a concentration-dependent manner. Additionally, the knockdown of SfREase improved RNAi efficiency. Finally, both RNAi and dual-luciferase reporter assay in Sf9 cells revealed that SfREase is negatively regulated by FOXO. These data provide insights into the function and regulatory mechanism of REase and have applied implications for the development of an RNAi-based control strategy of S. frugiperda .

The interaction of water with surfaces is crucially important in a wide range of natural and technological settings. In particular, at low temperatures, unveiling the atomistic structure of adsorbed water clusters would provide valuable data for understanding the ice nucleation process. Using high-resolution atomic force microscopy (AFM) and scanning tunneling microscopy, several studies have demonstrated the presence of water pentamers, hexamers, and heptamers (and of their combinations) on a variety of metallic surfaces, as well as the initial stages of 2D ice growth on an insulating surface. However, in all of these cases, the observed structures were completely flat, providing a relatively straightforward path to interpretation. Here, we present high-resolution AFM measurements of several water clusters on Au(111) and Cu(111), whose understanding presents significant challenges due to both their highly 3D configuration and their large size. For each of them, we use a combination of machine learning, atomistic modeling with neural network potentials, and statistical sampling to propose an underlying atomic structure, finally comparing its AFM simulated images to the experimental ones. These results provide insights into the early phases of ice formation, which is a ubiquitous phenomenon ranging from biology to astrophysics.

The development of synthetic agonists for the orphan receptor GPR88 has recently attracted significant interest, given the promise of GPR88 as a novel drug target for psychiatric and neurodegenerative disorders. Examination of structure-activity relationships of two known agonist scaffolds 2-PCCA and 2-AMPP, as well as the recently resolved cryo-EM structure of 2-PCCA-bound GPR88, led to the design of a new scaffold based on the "reversed amide" strategy of 2-AMPP. A series of novel (4-substituted-phenyl)acetamides were synthesized and assessed in cAMP accumulation assays as GPR88 agonists, which led to the discovery of several compounds with better or comparable potencies to 2-AMPP. Computational docking studies suggest that these novel GPR88 agonists bind to the same allosteric site of GPR88 that 2-PCCA occupies. Collectively, our findings provide structural insight and SAR requirement at the allosteric site of GPR88 and a new scaffold for further development of GPR88 allosteric agonists.

The chemical industry is a significant source of nonmethane volatile organic compounds (NMVOCs), pivotal precursors to ambient ozone (O 3 ), and secondary organic aerosol (SOA). Despite their importance, precise estimation of these emissions remains challenging, impeding the implementation of NMVOC controls. Here, we present the first comprehensive plant-level assessment of NMVOC emissions from the chemical industry in China, encompassing 3461 plants, 127 products, and 50 NMVOC compounds from 2010 to 2019. Our findings revealed that the chemical industry in China emitted a total of 3105 (interquartile range: 1179-8113) Gg of NMVOCs in 2019, with a few specific products accounting for the majority of the emissions. Generally, plants engaged in chemical fibers production or situated in eastern China pose a greater risk to public health due to their higher formation potentials of O 3 and SOA or their proximity to residential areas or both. We demonstrated that targeting these high-risk plants for emission reduction could enhance health benefits by 7-37% per unit of emission reduction on average compared to the current situation. Consequently, this study provides essential insights for developing effective plant-specific NMVOC control strategies within China's chemical industry.

Quantum spins, also known as spin operators that preserve SU(2) symmetry, lack a specific orientation in space and are hypothesized to display unique interactions with superconductivity. However, spin-orbit coupling and crystal field typically cause a significant magnetic anisotropy in d/f shell spins on surfaces. Here, we fabricate atomically precise S = 1/2 magnetic nanographenes on Pb(111) through engineering sublattice imbalance in the graphene honeycomb lattice. Through tuning the magnetic exchange strength between the unpaired spin and Cooper pairs, a quantum phase transition from the singlet to the doublet state has been observed, consistent with the quantum spin models. From our calculations, the particle-hole asymmetry is induced by the Coulomb scattering potential and gives a transition point about k B T k ≈ 1.6Δ. Our work demonstrates that delocalized π electron magnetism hosts highly tunable magnetic bound states, which can be further developed to study the Majorana bound states and other rich quantum phases of low-dimensional quantum spins on superconductors.

The iron and steel industry (ISI) is important for socio-economic progress but emits greenhouse gases and air pollutants detrimental to climate and human health. Understanding its historical emission trends and drivers is crucial for future warming and pollution interventions. Here, we offer an exhaustive analysis of global ISI emissions over the past 60 years, forecasting up to 2050. We evaluate emissions of carbon dioxide and conventional and unconventional air pollutants, including heavy metals and polychlorinated dibenzodioxins and dibenzofurans. Based on this newly established inventory, we dissect the determinants of past emission trends and future trajectories. Results show varied trends for different pollutants. Specifically, PM 2.5 emissions decreased consistently during the period 1970 to 2000, attributed to adoption of advanced production technologies. Conversely, NO x and SO 2 began declining recently due to stringent controls in major contributors such as China, a trend expected to persist. Currently, end-of-pipe abatement technologies are key to PM 2.5 reduction, whereas process modifications are central to CO 2 mitigation. Projections suggest that by 2050, developing nations (excluding China) will contribute 52-54% of global ISI PM 2.5 emissions, a rise from 29% in 2019. Long-term emission curtailment will necessitate the innovation and widespread adoption of new production and abatement technologies in emerging economies worldwide.

