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Benefiting from high energy density of ultrahigh-nickel cathode materials and good safety of PEO-based electrolytes, PEO-based ultrahigh-nickel solid-state lithium batteries (SLMBs) are considered to be new-generation energy storage devices. However, the incompatibility of ultrahigh-nickel cathode materials and PEO-based electrolytes is the main challenge due to serious interfacial side reactions. Therefore, the modification of the cathode/electrolyte interface is crucial. Herein, the residual lithium on the surface of LiNi0.9Co0.06Mn0.04O2 is utilized to construct an interfacial coating layer by reacting with H3BO3. The in situ formed xLi2O-B2O3 coating layer (LBO1-NCM) with high ionic conductivity can be regulated with different crystal structures during the sintering process. Besides, an all-solid-state three-electrode cell is fabricated, which verifies that the xLi2O-B2O3 coating can effectively stabilize the interface. Astonishingly, uneven Li anode deposition is observed in SLMBs, which is caused by the breakage of PEO molecular chains due to the strong oxidation of the cathode, while this crosstalk is also suppressed by the xLi2O-B2O3 coating layer. Consequently, Li|PEO|LBO1-NCM achieves a substantially improved electrochemical performance, exhibiting 90.5% of capacity retention after 100 cycles for the coin cell and 80.3% of capacity retention after 200 cycles for the pouch cell. Apparently, the targeted modification of interfaces should be paid as much attention as electrolyte optimization in SLMBs.
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The matching of poly(ethylene oxide) (PEO)-based electrolytes with ultrahigh-nickel cathode materials is crucial for designing new-generation high-energy-density solid-state lithium metal batteries (SLMBs), but it is limited by serious interfacial side reactions between PEO and ultrahigh-nickel materials. Here, a high-concentration electrolyte (HCE) interface with a customized Li+ solvation sheath is constructed between the cathode and the electrolyte. It induces the formation of an anion-regulated robust cathode/electrolyte interface (CEI), reduces the unstable free-state solvent, and finally achieves the compatibility of PEO-based electrolytes with ultrahigh-nickel cathode materials. Meanwhile, the corrosion of the Al current collector caused by lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) ions is prevented by lithium difluoro(oxalato)borate (LiDFOB) ions. The synergistic effect of the double lithium salt is achieved by a well-tailored ratio of TFSI- and DFOB- in the first solvation sheath of Li+. Compared with reported PEO-based SLMBs matched with ultrahigh-nickel (Ni ≥ 90%) cathodes, the SLMB in this work delivers a high discharge specific capacity of 216.4 mAh g-1 (0.1C) even at room temperature. This work points out a direction to optimize the cathode/electrolyte interface.
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Because of the high specific capacity and low cost, Ni-rich layered oxide (NRLO) cathodes are one of the most promising cathode candidates for the next high-energy-density lithium-ion batteries. However, they face structure and interface instability challenges, especially the battery safety risk caused by using an intrinsic flammable organic liquid electrolyte. In this regard, a solid electrolyte with high safety is of great significance to promote the development of energy storage. Among them, sulfide electrolytes are considered to be the most potential substitutes for liquid electrolytes because of their high ionic conductivity and good processing properties. Nevertheless, the interfacial incompatibility between the sulfide electrolyte and NRLO cathode is the critical challenge for high-performance sulfide all-solid-state lithium batteries (ASSLBs). In this review, we summarize the problems of the Ni-rich cathode/sulfide solid electrolyte interface and the strategies to improve the interface stability. On the basis of these insights, we highlight the scientific problems and technological challenges that need to be resolved urgently and propose several potential directions to further improve the interface stability. The objective of this study is to provide a comprehensive understanding and insightful recommendations for the enhancement of the sulfide ASSLBs with NRLO cathode.
