Infection with wild-type SARS-CoV-2 elicits broadly neutralizing and protective antibodies against omicron subvariants.

The omicron variants of SARS-CoV-2 have substantial ability to escape infection- and vaccine-elicited antibody immunity. Here, we investigated the extent of such escape in nine convalescent patients infected with the wild-type SARS-CoV-2 during the first wave of the pandemic. Among the total of 476 monoclonal antibodies (mAbs) isolated from peripheral memory B cells, we identified seven mAbs with broad neutralizing activity to all variants tested, including various omicron subvariants. Biochemical and structural analysis indicated the majority of these mAbs bound to the receptor-binding domain, mimicked the receptor ACE2 and were able to accommodate or inadvertently improve recognition of omicron substitutions. Passive delivery of representative antibodies protected K18-hACE2 mice from infection with omicron and beta SARS-CoV-2. A deeper understanding of how the memory B cells that produce these antibodies could be selectively boosted or recalled can augment antibody immunity against SARS-CoV-2 variants.

The humoral response and antibodies against SARS-CoV-2 infection.

Two and a half years into the COVID-19 pandemic, we have gained many insights into the human antibody response to the causative SARS-CoV-2 virus. In this Review, we summarize key observations of humoral immune responses in people with COVID-19, discuss key features of infection- and vaccine-induced neutralizing antibodies, and consider vaccine designs for inducing antibodies that are broadly protective against different variants of the SARS-CoV-2 virus.

Dissecting the intricacies of human antibody responses to SARS-CoV-1 and SARS-CoV-2 infection.

The 2003 severe acute respiratory syndrome coronavirus (SARS-CoV-1) causes more severe disease than SARS-CoV-2, which is responsible for COVID-19. However, our understanding of antibody response to SARS-CoV-1 infection remains incomplete. Herein, we studied the antibody responses in 25 SARS-CoV-1 convalescent patients. Plasma neutralization was higher and lasted longer in SARS-CoV-1 patients than in severe SARS-CoV-2 patients. Among 77 monoclonal antibodies (mAbs) isolated, 60 targeted the receptor-binding domain (RBD) and formed 7 groups (RBD-1 to RBD-7) based on their distinct binding and structural profiles. Notably, RBD-7 antibodies bound to a unique RBD region interfaced with the N-terminal domain of the neighboring protomer (NTD proximal) and were more prevalent in SARS-CoV-1 patients. Broadly neutralizing antibodies for SARS-CoV-1, SARS-CoV-2, and bat and pangolin coronaviruses were also identified. These results provide further insights into the antibody response to SARS-CoV-1 and inform the design of more effective strategies against diverse human and animal coronaviruses.

Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93.

The interleukin (IL)-17 family, consisting of six members, promotes host defense but can in some context promote the development of autoimmune disease. Here, we examined the role of IL-17D, a poorly understood member in the IL-17 family. IL-17D was expressed primarily by colonic epithelial cells. Il17d-/- mice were more susceptible to acute colitis, bacterial infection and experimentally induced colon cancer than their wildtype counterparts. Il17d deficiency impaired IL-22 production by group 3 innate lymphoid cells (ILC3s) and reduced expression of IL-22-dependent antimicrobial peptides, RegIIIß and RegIIIγ, in colon tissue at steady state and in colitis; this was associated with changes in microbial composition and dysbiosis. Protein purification studies revealed that IL-17D bound not canonical IL-17 receptors, but rather CD93, a glycoprotein expressed on mature ILC3s. Mice lacking Cd93 in ILC3s exhibited impaired IL-22 production and aggravated colonic inflammation in experimental colitis. Thus, an IL-17D-CD93 axis regulates ILC3 function to preserve intestinal homeostasis.

Analysis of SARS-CoV-2 variant mutations reveals neutralization escape mechanisms and the ability to use ACE2 receptors from additional species.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge during the global pandemic and may facilitate escape from current antibody therapies and vaccine protection. Here we showed that the South African variant B.1.351 was the most resistant to current monoclonal antibodies and convalescent plasma from coronavirus disease 2019 (COVID-19)-infected individuals, followed by the Brazilian variant P.1 and the United Kingdom variant B.1.1.7. This resistance hierarchy corresponded with Y144del and 242-244del mutations in the N-terminal domain and K417N/T, E484K, and N501Y mutations in the receptor-binding domain (RBD) of SARS-CoV-2. Crystal structure analysis of the B.1.351 triple mutant (417N-484K-501Y) RBD complexed with the monoclonal antibody P2C-1F11 revealed the molecular basis for antibody neutralization and escape. B.1.351 and P.1 also acquired the ability to use mouse and mink ACE2 receptors for entry. Our results demonstrate major antigenic shifts and potential broadening of the host range for B.1.351 and P.1 variants, which poses serious challenges to current antibody therapies and vaccine protection.

Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals.

The World Health Organization has declared SARS-CoV-2 virus outbreak a worldwide pandemic. However, there is very limited understanding on the immune responses, especially adaptive immune responses to SARS-CoV-2 infection. Here, we collected blood from COVID-19 patients who have recently become virus-free, and therefore were discharged, and detected SARS-CoV-2-specific humoral and cellular immunity in eight newly discharged patients. Follow-up analysis on another cohort of six patients 2 weeks post discharge also revealed high titers of immunoglobulin G (IgG) antibodies. In all 14 patients tested, 13 displayed serum-neutralizing activities in a pseudotype entry assay. Notably, there was a strong correlation between neutralization antibody titers and the numbers of virus-specific T cells. Our work provides a basis for further analysis of protective immunity to SARS-CoV-2, and understanding the pathogenesis of COVID-19, especially in the severe cases. It also has implications in developing an effective vaccine to SARS-CoV-2 infection.

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.

A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide and to other countries around the world1-3. Here, to better understand the initial step of infection at an atomic level, we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural analysis identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1-3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analysed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.

Human neutralizing antibodies elicited by SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global health emergency that is in urgent need of intervention1-3. The entry of SARS-CoV-2 into its target cells depends on binding between the receptor-binding domain (RBD) of the viral spike protein and its cellular receptor, angiotensin-converting enzyme 2 (ACE2)2,4-6. Here we report the isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells from 8 individuals infected with SARS-CoV-2. We identified antibodies that potently neutralize SARS-CoV-2; this activity correlates with competition with ACE2 for binding to RBD. Unexpectedly, the anti-SARS-CoV-2 antibodies and the infected plasma did not cross-react with the RBDs of SARS-CoV or Middle East respiratory syndrome-related coronavirus (MERS-CoV), although there was substantial plasma cross-reactivity to their trimeric spike proteins. Analysis of the crystal structure of RBD-bound antibody revealed that steric hindrance inhibits viral engagement with ACE2, thereby blocking viral entry. These findings suggest that anti-RBD antibodies are largely viral-species-specific inhibitors. The antibodies identified here may be candidates for development of clinical interventions against SARS-CoV-2.

Structural determinants of spike infectivity in bat SARS-like coronaviruses RsSHC014 and WIV1.

The recurrent spillovers of coronaviruses (CoVs) have posed severe threats to public health and the global economy. Bat severe acute respiratory syndrome (SARS)-like CoVs RsSHC014 and WIV1, currently circulating in bat populations, are poised for human emergence. The trimeric spike (S) glycoprotein, responsible for receptor recognition and membrane fusion, plays a critical role in cross-species transmission and infection. Here, we determined the cryo-electron microscopy (EM) structures of the RsSHC014 S protein in the closed state at 2.9 Å, the WIV1 S protein in the closed state at 2.8 Å, and the intermediate state at 4.0 Å. In the intermediate state, one receptor-binding domain (RBD) is in the "down" position, while the other two RBDs exhibit poor density. We also resolved the complex structure of the WIV1 S protein bound to human ACE2 (hACE2) at 4.5 Å, which provides structural basis for the future emergence of WIV1 in humans. Through biochemical experiments, we found that despite strong binding affinities between the RBDs and both human and civet ACE2, the pseudoviruses of RsSHC014, but not WIV1, failed to infect 293T cells overexpressing either human or civet ACE2. Mutagenesis analysis revealed that the Y623H substitution, located in the SD2 region, significantly improved the cell entry efficiency of RsSHC014 pseudoviruses, which is likely accomplished by promoting the open conformation of spike glycoproteins. Our findings emphasize the necessity of both efficient RBD lifting and tight RBD-hACE2 binding for viral infection and underscore the significance of the 623 site of the spike glycoprotein for the infectivity of bat SARS-like CoVs. IMPORTANCE: The bat SARS-like CoVs RsSHC014 and WIV1 can use hACE2 for cell entry without further adaptation, indicating their potential risk of emergence in human populations. The S glycoprotein, responsible for receptor recognition and membrane fusion, plays a crucial role in cross-species transmission and infection. In this study, we determined the cryo-EM structures of the S glycoproteins of RsSHC014 and WIV1. Detailed comparisons revealed dynamic structural variations within spike proteins. We also elucidated the complex structure of WIV1 S-hACE2, providing structural evidence for the potential emergence of WIV1 in humans. Although RsSHC014 and WIV1 had similar hACE2-binding affinities, they exhibited distinct pseudovirus cell entry behavior. Through mutagenesis and cryo-EM analysis, we revealed that besides the structural variations, the 623 site in the SD2 region is another important structural determinant of spike infectivity.