Despite intensive investigations on the droplet receding contact angle on superhydrophobic surfaces, i.e., a key parameter characterizing surface wettability and adhesion, the quantitative correlation between the surface structure mechanical properties (softness) and the droplet receding contact angles remains vague. By systematically varying the geometric dimensions and mechanical properties of soft pillar arrays, we find that the droplet receding contact angles decrease with the decrease in the pillar spring constant. Most surprisingly, the densely packed pillar arrays may result in larger receding contact angles than those on sparsely packed pillars, opposing the understanding of rigid pillar arrays, where the receding contact angles increase with a decrease in the packing density of pillars. This is attributed to the collective effects of capillarity and elasticity, where the energy consumed by the sliding contact line, the energy stored in the distorted liquid-vapor interface, and the energy stored in the deflected pillar contribute to the droplet depinning characteristics. We develop an analytical model to predict the droplet receding contact angles on soft superhydrophobic pillar arrays with knowledge of the material intrinsic receding contact angle, the pillar geometry, and the pillar mechanical properties. The predictions are corroborated by the experimental data measured in this and prior studies.

As the rate-limiting enzyme in de novo Glutathione (GSH) biosynthesis, the mammalian glutamate cysteine ligase (Gcl) catalytic (Gclc) and modifier (Gclm) subunits are regulated at multiple levels, whereas the function and regulatory mechanism of insect Gcl remain to be explored. In this study, we identified and characterized SfGclc and SfGclm in Spodoptera frugiperda . SfGclc and SfGclm were highly expressed in the hindgut and relatively less expressed in other tissues. The exposure of the third instar larvae to LC 30 of emamectin benzoate (EMB) significantly reduced the GSH content with a concomitant upregulation of SfGclc and SfGclm. Further in vivo pretreatment with L-BSO, the Gcl inhibitor, increased the susceptibility of S. frugiperda to EMB. Consistently, overexpression of SfGclc and SfGclm increased the Sf9 cell viability under EMB treatment. Finally, both RNAi and the dual-luciferase reporter assay in Sf9 cells revealed that SfGclc is regulated by transcription factor CncC. These data provide insights into the function and regulatory mechanism of insect Gcl, and they imply that disruption of the redox homeostasis might be a practical strategy to enhance the insecticidal activity of EMB and other insecticides.

The Ames test is a gold standard mutagenicity assay that utilizes various Salmonella typhimurium strains with and without S9 fraction to provide insights into the mechanisms by which a chemical can mutate DNA. Multitask deep learning is an ideal framework for developing QSAR models with multiple end points, such as the Ames test, as the joint training of multiple predictive tasks may synergistically improve the prediction accuracy of each task. This work investigated how toxicology domain knowledge can be used to handcraft task groupings that better guide the training of multitask neural networks compared to a naïve ungrouped multitask neural network developed on a complete set of tasks. Sixteen S. typhimurium ± S9 strain tasks were used to generate groupings based on mutagenic and metabolic mechanisms that were reflected in correlation data analyses. Both grouped and ungrouped multitask neural networks predicted the 16 strain tasks with a higher balanced accuracy compared with single task controls, with grouped multitask neural networks consistently featuring incremental increases in predictivity over the ungrouped approach. We conclude that the main variable driving these performance improvements is the general multitask effect with mechanistic task groupings acting as an enhancement step to further concentrate synergistic training signals united by a common biological mechanism. This approach enables incorporation of toxicology domain knowledge into multitask QSAR model development allowing for more transparent and accurate Ames mutagenicity prediction.

The prediction of Ames mutagenicity continues to be a concern in both regulatory and pharmacological toxicology. Traditional quantitative structure-activity relationship (QSAR) models of mutagenicity make predictions based on molecular descriptors calculated on a chemical data set used in their training. However, it is known that molecules such as aromatic amines can be non-mutagenic themselves but metabolically activated by S9 rodent liver enzyme in Ames tests forming molecules such as iminoquinones or amine substituents that better stabilize mutagenic nitrenium ions in known pathways of mutagenicity. Modern in silico modeling methods can implicitly model these metabolites through consideration of the structural elements relevant to their formation but do not include explicit modeling of these metabolites' potential activity. These metabolites do not have a known individual mutagenicity label and, in their current state, cannot be fitted into a traditional QSAR model. Multiple instance learning (MIL) however can be applied to a group of metabolites and their parent under a single mutagenicity label. Here we trained MIL models on Ames data, first with an aromatic amines data set ( n = 457), a class known to require metabolic activation, and subsequently on a larger data set ( n = 6505) incorporating multiple molecular species. MIL was shown to be able to predict Ames mutagenicity with performance in line with previously established models (balanced accuracy = 0.778), suggesting its potential utility in Ames prediction applications. Furthermore, the MIL model predicted well on identified hard-to-predict molecule groups relative to the models in which these molecule groups were identified. These results are presumably due to the increased consideration of the metabolic contribution to the mutagenic outcome. Further exploration of MIL as a supplement to existing models could aid in the prediction of chemicals where implicit modeling of metabolites cannot fully grasp their characteristics. This paper demonstrates the potential of an MIL approach to modeling Ames tests with S9 and is particularly relevant to metabolically activated xenobiotic mutagens.