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Soluble N-glycosyltransferase from Actinobacillus pleuropneumoniae (ApNGT) catalyzes the glycosylation of asparagine residues, and represents one of the most encouraging biocatalysts for N-glycoprotein production. Since the sugar tolerance of ApNGT is restricted to limited monosaccharides (e.g., Glc, GlcN, Gal, Xyl, and Man), tremendous efforts are devoted to expanding the substrate scope of ApNGT via enzyme engineering. However, rational design of novel NGT variants suffers from an elusive understanding of the substrate-binding process from a dynamic point of view. Here, by employing extensive all-atom molecular dynamics (MD) simulations integrated with a kinetic model, we reveal, at the atomic level, the complete donor-substrate binding process from the bulk solvent to the ApNGT active-site, and the key intermediate states of UDP-Glc during its loading dynamics. We are able to determine the critical transition event that limits the overall binding rate, which guides us to pinpoint the key ApNGT residues dictating the donor-substrate entry. The functional roles of several identified gating residues were evaluated through site-directed mutagenesis and enzymatic assays. Two single-point mutations, N471A and S496A, could profoundly enhance the catalytic activity of ApNGT. Our work provides deep mechanistic insights into the structural dynamics of the donor-substrate loading process for ApNGT, which sets a rational basis for design of novel NGT variants with desired substrate specificity.
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Actinobacillus pleuropneumoniae , Glicosiltransferasas , Simulación de Dinámica Molecular , Actinobacillus pleuropneumoniae/enzimología , Actinobacillus pleuropneumoniae/metabolismo , Actinobacillus pleuropneumoniae/genética , Cinética , Especificidad por Sustrato , Glicosiltransferasas/metabolismo , Glicosiltransferasas/química , Glicosiltransferasas/genética , Mutagénesis Sitio-Dirigida , Dominio CatalíticoRESUMEN
Background: In China, mental health services do not currently meet the needs of bereaved people with symptoms of prolonged grief disorder (PGD). Internet-based grief interventions may help fill this gap, but such programmes have not yet been developed or evaluated in China. The proposed study aims to investigate the effectiveness, acceptability, and feasibility of an online self-help intervention programme named Healing Grief for bereaved Chinese with prolonged grief, and to explore the psychological mechanisms of potential improvements.Methods: We designed a two-arm randomised controlled trial. At least 128 participants will be randomly assigned to either an Internet-based intervention group or a waitlist-control group. The Internet-based intervention will be developed based on the dual process model, integrating techniques of psychoeducation, behavioural activation, cognitive reappraisal, and meaning reconstruction, and will be delivered via expressive writing. The intervention comprises six modules, with two sessions in each module, and requires participants to complete two sessions per week and complete the intervention in 6 weeks. The primary outcomes include effectiveness, acceptability, and feasibility. The effectiveness will be assessed by measures of prolonged grief, posttraumatic stress, anxiety, and depressive symptoms. Acceptability and feasibility will be evaluated using survey and interview on user experience characteristics. Secondary outcomes include moderators and mediators, such as dual process coping, grief rumination, mindfulness, and continuing bond, to explore the psychological mechanisms of potential improvement. Assessments will take place at pre-intervention, post-intervention, and 3-month follow-up.Conclusion: The proposed study will determine the effectiveness, acceptability, and feasibility of the newly developed online self-help intervention for bereaved Chinese with prolonged grief and clarify how the intervention helps with symptom improvements. Such an intervention may play an important role in easing the imbalance between the delivery and receipt of bereavement psychological services in China.
In China, mental health services are not widely available for bereaved people.The proposed study will be the first one to develop and evaluate an Internet-based self-help grief intervention for bereaved Chinese with prolonged grief.The proposed study will determine whether and how the intervention helps to improve the mental health of bereaved Chinese with prolonged grief.
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Aflicción , Terapia Cognitivo-Conductual , Intervención basada en la Internet , Humanos , Terapia Cognitivo-Conductual/métodos , Resultado del Tratamiento , Pesar , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Stroke stands as the second leading cause of death globally, surpassed only by ischemic heart disease. It accounts for 9% of total worldwide deaths. Given the swiftly evolving landscape, medical professionals and researchers are devoting increased attention to identifying more effective and safer treatments. Recent years have witnessed a focus on exosomes derived from mesenchymal stem cells cultivated under hypoxic conditions, referred to as Hypo-Exo. These specialized exosomes contain an abundance of components that facilitate the restoration of ischemic tissue, surpassing the content found in normal exosomes. Despite advancements, the precise role of Hypo-Exo in cases of cerebral ischemia remains enigmatic. Therefore, this study was designed to shed light on the potential efficacy of Hypo-Exo in stroke treatment. Our investigations unveiled promising outcomes, as the administration of Hypo-Exo led to improved behavioral deficits and reduced infarct areas in mice affected by ischemic conditions. Notably, these positive effects were hindered when Hypo-Exo loaded with anti-miR-214-3p were introduced, implying that the neuroprotective attributes of Hypo-Exo are reliant on miR-214-3p. This conclusion was substantiated by the high levels of miR-214-3p detected within Hypo-Exo. Furthermore, our examination of the ischemic penumbra zone revealed a gradual and sustained escalation in PTEN expression, a phenomenon effectively countered by Hypo-Exo treatment. Collectively, our findings suggest the existence of a regulatory pathway centered on miR-214-3p within Hypo-Exo. This pathway exerts a downregulating influence on the PTEN/Akt signaling pathway, thereby contributing to the amelioration of neurological function subsequent to ischemia-reperfusion events.