Integrated QuEChERS combined with LC-MS/MS for high-throughput analysis of per- and polyfluoroalkyl substances in milk.

In this study, an integrated QuEChERS method was developed for the rapid determination of 22 per- and polyfluoroalkyl substances (PFASs) in milk by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The extraction and purification processes were combined into one step with this method. Meanwhile, the solid-liquid separation was carried out by magnetic suction (Fe3O4-SiO2) instead of the centrifugal process. The primary experimental parameters were optimized, including the type of extraction solvent, the amounts of magnetic nanomaterials (Fe3O4-SiO2), and the purification materials (ZrO2 and C18). The developed method exhibits high precision (RSDs < 9.9%), low limits of detection (0.004-0.079 µg/kg) and limits of quantitation (0.01-0.26 µg/kg), and acceptable recovery (71.7-116%) under optimized conditions. The developed integrated QuEChERS method had clear superiority in terms of sample pretreatment time, operating procedures, reagent amount, and recovery. This makes it an excellent alternative analytical technique for PFAS residue measurement at low micrograms-per-kilogram ranges with desirable sensitivity.

Native T1-mapping as a predictor of progressive renal function decline in chronic kidney disease patients.

BACKGROUND: To investigate the potential of Native T1-mapping in predicting the prognosis of patients with chronic kidney disease (CKD). METHODS: We enrolled 119 CKD patients as the study subjects and included 20 healthy volunteers as the control group, with follow-up extending until October 2022. Out of these patients, 63 underwent kidney biopsy measurements, and these patients were categorized into high (25-50%), low (< 25%), and no renal interstitial fibrosis (IF) (0%) groups. The study's endpoint event was the initiation of renal replacement therapy, kidney transplantation, or an increase of over 30% in serum creatinine levels. Cox regression analysis determined factors influencing unfavorable kidney outcomes. We employed Kaplan-Meier analysis to contrast kidney survival rates between the high and low T1 groups. Additionally, receiver-operating characteristic (ROC) curve analysis assessed the predictive accuracy of Native T1-mapping for kidney endpoint events. RESULTS: T1 values across varying fibrosis degree groups showed statistical significance (F = 4.772, P < 0.05). Multivariate Cox regression pinpointed 24-h urine protein, cystatin C(CysC), hemoglobin(Hb), and T1 as factors tied to the emergence of kidney endpoint events. Kaplan-Meier survival analysis revealed a markedly higher likelihood of kidney endpoint events in the high T1 group compared to the low T1 value group (P < 0.001). The ROC curves for variables (CysC, T1, Hb) tied to kidney endpoint events demonstrated area under the curves(AUCs) of 0.83 (95%CI: 0.75-0.91) for CysC, 0.77 (95%CI: 0.68-0.86) for T1, and 0.73 (95%CI: 0.63-0.83) for Hb. Combining these variables elevated the AUC to 0.88 (95%CI: 0.81-0.94). CONCLUSION: Native T1-mapping holds promise in facilitating more precise and earlier detection of CKD patients most at risk for end-stage renal disease.

Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2.

The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs-including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria-could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.

Study on the enantioselective behaviors, activity, toxicity and mechanism of novel SDHI fungicide benzovindiflupyr to reduce the environmental risks.