PD-1/PD-L1 checkpoint blockade has demonstrated great success in cancer immunotherapy. Small-molecule PD-L1 inhibitors also attract significant research interests but remain challenging in the efficacy and safety. Carbohydrate moiety and carbohydrate-binding proteins (lectins) play important roles in immune modulation including antigen recognition and presenting. Herein, we reported a novel strategy to strengthen the immunotherapeutic effect of small-molecule PD-L1 inhibitors by introducing sugar motifs, which may utilize the carbohydrate-mediated immune enhancement for cancer treatment. The data revealed that glycoside compounds containing mannose or N -acetylglucosamine exhibited the best results in IFN-γ secretion. Moreover, compared to the nonglycosylated compounds, glycosides C3 and C15 demonstrated significant lower cytotoxicity and effective in vivo antitumor potency in the CT26 and melanoma B16-F10 tumor models with good tolerance. Notably, tumor-infiltrating lymphocyte (TIL) analysis validated increased CD3+, CD4+, CD8+, and granzyme B+ T cells after glycoside treatments. This work presents a new concept to improve the immunotherapy.

The emergence of quantum magnetism in nanographenes provides ample opportunities to fabricate purely organic devices for spintronics and quantum information. Although heteroatom doping is a viable way to engineer the electronic properties of nanographenes, the synthesis of doped nanographenes with collective quantum magnetism remains elusive. Here, a set of nitrogen-doped nanographenes (N-NGs) with atomic precision are fabricated on Au(111) through a combination of imidazole [2+2+2]-cyclotrimerization and cyclodehydrogenation reactions. High-resolution scanning probe microscopy measurements reveal the presence of collective quantum magnetism for nanographenes with three radicals, with spectroscopic features which cannot be captured by mean-field density functional theory calculations but can be well reproduced by Heisenberg spin model calculations. In addition, the mechanism of magnetic exchange interaction of N-NGs has been revealed and compared with their counterparts with pure hydrocarbons. Our findings demonstrate the bottom-up synthesis of atomically precise N-NGs which can be utilized to fabricate low-dimensional extended graphene nanostructures for realizing ordered quantum phases.

The mammalian heme oxygenase (HO) plays an important role in cytoprotection against oxidative-stress-induced cell damage; however, functional characterization of insect HO is still limited. In this study, cDNA encoding a HO, named SfHO , was cloned from Spodoptera frugiperda . Analysis of the transcription level and enzymatic activity showed that exposure of the LC 30 concentration of chlorantraniliprole to the third instar larvae significantly upregulated both the mRNA level and enzymatic activity of SfHO at 24 h after treatment. Further injection of the HO activator, hemin, into the third instar larvae led to the upregulation of SfHO as well as decreased susceptibility of S. frugiperda to chlorantraniliprole. Consistently, overexpression of SfHO increased the Sf9 cell viability under chlorantraniliprole treatment. Strikingly, both RNAi and the dual-luciferase reporter assay in Sf9 cells revealed that, unlike mammalian HO that is regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), SfHO was not subject to the regulation by cap 'n' collar isoform C (CncC), the Nrf2 homologue in insects. These data provide insights into the function and regulatory mechanism of insect HOs and had applied implications for the control of S. frugiperda .

Automation and efficiency requirements of environmental monitoring are the pursuit of spontaneous sampling and ultrasensitivity for current sensory systems or detection apparatuses. In this work, inspired by cactus hierarchical structures, we develop a cactus-inspired photonic crystal chip to integrate spontaneous droplet sampling and fluorescence enhancement for sensitive multi-analyte detection. A conical hydrophilic pattern on hydrophobic surfaces can give rise to unidirectional Laplace pressure, which drives droplet transport to the assigned photonic crystal site. The nanostructure of photonic crystals has bigger capillarity to drive the droplet wetting uniformly into the photonic crystal matrix while performing prominent fluorescence enhancement by their photonic bandgap. A low to attomolar (2.24 × 10 -19 M) fluorescence limit of detection (LOD) sensitivity can be achieved by the synergy of spontaneous droplet sampling and fluorescence enhancement. Focused on eutrophic water problems and algae pollution monitoring, a femtomolar (1.83 × 10 -15 M) LOD and identification of various microcystins in urban environmental water can be achieved. The suitable integration of the unidirectional droplet transport by Laplace pressure and fluorescence enhancement by photonic crystals can achieve the spontaneous sampling and signal enhancement for ultratrace detections and sample survey of environmental monitoring and disease diagnosis.