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Hemagglutinins (HAs) from human influenza viruses descend from avian progenitors that bind α2-3-linked sialosides and must adapt to glycans with α2-6-linked sialic acids on human airway cells to transmit within the human population. Since their introduction during the 1968 pandemic, H3N2 viruses have evolved over the past five decades to preferentially recognize human α2-6-sialoside receptors that are elongated through addition of poly-LacNAc. We show that more recent H3N2 viruses now make increasingly complex interactions with elongated receptors while continuously selecting for strains maintaining this phenotype. This change in receptor engagement is accompanied by an extension of the traditional receptor-binding site to include residues in key antigenic sites on the surface of HA trimers. These results help explain the propensity for selection of antigenic variants, leading to vaccine mismatching, when H3N2 viruses are propagated in chicken eggs or cells that do not contain such receptors.
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Subtipo H3N2 del Virus de la Influenza A , Gripe Humana , Animales , Humanos , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/metabolismo , Receptores Virales/química , Ácidos Siálicos/metabolismo , Polisacáridos/metabolismo , Pollos , Glicoproteínas Hemaglutininas del Virus de la InfluenzaRESUMEN
Implicit learning refers to the process of unconsciously learning complex knowledge through feedback. Previous studies investigated the influences of different types of feedback (e.g., social and non-social feedback) on implicit learning. This study focused on the social information presented in the learning situation and tried to explore the effects of different social feedback on implicit rule learning. We assigned participants randomly into an encouraging facial feedback group (happy expression for correct answer, neutral but not negative expression for incorrect answer) and a discouraging facial feedback group (neutral but not happy expression for correct answer, negative expression for incorrect answer). The implicit learning task included four difficulty levels, and social feedback was presented in the learning phase but not the testing phase in two experiments. The only difference between the two experiments was that the sad face used as negative feedback in Experiment 1 was replaced with an angry face in Experiment 2 to enhance the ecological validity of the discouraging facial feedback group. These two experiments yielded consistent results: the performances in the encouraging facial feedback group were more accurate in both the learning and the testing phases at all difficulty levels. These findings indicated that the influence of encouraging social feedback for a better implicit learning achievement was stable and established a new groundwork for future research on incentive-based education, making it critical to investigate the impact of various forms of encouraging-based education on learning.
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Lithium (Li) metal is regarded as a potential candidate for the next generation of lithium secondary batteries, but it has poor cycling stability with the broadly used carbonate-based electrolytes due to the uncontrollable dendritic growth and low Coulombic efficiency (CE). LiNO3 is an effective additive and its limited solubility (<800 ppm) in carbonate-based electrolytes is still a challenge, as reported. Herein, using BF3 (Lewis acid) is proposed to enhance the solubility of LiNO3 in carbonate-based electrolytes. The dissolved NO3 - can be involved in the first solvation shell of Li+, reducing the coordination number of PF6 - and EC (ethylene carbonate). In addition, the NO3 - is proved to be preferentially reduced on Li metal by differential electrochemical mass spectrometry so that the decomposition of PF6 - and EC is suppressed. Therefore, a SEI layer containing Li3N can be obtained, which exhibits high lithium-ion conductivity, achieving even and dense Li deposits. Consequently, the CE of Li||Cu cell with BF3/LiNO3 can be increased to 98.07%. Moreover, the capacity retention of Li||LiFePO4 with a low N/P ratio (3:1) is as high as 90% after 300 cycles (≈1500 h). This work paved a new way for incorporating LiNO3 into carbonate-based electrolytes and high-performance lithium metal batteries.