Benzovindiflupyr (BEN) has emerged as one of the fastest-growing SDHI fungicides in recent years, but it is considered "very highly toxic" to aquatic fish, invertebrates and crustaceans (EC50 or LC50, 0.0035-0.056 mg/L, acute toxicity). The comprehensive study on bioactivity, toxicity, and degradation behaviors of BEN at the enantiomeric level would facilitate the development of a high-efficiency and low-risk application method. The bioactivities of 1S, 4R-(-)-BEN against five target pathogens (Alternaria alternata, Phoma multirostrata, Selerotium rolfsii, Magnaporthe oryzae, and Rhizoctonia solani) (EC50, 0.00562-0.329 mg/L, high-efficiency) were 6.7-1029 times higher than 1R, 4S-(+)-BEN, demonstrating significant enantioselectivity. For Danio rerio, 1S, 4R-(-)-BEN (LC50, 0.0360 mg/L, "very highly toxic") exhibited higher toxicity than 1 R, 4S-(+)-BEN, but the toxic interaction was concentration addition (TUrac, 0.94), indicating an enhanced toxicity in the presence of 1R, 4S-(+)-BEN. Molecular docking was employed to offer insights at the molecular level and elucidate the factors influencing enantioselectivity. The stronger binding affinity of 1S, 4R-(-)-BEN with SDH was in line with the quantitative experimental findings. The degradation of two BEN enantiomers in four different fruits followed the first-order degradation kinetics equation, and displayed enantioselectivity. The preferential degradation of 1R, 4S-(+)-BEN was found in pears and grapes, while varying enantioselectivity was found at different stages in tomatoes and watermelons. The residual concentrations of BEN in grapes were higher than the EU's MRL, which in the other three fruits were below the MRLs during the sampling. In conclusion, 1S, 4R-(-)-BEN proved to be the more effective monomer. Utilizing the pure monomer could not only reduce the dosage of racemate by about 44-59 %, but also mitigate the risk of introducing inefficient monomer into the environment (especially for fish).

Susceptibilities of Human ACE2 Genetic Variants in Coronavirus Infection.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 235 million cases worldwide and 4.8 million deaths (October 2021), with various incidences and mortalities among regions/ethnicities. The coronaviruses SARS-CoV, SARS-CoV-2, and HCoV-NL63 utilize the angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells. We hypothesized that the genetic variability in ACE2 may contribute to the variable clinical outcomes of COVID-19. To test this hypothesis, we first conducted an in silico investigation of single-nucleotide polymorphisms (SNPs) in the coding region of ACE2. We then applied an integrated approach of genetics, biochemistry, and virology to explore the capacity of select ACE2 variants to bind coronavirus spike proteins and mediate viral entry. We identified the ACE2 D355N variant that restricts the spike protein-ACE2 interaction and consequently limits infection both in vitro and in vivo. In conclusion, ACE2 polymorphisms could modulate susceptibility to SARS-CoV-2, which may lead to variable disease severity. IMPORTANCE There is considerable variation in disease severity among patients infected with SARS-CoV-2, the virus that causes COVID-19. Human genetic variation can affect disease outcome, and the coronaviruses SARS-CoV, SARS-CoV-2, and HCoV-NL63 utilize human ACE2 as the receptor to enter cells. We found that several missense ACE2 single-nucleotide variants (SNVs) that showed significantly altered binding with the spike proteins of SARS-CoV, SARS-CoV-2, and NL63-HCoV. We identified an ACE2 SNP, D355N, that restricts the spike protein-ACE2 interaction and consequently has the potential to protect individuals against SARS-CoV-2 infection. Our study highlights that ACE2 polymorphisms could impact human susceptibility to SARS-CoV-2, which may contribute to ethnic and geographical differences in SARS-CoV-2 spread and pathogenicity.

Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption.

COVID-19 patients transmitted SARS-CoV-2 to minks in the Netherlands in April 2020. Subsequently, the mink-associated virus (miSARS-CoV-2) spilled back over into humans. Genetic sequences of the miSARS-CoV-2 identified a new genetic variant known as "Cluster 5" that contained mutations in the spike protein. However, the functional properties of these "Cluster 5" mutations have not been well established. In this study, we found that the Y453F mutation located in the RBD domain of miSARS-CoV-2 is an adaptive mutation that enhances binding to mink ACE2 and other orthologs of Mustela species without compromising, and even enhancing, its ability to utilize human ACE2 as a receptor for entry. Structural analysis suggested that despite the similarity in the overall binding mode of SARS-CoV-2 RBD to human and mink ACE2, Y34 of mink ACE2 was better suited to interact with a Phe rather than a Tyr at position 453 of the viral RBD due to less steric clash and tighter hydrophobic-driven interaction. Additionally, the Y453F spike exhibited resistance to convalescent serum, posing a risk for vaccine development. Thus, our study suggests that since the initial transmission from humans, SARS-CoV-2 evolved to adapt to the mink host, leading to widespread circulation among minks while still retaining its ability to efficiently utilize human ACE2 for entry, thus allowing for transmission of the miSARS-CoV-2 back into humans. These findings underscore the importance of active surveillance of SARS-CoV-2 evolution in Mustela species and other susceptible hosts in order to prevent future outbreaks.