Nanomaterial is the Holy Grail of material science, which has been widely applied in the fields of energy, environment, chemistry, and biomedicine. Its catalytic merits were usually ascribed to the advantages of size effect, strain effect, and covalent effect. Noncovalent interactions are critical in the catalysis processes but often overlooked. Herein, different from the traditional understandings, we discover for the first time and give systematic insights into a unique noncovalent terminal σ-hole phenomenon in the 3 d- metal-based nanorods, which should be one of the key origins of nanomaterial activity. As a proof-of-concept, pure metal and alloyed core-shell nanoclusters/nanorods composed of the two most important 3 d metals (Co and Ni) growing from 0.5 to 2.5 nm are investigated. Unlike nanoclusters, the σ-hole only appears at the terminal sites of nanorods and the magnitude of the terminal σ-hole generally enhances with the growing processes. Further investigations show that this terminal σ-hole is closely related to the important physicochemical properties of nanorods. For example, the work function along the axis of the terminal σ-hole is smaller than other directions, contributing to the facile electronic transport along the axis of the terminal σ-hole. Most importantly, we find that the d -orbital center of the atoms around the terminal σ-hole shifts closer to the Fermi level as compared with other atoms, which can endow the terminal sites in nanorods with the higher chemical adsorption capability. We believe that this work will provide critical guidance for the rational design of nanomaterials in many potential applications.

The diffusion and mobility in biomembranes are crucial for various cell functions; however, the mechanisms involved in such processes remain ambiguous due to the complex membrane structures. Herein, we investigate how the heterogeneous nanostructures cause anomalous diffusion in dipalmitoylphosphatidylcholine (DPPC) monolayers. By identifying the existence of condensed nanodomains and clarifying their impact, our findings renew the understanding of the hydrodynamic description and the statistical feature of the diffusion in the monolayers. We find a universal characteristic of the multistage mean square displacement (MSD) with an intermediate crossover, signifying two membrane viscosities at different scales: the short-time scale describes the local fluidity and is independent of the nominal DPPC density, and the long-time scale represents the global continuous phase taking into account nanodomains and increases with DPPC density. The constant short-time viscosity reflects a dynamic equilibrium between the continuous fluid phase and the condensed nanodomains in the molecular scale. Notably, we observe an "anomalous yet Brownian" phenomenon exhibiting an unusual double-peaked displacement probability distribution (DPD), which is attributed to the net dipolar repulsive force from the heterogeneous nanodomains around the microdomains. The findings provide physical insights into the transport of membrane inclusions that underpin various biological functions and drug deliveries.

The metal-intercalated bilayer graphene has a flat band with a high density of states near the Fermi energy and thus is anticipated to exhibit an enhanced strong correlation effect and associated fascinating phenomena, including superconductivity. By using a self-developed multifunctional scanning tunneling microscope, we succeeded in observing the superconducting energy gap and diamagnetic response of a Ca-intercalated bilayer graphene below a critical temperature of 8.83 K. The revealed high value of gap ratio, 2Δ/ k B T c ≈ 5.0, indicates a strong coupling superconductivity, while the variation of penetration depth with temperature and magnetic field indicates an isotropic s -wave superconductor. These results provide crucial experimental clues for understanding the origin and mechanism of superconductivity in carrier-doped graphene.

Breaking time reversal symmetry in a topological insulator may lead to quantum anomalous Hall effect and axion insulator phase. MnBi 4 Te 7 is a recently discovered antiferromagnetic topological insulator with T N ∼ 12.5 K, which is composed of an alternatively stacked magnetic layer (MnBi 2 Te 4 ) and nonmagnetic layer (Bi 2 Te 3 ). By means of scanning tunneling spectroscopy, we clearly observe the electronic state present at a step edge of a magnetic MnBi 2 Te 4 layer but absent at nonmagnetic Bi 2 Te 3 layers at 4.5 K. Furthermore, we find that as the temperature rises above T N the edge state vanishes, while the point defect induced state persists upon an increase in temperature. These results confirm the observation of magnetism-induced edge states. Our analysis based on an axion insulator theory reveals that the nontrivial topological nature of the observed edge state.

Gram-negative bacteria, especially the ones with multidrug resistance, post dire challenges to antibiotic treatments due to the presence of the outer membrane (OM), which blocks the entry of many antibiotics. Current solutions for such permeability issues, namely lipophilic-cationic derivatization of antibiotics and sensitization with membrane-active agents, cannot effectively potentiate the large, globular, and hydrophilic antibiotics such as vancomycin, due to ineffective disruption of the OM. Here, we present our solution for high-degree OM binding of vancomycin via a hybrid "derivatization-for-sensitization" approach, which features a combination of LPS-targeting lipo-cationic modifications on vancomycin and OM disruption activity from a sensitizing adjuvant. 10 6 - to 10 7 -fold potentiation of vancomycin and 20-fold increase of the sensitizer's effectiveness were achieved with a combination of a vancomycin derivative and its sensitizer. Such potentiation is the result of direct membrane lysis through cooperative membrane binding for the sensitizer-antibiotic complex, which strongly promotes the uptake of vancomycin and adds to the extensive antiresistance effectiveness. The potential of such derivatization-for-sensitization approach was also supported by the combination's potent in vivo antimicrobial efficacy in mouse model studies, and the expanded application of such strategy on other antibiotics and sensitizer structures.