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Implicit learning refers to the fact that people acquire new knowledge (structures or rules) without conscious awareness. Previous studies have shown that implicit learning is affected by feedback. However, few studies have investigated the role of social feedback in implicit learning concretely. Here, we conducted two experiments to explore how in-group and out-group facial feedback impact different difficulty levels of implicit rule learning. In Experiment 1, the Chinese participants in each group could only see one type of facial feedback, i.e., either in-group (East Asian) or out-group (Western) faces, and learned the implicit rule through happy and sad facial expressions. The only difference between Experiment 2 and Experiment 1 was that the participants saw both the in-group and out-group faces before group assignment to strengthen the contrast between the two group identities. The results showed that only in Experiment 2 but not Experiment 1 was there a significant interaction effect in the accuracy of tasks between the difficulty levels and groups. For the lowest difficulty level, the learning accuracy of the in-group facial feedback group was significantly higher than that of the out-group facial feedback group, whereas this did not happen at the two highest levels of difficulty. In conclusion, when the contrast of group identities was highlighted, out-group feedback reduced the accuracy of the least difficult task; on the contrary, there was no accuracy difference between out-group and in-group feedback conditions. These findings have extensively important implications for our understanding of implicit learning and improving teaching achievement in the context of educational internationalization.
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BACKGROUND: Germinal matrix hemorrhage (GMH) is a devastating neonatal stroke, in which neuroinflammation is a critical pathological contributor. Slit2, a secreted extracellular matrix protein, plays a repulsive role in axon guidance and leukocyte chemotaxis via the roundabout1 (Robo1) receptor. This study aimed to explore effects of recombinant Slit2 on neuroinflammation and the underlying mechanism in a rat model of GMH. METHODS: GMH was induced by stereotactically infusing 0.3 U of bacterial collagenase into the germinal matrix of 7-day-old Sprague Dawley rats. Recombinant Slit2 or its vehicle was administered intranasally at 1 h after GMH and daily for 3 consecutive days. A decoy receptor recombinant Robo1 was co-administered with recombinant Slit2 after GMH. Slit2 siRNA, srGAP1 siRNA or the scrambled sequences were administered intracerebroventricularly 24 h before GMH. Neurobehavior, brain water content, Western blotting, immunofluorescence staining and Cdc42 activity assays were performed. RESULTS: The endogenous brain Slit2 and Robo1 expressions were increased after GMH. Robo1 was expressed on neuron, astrocytes and infiltrated peripheral immune cells in the brain. Endogenous Slit2 knockdown by Slit2 siRNA exacerbated brain edema and neurological deficits following GMH. Recombinant Slit2 (rSlit2) reduced neurological deficits, proinflammatory cytokines, intercellular adhesion molecules, peripheral immune cell markers, neuronal apoptosis and Cdc42 activity in the brain tissue after GMH. The anti-neuroinflammation effects were reversed by recombinant Robo1 co-administration or srGAP1 siRNA. CONCLUSIONS: Recombinant Slit2 reduced neuroinflammation and neuron apoptosis after GMH. Its anti-neuroinflammation effects by suppressing onCdc42-mediated brain peripheral immune cells infiltration was at least in part via Robo1-srGAP1 pathway. These results imply that recombinant Slit2 may have potentials as a therapeutic option for neonatal brain injuries.