Comparative analysis reveals the species-specific genetic determinants of ACE2 required for SARS-CoV-2 entry.

Coronavirus interaction with its viral receptor is a primary genetic determinant of host range and tissue tropism. SARS-CoV-2 utilizes ACE2 as the receptor to enter host cell in a species-specific manner. We and others have previously shown that ACE2 orthologs from New World monkey, koala and mouse cannot interact with SARS-CoV-2 to mediate viral entry, and this defect can be restored by humanization of the restrictive residues in New World monkey ACE2. To better understand the genetic determinants behind the ability of ACE2 orthologs to support viral entry, we compared koala and mouse ACE2 sequences with that of human and identified the key residues in koala and mouse ACE2 that restrict viral receptor activity. Humanization of these critical residues rendered both koala and mouse ACE2 capable of binding the spike protein and facilitating viral entry. Our study shed more lights into the genetic determinants of ACE2 as the functional receptor of SARS-CoV-2, which facilitates our understanding of viral entry.

Effect of Intensive Lipid-Lowering Therapy on Coronary Plaque Stabilization Derived from Optical Coherence Tomography: a Meta-analysis and Meta-regression.

PURPOSE: The definitive impacts of intensive lipid-lowering therapy (LLT) on plaque stabilization and the relationship between the key markers during LLT and plaque stability remain unquestioned. Thus, these meta-analysis and meta-regression intend to holistically evaluate the influence exerted by rigorous LLT on the minimum fibrous cap thickness (FCT) and maximum lipid arc as discerned through optical coherence tomography (OCT). This study further scrutinizes the correlation of this impact with variations in high-sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), or additional parameters within patients diagnosed with coronary artery disease (CAD). METHODS: Comprehensive searches were conducted on platforms including PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) published until June 1, 2023. The search was language agnostic and targeted RCTs elaborating on the correlation between high-intensity statin therapy or statins used concomitantly with other lipid-lowering medications and the minimum FCT and maximum lipid arc as assessed by OCT. The meta-analyses were executed employing a standard mean difference (SMD) algorithm with random-effects on continuous variables. These methodologies align with the Preferred Reporting Items for Systematic and Meta-analysis (PRISMA) guidelines. RESULTS: A spectrum of 12 RCTs engaging 972 patients were identified and mobilized for these analyses. Meta-analysis outcomes depicted a conspicuous correlation between intensive LLT and an enhanced minimum FCT (12 studies with 972 participants; SMD, 0.87; 95% CI, 0.54 to 1.21; P < 0.01), reduced maximum lipid arc (9 studies with 564 participants; SMD, -0.43; 95% CI, -0.58 to -0.29; P < 0.01). Meta-regression analysis has determined an association of elevated minimum FCT with decreased LDL-C (ß, -0.0157; 95% CI, -0.0292 to -0.0023; P = 0.025), total cholesterol (TC) (ß, -0.0154; 95% CI, -0.0303 to -0.0005; P = 0.044), and apolipoprotein B (ApoB) (ß, -0.0209; 95% CI, -0.0361 to -0.0057; P = 0.022). However, no significant association was discerned relative to variations in hs-CRP/CRP (ß, -0.1518; 95% CI, -1.3766 to -1.0730; P = 0.772), triglyceride (TG) (ß, -0.0030; 95% CI, -0.0258 to -0.0318; P = 0.822), and high-density lipoprotein cholesterol (HDL-C) (ß, 0.0313; 95% CI, -0.0965 to 0.1590; P = 0.608). Subsequent subgroup meta-analysis demonstrated that high-intensity statin therapy (5 studies with 204 participants; SMD, 1.03; 95% CI, 0.67 to 1.39; P < 0.01), as well as a combinative approach including PCSK9 antibodies and statins (3 studies with 522 participants; SMD, 1.17; 95% CI, 0.62 to 1.73; P < 0.01) contributed to an increase in minimum FCT. Parallelly, high-intensity statin therapy (4 studies with 183 participants; SMD, -0.42; 95% CI, -0.65 to -0.19; P < 0.01) or the combined application of PCSK9 antibodies and statins (2 studies with 222 participants; SMD, -0.98; 95% CI, -1.26 to -0.70; P < 0.01) was evidenced to decrease the maximum lipid arc. CONCLUSIONS: Intensive LLT, mainly high-intensity statin therapy and combined PCSK9 antibody with statin, has a beneficial effect on coronary plaque stabilization derived from OCT in patients with CAD. Coronary plaque stabilization is primarily due to lipid-lowering effect, not anti-inflammatory effect. Moreover, the lipid-lowering effect has nothing to do with the changes in HDL-C and TG, but is mainly related to the reduction of LDL-C, TC, and ApoB.