The neuropeptide relaxin-3/RXFP3 system is involved in many important physiological processes such as stress responses, appetite control, and motivation for reward. To date, pharmacological studies of RXFP3 have been limited to peptide ligands. In this study, we report the discovery of the first small-molecule antagonists of RXFP3 through a high-throughput screening campaign. Focused structure-activity relationship studies of the hit compound resulted in RLX-33 ( 33 ) that was able to inhibit relaxin-3 activity in a battery of functional assays. RLX-33 is selective for RXFP3 over RXFP1 and RXFP4, two related members in the relaxin/insulin superfamily, and has favorable pharmacokinetic properties for behavioral assessment. When administered to rats intraperitoneally, RLX-33 blocked food intake induced by the RXFP3-selective agonist R3/I5. Collectively, our findings demonstrated that RLX-33 represents a promising antagonist scaffold for the development of drugs targeting the relaxin-3/RXFP3 system.

The most essential issue facing the world today is the provision of energy and sustainable consumption of natural resources. Pretreatment is an essential step to produce biofuels from lignocellulosic biomass. In this study, ammonia fiber explosion (AFEX) combined with NaOH (A-NaOH) pretreatment effects on the characteristics of Pennisetum sinese (herbaceous), oak (hardwood), and camphor wood (softwood) were assessed using enzymatic efficiency analysis, thereby identifying the composition properties of subsequent bio-H 2 production. The results show that the lignin removal (84.2%, 59.7%, and 36.7%, respectively) at 5%A-NaOH conditions and enzymatic efficiency (36.2%, 9.7%, and 6.5%, respectively) of Pennisetum sinese ( P. sinese ), oak, and camphor wood were significantly increased under 4% A-NaOH conditions. Further A-NaOH pretreatment significantly promoted dark fermentation bio-H 2 production (152.3, 99.1, and 76.9 mL/g TS, respectively) and volatile acid production (4660.2, 3720.2, and 3496.2 mg/L, respectively) of P. sinese , oak, and camphor wood. These findings show that A-NaOH pretreatment is an effective means of utilization of lignocellulose resources., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Chilo suppressalis has developed high levels of resistance to abamectin in many areas of China, while the underline resistance mechanisms are largely unclear. ATP-binding cassette (ABC) transporters function in transporting a large diversity of substrates including insecticides and play important roles in the detoxification metabolism of insects. In this study, synergism bioassay revealed that the ABC transporters were involved in the detoxification of C. suppressalis to abamectin. Six ABC transporter genes were upregulated in C. suppressalis after abamectin exposure, among which five genes CsABCC8 , CsABCE1 , CsABCF1 , CsABCF2 , and CsABCH1 were induced in the detoxification-related tissues. In addition, the five ABC transporters were recombinantly expressed in Sf9 cells, and the cytotoxicity assay showed that the viabilities of cells expressing CsABCC8 or CsABCH1 were significantly increased when compared with the viabilities of cells expressing EGFP after abamectin, chlorantraniliprole, cyantraniliprole, fipronil, and chlorpyrifos treatment, respectively. Overexpression of CsABCE1 significantly increased the viabilities of cells to abamectin, chlorantraniliprole, deltamethrin, and indoxacarb exposure, respectively. These results suggested that CsABCC8, CsABCE1, and CsABCH1 might participate in the detoxification and transport of abamectin and several other classes of insecticides in C. suppressalis . Our study provides valuable insights into the transport-related detoxification mechanisms in C. suppressalis and other insects.

The triboelectric nanogenerator (TENG) has been invented as a technology for harvesting mechanical energy, as well as for allocating quantized charge for scientific instruments. The charge generation of the TENG is mainly related to the triboelectric effect or contact electrification (CE) as usually described by the potential-well-electron-cloud model, while the triboelectric charge transfer is related to the difference in the occupied energy levels of electrons. However, in our experiment, we observed an abnormal triboelectric charge generation phenomena between ternary materials, which cannot be explained by the occupied energy level difference only. To address this issue, we proposed the model based on the density of surface states (DOSS) as another key contributing factor to the triboelectric charge generation. To demonstrate our model, we introduced an approach to measure the DOSS through applying external electric field between two triboelectric surfaces. Our experiments confirmed the contribution of the DOSS to the triboelectric charge generation, with the derived charge density consistent with the measured results, which verified our model. We also predicted that the FEP has the potential to achieve a high charge density of ∼5.6 × 10 -4 C/m 2 , which is close to the reported maximum values. This study provides another key contributing factor to the triboelectric charge generation, which may provide a more complete model for guiding the material selection and modification to tailor the surface charge generated by the CE.