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Proteínas del Tejido Nervioso , Transducción de Señal , Ratas , Animales , Ratas Sprague-Dawley , Proteínas del Tejido Nervioso/metabolismo , Enfermedades Neuroinflamatorias , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Encéfalo/metabolismo , Hemorragia Cerebral , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico , ARN Interferente Pequeño/farmacología , Proteínas Activadoras de GTPasa/metabolismoRESUMEN
The soluble N-glycosyltransferase from Actinobacillus pleuropneumoniae (ApNGT) can establish an N-glycosidic bond at the asparagine residue in the Asn-Xaa-Ser/Thr consensus sequon and is one of the most promising tools for N-glycoprotein production. Here, by integrating computational and experimental strategies, we revealed the molecular mechanism of the substrate recognition and following catalysis of ApNGT. These findings allowed us to pinpoint a key structural motif (215DVYM218) in ApNGT responsible for the peptide substrate recognition. Moreover, Y222 and H371 of ApNGT were found to participate in activating the acceptor Asn. The constructed models were supported by further crystallographic studies and the functional roles of the identified residues were validated by measuring the glycosylation activity of various mutants against a library of synthetic peptides. Intriguingly, with particular mutants, site-selective N-glycosylation of canonical or noncanonical sequons within natural polypeptides from the SARS-CoV-2 spike protein could be achieved, which were used to investigate the biological roles of the N-glycosylation in membrane fusion during virus entry. Our study thus provides in-depth molecular mechanisms underlying the substrate recognition and catalysis for ApNGT, leading to the synthesis of previously unknown chemically defined N-glycoproteins for exploring the biological importance of the N-glycosylation at a specific site.
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Ether-based electrolytes exhibit excellent performance when applied in different anode materials of sodium ion batteries (SIBs), but their exploration on cathode material is deficient and the degradation mechanism is still undiscovered. Herein, various battery systems with different operation voltage ranges are designed to explore the electrochemical performance of ether electrolyte. It is found for the first time that the deterioration mechanism of ether electrolyte is closely related to the "redox shuttle" between cathode and low-potential anode. The "shuttle" is discovered to occur when the potential of anodes is below 0.57 V, and the gas products coming from "shuttle" intermediates are revealed by differential electrochemical mass spectrometry (DEMS). Moreover, effective inhibition strategies by protecting low-potential anodes are proposed and verified; ethylene carbonate (EC) is found to be very effective as an additive by forming an inorganics-rich solid electrolyte interphase (SEI) on low-potential anodes, thereby suppressing the deterioration of ether electrolytes. This work reveals the failure mechanism of ether-based electrolytes applied in SIBs and proposes effective strategies to suppress the "shuttle," which provides a valuable guidance for advancing the application of ether-based electrolytes in SIBs.
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Malignant tumors are complex structures composed of cancer cells and tumor microenvironmental cells. In this complex structure, cells cross-talk and interact, thus jointly promoting cancer development and metastasis. Recently, immunoregulatory molecule-based cancer immunotherapy has greatly improved treatment efficacy for solid cancers, thus enabling some patients to achieve persistent responses or cure. However, owing to the development of drug-resistance and the low response rate, immunotherapy against the available targets PD-1/PD-L1 or CTLA-4 has limited benefits. Although combination therapies have been proposed to enhance the response rate, severe adverse effects are observed. Thus, alternative immune checkpoints must be identified. The SIGLECs are a family of immunoregulatory receptors (known as glyco-immune checkpoints) discovered in recent years. This review systematically describes the molecular characteristics of the SIGLECs, and discusses recent progress in areas including synthetic ligands, monoclonal antibody inhibitors, and Chimeric antigen receptor T (CAR-T) cells, with a focus on available strategies for blocking the sialylated glycan-SIGLEC axis. Targeting glyco-immune checkpoints can expand the scope of immune checkpoints and provide multiple options for new drug development.
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Neoplasias , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Humanos , Inmunoterapia , Neoplasias/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , PolisacáridosRESUMEN
Highly uniformly dense garnet type solid-state electrolyte plays a significant role in determining the performance of solid-state lithium batteries. Herein, a rational powder-covering sintering strategy is proposed and demonstrated, in which narrow-particle-size-distribution fine powder and uniform sintering temperature distribution are considered as very significant factors. It is suggested that powder materials with wider particle size distribution dramatically decrease the densified level of electrolytes. Slow temperature elevating rate and the overhead structure of bearing table are found to be beneficial to uniform densification. Moreover, the uniform densification process of sintering solid-state electrolyte is studied both microscopically and macroscopically, which can be divided into three phases according to the grain growing evolution and linear shrinkage patterns. The ionic conductivity of the as-prepared Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZTO) garnet electrolyte is determined to be 0.73 mS cm-1 at 303 K with an activation energy of 0.37 eV. The Li/LLZTO/Li symmetric cell exhibits a small interfacial impedance of 8.49 Ω cm2 and a high apparent critical current density of 2.15 mA cm-2 and also can be cycled for 1000 h continuously without short-circuit. Such results indicate the good feasibility of as-proposed sintering strategy to prepare uniformly dense garnet type solid-state electrolytes for solid-state lithium batteries.