Comprehensive evaluation of chiral penflufen metabolite (penflufen-3-hydroxy-butyl): Identification, synthesis, enantioseparation, toxicity and enantioselective metabolism.

Identification and evaluations of pesticide metabolites are necessary for risk assessment and toxicological research. In this study, the metabolites of penflufen (a widely used chiral pesticide) in rat liver microsomes were identified using liquid chromatography Q-Exactive Plus mass spectrometry. In total, 17 penflufen metabolites were identified, and most of them were hydroxylation products, which were generated by oxygenation at different candidate sites of penflufen. The relative abundance of metabolite M12 (penflufen-3-hydroxy-butyl, 32 %) was the largest, followed by M8 (15.6 %) and M2 (12.8 %). The major metabolite penflufen-3-hydroxy-butyl was first synthesized by 11 reactions with a 99.73 % purity. The absolute configuration of M12 enantiomers were confirmed after preparing enantiomers, and establishing the enantioseparation method. The M12 enantiomers toxicity to Danio rerio (LC50, >10 mg/L) and four kinds of phytopathogens (EC50, 148-34969 mg/L) were significantly lower than parents (LC50, 0.449-24.3 mg/L; EC50, 0.027-92.0 mg/L). In rat liver microsomes, approximately 40-47 % of the penflufen enantiomers were metabolized to M12 enantiomers, and R-penflufen was preferentially metabolized. The generation concentrations of S-M12 were higher than R-M12 after 10 min, and the metabolic half-lives of R-M12 (29.0-32.5 min) were shorter than S-M12 (35.2-38.1 min), and were approximately 4 times longer than parent penflufen enantiomers (4.5-9.5 min). Simultaneously, the generated contents (relative contents) of M8 (27.1-57 %) and M10 (2.22-8.36 %) from S-penflufen were lower than those from R-penflufen (M8, 24.7-92.4 %; M10, 27.4-69.5 %). The enantioselective evaluations of M12, M10 and M8 deserve further study. These findings were helpful in understanding the fate and risks of chiral penflufen.

Stable Lithium Plating and Stripping Enabled by a LiPON Nanolayer on PP Separator.

The practical application of the Li metal anode (LMA) is hindered by its low coulombic efficiency and dendrite formation. Although solid-state electrolytes hold promise as ideal partners for LMA, their effectiveness is limited by the poor workability and ionic conductivity. Herein, a modified separator combining the rapid Li+ transport of a liquid electrolyte and the interfacial stability of a solid-state electrolyte is explored to realize stable cycling of the LMA. A conformal nanolayer of LiPON is coated on a polypropylene separator by a scalable magnetron sputtering method, which is compatible with current Li-ion battery production lines and promising for the practical applications. The resulting LMA-electrolyte/separator interface is Li+ -conductive, electron-insulating, mechanically and chemically stable. Consequently, Li|Li cells maintain stable dendrite-free cycling with overpotentials of 10 and 40 mV over 2000 h at 1 and 5 mA cm-2 , respectively. Additionally, the Li|LiFePO4 full cells achieve a capacity retention of 92% after 550 cycles, confirming its application potential.

Structural insights into the assembly and activation of IL-1ß with its receptors.

Interleukin 1ß (IL-1ß) is a key orchestrator of inflammation and host defense that exerts its effects through IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP). How IL-1RAcP is recruited by IL-1ß-IL-1RI to form the signaling-competent complex remains elusive. Here we present the crystal structure of IL-1ß bound to IL-1 receptor type II (IL-1RII) and IL-1RAcP. IL-1ß-IL-1RII generated a composite binding surface to recruit IL-1RAcP. Biochemical analysis demonstrated that IL-1ß-IL-1RI and IL-1ß-IL-1RII interacted similarly with IL-1RAcP. It also showed the importance of two loops of IL-1 receptor antagonist (IL-1Ra) in determining its antagonism. Our results provide a structural basis for assembly and activation of the IL-1 receptor and offer a general cytokine-receptor architecture that governs the IL-1 family of cytokines.