The central relaxin-3/RXFP3 system plays important roles in stress responses, feeding, and motivation for reward. However, exploration of its therapeutic applications has been hampered by the lack of small molecule ligands and the cross-activation of RXFP1 in the brain and RXFP4 in the periphery. Herein, we report the first structure-activity relationship studies of a series of novel nonpeptide amidinohydrazone-based agonists, which were characterized by RXFP3 functional and radioligand binding assays. Several potent and efficacious RXFP3 agonists (e.g., 10d ) were identified with EC 50 values <10 nM. These compounds also had high potency at RXFP4 but no agonist activity at RXFP1, demonstrating > 100-fold selectivity for RXFP3/4 over RXFP1. In vitro ADME and pharmacokinetic assessments revealed that the amidinohydrazone derivatives may have limited brain permeability. Collectively, our findings provide the basis for further optimization of lead compounds to develop a suitable agonist to probe RXFP3 functions in the brain.

Electrochemical CO 2 reduction (ECR) technology is promising to produce value-added chemicals and alleviate the climate deterioration. Interface engineering is demonstrated to improve the ECR performance for metal and oxide composite catalysts. However, the approach to form a substantial interface is still limited. In this work, we report a facile one-pot coprecipitation method to synthetize novel silver and silver-doped ceria (Ag/CeO 2 ) nanocomposites. This catalyst provides a rich 3D interface and high Ce 3+ concentration (33.6%), both of which are beneficial for ECR to CO. As a result, Ag/CeO 2 exhibits a 99% faradaic efficiency and 10.5 A g -1 mass activity to convert CO 2 into CO at an overpotential of 0.83 V. The strong interfacial interaction between Ag and CeO 2 may enable the presence of surface Ce 3+ and guarantee the improved durability during the electrolysis. We also develop numerical simulation to understand the local pH effect on the ECR performance and propose that the superior ECR performance of Ag/CeO 2 is mainly due to the accelerated CO formation rate rather than the suppressed hydrogen evolution reaction.

The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum , by targeting Pf ATP4, an essential ion pump on the parasite surface. The structure of Pf ATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of Pf ATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds. Competition participants could see all entries as they were submitted. In the final round, featuring private sector entrants specializing in machine learning methods, the best-performing models were used to predict novel inhibitors, of which several were synthesized and evaluated against the parasite. Half possessed biological activity, with one featuring a motif that the human chemists familiar with this series would have dismissed as "ill-advised". Since all data and participant interactions remain in the public domain, this research project "lives" and may be improved by others.

Metal halide perovskite quantum dots, with high light-absorption coefficients and tunable electronic properties, have been widely studied as optoelectronic materials, but their applications in photocatalysis are hindered by their insufficient stability because of the oxidation and agglomeration under light, heat, and atmospheric conditions. To address this challenge, herein, we encapsulated CsPbBr 3 nanocrystals into a stable iron-based metal-organic framework (MOF) with mesoporous cages (∼5.5 and 4.2 nm) via a sequential deposition route to obtain a perovskite-MOF composite material, CsPbBr 3 @PCN-333(Fe), in which CsPbBr 3 nanocrystals were stabilized from aggregation or leaching by the confinement effect of MOF cages. The monodispersed CsPbBr 3 nanocrystals (4-5 nm) within the MOF lattice were directly observed by transmission electron microscopy and corresponding mapping analysis and further confirmed by powder X-ray diffraction, infrared spectroscopy, and N 2 adsorption characterizations. Density functional theory calculations further suggested a significant interfacial charge transfer from CsPbBr 3 quantum dots to PCN-333(Fe), which is ideal for photocatalysis. The CsPbBr 3 @PCN-333(Fe) composite exhibited excellent and stable oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) catalytic activities in aprotic systems. Furthermore, CsPbBr 3 @PCN-333(Fe) composite worked as the synergistic photocathode in the photoassisted Li-O 2 battery, where CsPbBr 3 and PCN-333(Fe) acted as optical antennas and ORR/OER catalytic sites, respectively. The CsPbBr 3 @PCN-333(Fe) photocathode showed lower overpotential and better cycling stability compared to CsPbBr 3 nanocrystals or PCN-333(Fe), highlighting the synergy between CsPbBr 3 and PCN-333(Fe) in the composite.

Herein, we report the total and semisyntheses of a series of polymyxin analogues with 2-Thr and 10-Thr modifications to reveal the structure-activity relationship (SAR), which has not been fully elucidated previously. We employed two total-synthetic strategies to facilitate the diversified replacements on 2-Thr or 10-Thr, respectively. Moreover, semisynthetic approaches were utilized to achieve selective esterification of 2-Thr or dual esterification of both 2- and 10-Thr. Based on the results of in vitro antibacterial assays, SAR analysis implicated that the replacement of 2-/10-Thr with amino acids carrying hydrophobic side chains can maintain the activity against Pseudomonas aeruginosa but had varied effects on other tested Gram-negative bacteria. The aminoacetyl esterification on 2-/10-Thr achieved excellent antibacterial activity, and the compound 76 exhibited 2-8-fold higher activity against different strains and lower toxicity toward the HK-2 cell line. This work explored the SAR of polymyxin 2-/10-Thr and provided a promising strategy for the development of novel polymyxin derivatives.