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Whole -genome sequencing projects of millions of subjects contain enormous genotypes, entailing a huge memory burden and time for computation. Here, we present GBC, a toolkit for rapidly compressing large-scale genotypes into highly addressable byte-encoding blocks under an optimized parallel framework. We demonstrate that GBC is up to 1000 times faster than state-of-the-art methods to access and manage compressed large-scale genotypes while maintaining a competitive compression ratio. We also showed that conventional analysis would be substantially sped up if built on GBC to access genotypes of a large population. GBC's data structure and algorithms are valuable for accelerating large-scale genomic research.
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Compresión de Datos , Programas Informáticos , Humanos , Algoritmos , Genotipo , Compresión de Datos/métodos , Genómica/métodosRESUMEN
The Ni-rich layered cathode material LiNi0.8Co0.1Mn0.1O2 (NCM811) with high specific capacity and acceptable rate performance is one of the key cathode materials for high-energy-density lithium-ion batteries. Coprecipitation, the widely utilized method in the precursor synthesis of NCM811 materials, however, suffers long synthetic processes and challenges in uniform element distribution. The spray pyrolysis method is able to prepare oxide precursors in seconds where all transition-metal elements are well distributed, but the difficulty of lithium distribution will also arise when the lithium salts are added in the subsequent sintering process. Herein, a fresh one-step spray pyrolysis approach is proposed for preparing high-performance NCM811 cathode materials by synthesizing lithium-contained precursors in which all elements are well distributed at a molecular level. The precursors with folded morphology and exceptional uniformity are successfully obtained at a low pyrolysis temperature of 300 °C by an acetate system. Furthermore, the final products commendably inherit the folded morphology of the precursors and exhibit excellent cyclic retentions of 94.6% and 88.8% after 100 and 200 cycles at 1 C (1 C = 200 mA g-1), respectively.
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Nematodes are one of the largest groups of animals on the planet. Many of them are major pathogens of humans, animals and plants, and cause destructive diseases and socioeconomic losses worldwide. Despite their adverse impacts on human health and agriculture, nematodes can be challenging to control, because anthelmintic treatments do not prevent re-infection, and excessive treatment has led to widespread drug resistance in nematode populations. Indeed, many nematode species of livestock animals have become resistant to almost all classes of anthelmintics used. Most efforts to develop commercial anti-nematode vaccines (native or recombinant) for use in animals and humans have not succeeded, although one effective (dead) vaccine (Barbervax) has been developed to protect animals against one of the most pathogenic parasites of livestock animals - Haemonchus contortus (the barber's pole worm). This vaccine contains native molecules, called H11 and H-Gal-GP, derived from the intestine of this blood-feeding worm. In its native form, H11 alone consistently induces high levels (75-95%) of immunoprotection in animals against disease (haemonchosis), but recombinant forms thereof do not. Here, to test the hypothesis that post-translational modification (glycosylation) of H11 plays a crucial role in achieving such high immunoprotection, we explored the N-glycoproteome and N-glycome of H11 using the high-resolution mass spectrometry and assessed the roles of N-glycosylation in protective immunity against H. contortus. Our results showed conclusively that N-glycan moieties on H11 are the dominant immunogens, which induce high IgG serum antibody levels in immunised animals, and that anti-H11 IgG antibodies can confer specific, passive immunity in naïve animals. This work provides the first detailed account of the relevance and role of protein glycosylation in protective immunity against a parasitic nematode, with important implications for the design of vaccines against metazoan parasites.