The rapid development of the internet of things and autonomous vehicles requires plenty of sensors to monitor environmental conditions continuously. Hence, the high energy density and reliable power supply are demanded. The nonlinear oscillator has been widely utilized to enhance the output performance of piezoelectric and electromagnetic energy harvesters, which can operate in high-energy orbits under proper excitation frequencies. Here, the nonlinear oscillator-based triboelectric nanogenerator (NL-TENG) is proposed based on the grating structure. The mechanism to boost the output of the NL-TENG is analyzed and discussed with an electromechanical coupling model proposed, and the impacts of excitation frequency, external resistance, and spring stiffness were investigated. The peak power of the fabricated NL-TENG is 22 mW, which is 3 times enlarged compared to the traditional linear configuration. Furthermore, the stable and continuous power output of up to 244 W/m 3 is demonstrated, which can power a calculator and a large quantity of light-emitting diodes persistently. This study presents a new perspective to boost the output of the TENG by utilizing the benefits from the nonlinear oscillator.

The porphyrin macrocycle can stabilize a set of magnetic metal ions, thus introducing localized net spins near the center. However, it remains elusive but most desirable to introduce delocalized spins in porphyrins with wide implications, for example, for building correlated quantum spins. Here, we demonstrate that metal-free porphyrins host delocalized π-electron magnetism, as revealed by scanning probe microscopy and a different level of theory calculations. Our results demonstrate that engineering of π-electron topologies introduces a spin-polarized singlet state and delocalized net spins in metal-free porphyrins. In addition, the π-electron magnetism can be switched on/off via scanning tunneling microscope manipulation by tuning the interfacial charge transfer. Our results provide an effective way to precisely control the π-electron magnetism in metal-free porphyrins, which can be further extended to design new magnetic functionalities of porphyrin-based architectures.

While present international CO 2 mitigation agreements account for the impact of population composition and structure on emissions, the impact of international migration is overlooked. This study quantifies the CO 2 footprint of international immigrants and reveals their non-negligible impacts on global CO 2 emissions. Results show that the CO 2 footprint of international immigrants has increased from 1.8 gigatonnes (Gt) in 1995 to 2.9 Gt in 2015. In 2015, the U.S. had the largest total and per capita CO 2 emissions caused by international immigrants. Oceania and the Middle East are highlighted for their large portions of immigrant-caused CO 2 emissions in total CO 2 emissions (around 20%). Changes in the population and structure of global migration have kept increasing global CO 2 emissions during 1995-2015, while the reduction of CO 2 emission intensity helped offset global CO 2 emissions. The global CO 2 mitigation targets must consider the effects of global migration. Moreover, demand-side measures need to focus on major immigrant influx nations.

The quinoid structure, a resonance structure of benzenoid, gives rise to peculiar chemical reactivity and physical properties. A complete characterization of its geometric and electronic properties on the atomic scale is of vital importance to understand and engineer the chemical and physical properties of quinoid molecules. Here, we report a real-space structural and electronic characterization of quinoid poly( para -phenylene) (PPP) chains by using noncontact atomic force microscopy and scanning tunneling microscopy. Our results reveal that quinoid PPP chains adopt a coplanar adsorption configuration on Cu(111) and host in-gap states near Fermi level. In addition, intra- and interchain hopping of quinoid structure are observed, indicative of a quasiparticle behavior originating from charge-lattice interactions. The experimental results are nicely reproduced by tight-binding calculations. Our study provides a comprehensive understanding of the structural and electronic properties of quinoid PPP chains in real space and may be further extended to address the dynamics of nonlinear excitations in quinoid molecules.

With the development of the internet of things (IoT) and 5th generation communication technology, construction of smart cities is making a great progress. However, the IoT system needs millions of sensing nodes; therefore, it is rather challenging to power various sensors. Here, we design an electrostatic force-based switch (EFS) that can work as either an optical or an electrical switch. The EFS provides a method to directly detect or control high-voltage electrical systems with delay characteristics. Advantages of the EFS include self-contained delay characteristics, ease of fabrication, low cost, and high stability, especially when used in combination with the triboelectric nanogenerator (TENG) to realize self-powered sensors. Based on the self-powered sensor, a mechanical motion-sensing system is built with high sensitivity and active response to the mechanical trigger. This study proposes a multifunctional self-powered switch, which realizes a high-voltage delay control system and can also combine with the TENG to expand the application of self-powered smart sensing systems.