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Antihelmínticos , Hemoncosis , Haemonchus , Vacunas , Humanos , Animales , Hemoncosis/prevención & control , Polisacáridos , Inmunoglobulina GRESUMEN
Long-term exposure to low polycyclic aromatic hydrocarbon (PAH) concentration may ave detrimental effects, including changing platelet indices. Effects of chronic exposure to low PAH concentrations have been evaluated in cross-sectional, but not in longitudinal studies, to date. We aimed to assess the effects of long-term exposure to the low-concentration PAHs on alterations in platelet indices in the Chinese population. During 2014-2017, we enrolled 222 participants who had lived in a village in northern China, 1-2 km downwind from a coal plant, for more than 25 years, but who were not employed by the plant or related businesses. During three follow-ups, annually in June, demographic information and urine and blood samples were collected. Eight PAHs were tested: namely 2-hydroxynaphthalene, 1-hydroxynaphthalene, 2-hydroxyfluorene, 9-hydroxyfluorene (9-OHFlu), 2-hydroxyphenanthrene (2-OHPh), 1-hydroxyphenanthrene (1-OHPh), 1-hydroxypyrene (1-OHP), and 3-hydroxybenzo [a] pyrene. Five platelet indices were measured: platelet count (PLT), platelet distribution width (PDW), mean platelet volume (MPV), platelet crit, and the platelet-large cell ratio. Generalized mixed and generalized linear mixed models were used to estimate correlations between eight urinary PAH metabolites and platelet indices. Model 1 assessed whether these correlations varied over time. Models 2 and 3 adjusted for additional personal information and personal habits. We found the following significant correlations: 2-OHPh (Model1 ß1 = 18.06, Model2 ß2 = 18.54, Model ß3 = 18.54), 1-OHPh (ß1 = 16.43, ß2 = 17.42, ß3 = 17.42), 1-OHP(ß1 = 13.93, ß2 = 14.03, ß3 = 14.03) with PLT, as well as 9-OHFlu with PDW and MPV (odds ratio or Model3 ORPDW[95%CI] = 1.64[1.3-2.06], ORMPV[95%CI] = 1.33[1.19-1.48]). Long-term exposure to low concentrations of PAHs, indicated by2-OHPh, 1-OHPh, 1-OHP, and 9-OHFlu, as urinary biomarkers, affects PLT, PDW, and MPV. 9-OHFlu increased both PDW and MPV after elimination of the effects of other PAH exposure modes.
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Hidrocarburos Policíclicos Aromáticos , Humanos , Hidrocarburos Policíclicos Aromáticos/metabolismo , Estudios Longitudinales , Estudios Transversales , Biomarcadores/orina , Volúmen Plaquetario MedioRESUMEN
The spike protein on sarbecovirus virions contains two external, protruding domains: an N-terminal domain (NTD) with unclear function and a C-terminal domain (CTD) that binds the host receptor, allowing for viral entry and infection. While the CTD is well studied for therapeutic interventions, the role of the NTD is far less well understood for many coronaviruses. Here, we demonstrate that the spike NTD from SARS-CoV-2 and other sarbecoviruses binds to unidentified glycans in vitro similarly to other members of the Coronaviridae family. We also show that these spike NTD (S-NTD) proteins adhere to Calu3 cells, a human lung cell line, although the biological relevance of this is unclear. In contrast to what has been shown for Middle East respiratory syndrome coronavirus (MERS-CoV), which attaches sialic acids during cell entry, sialic acids present on Calu3 cells inhibited sarbecovirus infection. Therefore, while sarbecoviruses can interact with cell surface glycans similarly to other coronaviruses, their reliance on glycans for entry is different from that of other respiratory coronaviruses, suggesting sarbecoviruses and MERS-CoV have adapted to different cell types, tissues, or hosts during their divergent evolution. Our findings provide important clues for further exploring the biological functions of sarbecovirus glycan binding and adds to our growing understanding of the complex forces that shape coronavirus spike evolution. IMPORTANCE Spike N-terminal domains (S-NTD) of sarbecoviruses are highly diverse; however, their function remains largely understudied compared with the receptor-binding domains (RBD). Here, we show that sarbecovirus S-NTD can be phylogenetically clustered into five clades and exhibit various levels of glycan binding in vitro. We also show that, unlike some coronaviruses, including MERS-CoV, sialic acids present on the surface of Calu3, a human lung cell culture, inhibit SARS-CoV-2 and other sarbecoviruses. These results suggest that while glycan binding might be an ancestral trait conserved across different coronavirus families, the functional outcome during infection can vary, reflecting divergent viral evolution. Our results expand our knowledge on the biological functions of the S-NTD across diverse sarbecoviruses and provide insight on the evolutionary history of coronavirus spike.