A two-dimensional topological insulator features (only) one bulk gap with nontrivial topology, which protects one-dimensional boundary states at the Fermi level. We find a quantum phase of matter beyond this category: a multiple topological insulator. It possesses a ladder of topological gaps; each gap protects a robust edge state. We prove a monolayer of van der Waals material PtBi 2 as a two-dimensional multiple topological insulator. By means of scanning tunneling spectroscopy, we directly visualize the one-dimensional hot electron (and hole) channels with nanometer size on the samples. Furthermore, we confirm the topological protection of these channels by directly demonstrating their robustness to variations of crystal orientation, edge geometry, and sample temperature. The discovered topological hot electron materials may be applied as efficient photocatalysts in the future.

Emeriones A-C (1-3), three highly methylated polyketides with bicyclo[4.2.0]octene and 3,6-dioxabicyclo[3.1.0]hexane functionalities, were isolated from Emericella nidulans. An additional peroxide bridge in compound 3 led to the construction of an unexpected 7,8-dioxatricyclo[4.2.2.0 2,5 ]decene scaffold. The structures of 1-3 were elucidated by comprehensive spectroscopic techniques, and their absolute configurations were confirmed by single-crystal X-ray crystallographic analyses and ECD calculations. Compound 1 shows weak inhibitory effects on NO production in LPS-induced RAW264.7 cells.

Carbon accounting results for the same city can differ due to differences in protocols, methods, and data sources. A critical review of these differences and the connection among them can help to bridge our knowledge between university-based researchers and protocol practitioners in accounting and taking further mitigation actions. The purpose of this study is to provide a review of published research and protocols related to city carbon accounting, paying attention to both their science and practical actions. To begin with, the most cited articles in this field are identified and analyzed by employing a citation network analysis to illustrate the development of city-level carbon accounting from three perspectives. We also reveal the relationship between research methods and accounting protocols. Furthermore, a timeline of relevant organizations, protocols, and projects is provided to demonstrate the applications of city carbon accounting in practice. The citation networks indicate that the field is dominated by pure-geographic production-based and community infrastructure-based accounting; however, emerging models that combine economic system analysis from a consumption-based perspective are leading to new trends in the field. The emissions accounted for by various research methods consist essentially of the scope 1-3, as defined in accounting protocols. The latest accounting protocols include consumption-based accounting, but most cities still limit their accounting and reporting from pure-geographic production-based and community infrastructure-based perspectives. In conclusion, we argue that protocol practitioners require support in conducting carbon accounting, so as to explore the potential in mitigation and adaptation from a number of perspectives. This should also be a priority for future studies.

Traditional processes usually cannot enable efficient water decontamination from toxic heavy metals complexed with organic ligands. Herein, we first reported the removal of Cu(II)-EDTA by a UV/chlorine process, where the Cu(II)-EDTA degradation obeyed autocatalytic two-stage kinetics, and Cu(II) was simultaneously removed as CuO precipitate. The scavenging experiments and EPR analysis indicated that Cl • accounted for the Cu(II)-EDTA degradation at diffusion-controlled rate (∼10 10 M -1 s -1 ). Mechanism study with mass spectrometry evidence of 11 key intermediates revealed that the Cu(II)-EDTA degradation by UV/chlorine was an autocatalytic successive decarboxylation process mediated by the Cu(II)/Cu(I) redox cycle. Under UV irradiation, Cu(I) was generated during the photolysis of the Cl • -attacked complexed Cu(II) via ligand-to-metal charge transfer (LMCT). Both free and organic ligand-complexed Cu(I) could form binary/ternary complexes with ClO - , which were oxidized back to Cu(II) via metal-to-ligand charge transfer (MLCT) with simultaneous production of Cl • , resulting in the autocatalytic effect on Cu(II)-EDTA removal. Effects of chlorine dosage and pH were examined, and the technological practicability was validated with authentic electroplating wastewater and other Cu(II)-organic complexes. This study shed light on a new mechanism of decomplexation by Cl • and broadened the applicability of the promising UV/chlorine process in water treatment.

Although PM 2.5 (particulate matter with aerodynamic diameters less than 2.5 μm) in the air originates from emissions, its concentrations are often affected by confounding meteorological effects. Therefore, direct comparisons of PM 2.5 concentrations made across two periods, which are commonly used by environmental protection administrations to measure the effectiveness of mitigation efforts, can be misleading. Here, we developed a two-step method to distinguish the significance of emissions and meteorological factors and assess the effectiveness of emission mitigation efforts. We modeled ambient PM 2.5 concentrations from 1980 to 2014 based on three conditional scenarios: realistic conditions, fixed emissions, and fixed meteorology. The differences found between the model outputs were analyzed to quantify the relative contributions of emissions and meteorological factors. Emission-related gridded PM 2.5 concentrations excluding the meteorological effects were predicted using multivariate regression models, whereas meteorological confounding effects on PM 2.5 fluctuations were characterized by probabilistic functions. When the regression models and probabilistic functions were combined, fluctuations in the PM 2.5 concentrations induced by emissions and meteorological factors were quantified for all model grid cells and regions. The method was then applied to assess the historical and future trends of PM 2.5 concentrations and potential fluctuations on global, national, and city scales. The proposed method may thus be used to assess the effectiveness of mitigation actions.