Identification of Noncoding Functional Regulatory Variants of STIM1 Gene in Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: STIM1 (stromal interaction molecule 1) regulates store-operated calcium entry and is involved in pulmonary artery vasoconstriction and pulmonary artery smooth muscle cell proliferation, leading to pulmonary arterial hypertension (PAH). METHODS: Bioinformatics analysis and a 2-stage matched case-control study were conducted to screen for noncoding variants that may potentially affect STIM1 transcriptional regulation in 242 patients with idiopathic PAH and 414 healthy controls. Luciferase reporter assay, real-time quantitative polymerase chain reaction, western blot, 5-ethynyl-2'-deoxyuridine (EdU) assay, and intracellular Ca2+ measurement were performed to study the mechanistic roles of those STIM1 noncoding variants in PAH. RESULTS: Five noncoding variants (rs3794050, rs7934581, rs3750996, rs1561876, and rs3750994) were identified and genotyped using Sanger sequencing. Rs3794050, rs7934581, and rs1561876 were associated with idiopathic PAH (recessive model, all P<0.05). Bioinformatics analysis showed that these 3 noncoding variants possibly affect the enhancer function of STIM1 or the microRNA (miRNA) binding to STIM1. Functional validation performed in HEK293 and pulmonary artery smooth muscle cells demonstrated that the noncoding variant rs1561876-G (STIM1 mutant) had significantly stronger transcriptional activity than the wild-type counterpart, rs1561876-A, by affecting the transcriptional regulatory function of both hsa-miRNA-3140-5p and hsa-miRNA-4766-5p. rs1561876-G enhanced intracellular Ca2+ signaling in human pulmonary artery smooth muscle cells secondary to calcium-sensing receptor activation and promoted proliferation of pulmonary artery smooth muscle cells under both normoxia and hypoxia conditions, suggesting a possible contribution to PAH development. CONCLUSIONS: The potential clinical implications of the 3 noncoding variants of STIM1, rs3794050, rs7934581, and rs1561876, are 2-fold, as they may help predict the risk and prognosis of idiopathic PAH and guide investigations on novel therapeutic pathway(s).

Selective lignin arylation for biomass fractionation and benign bisphenols.

Lignocellulose is mainly composed of hydrophobic lignin and hydrophilic polysaccharide polymers, contributing to an indispensable carbon resource for green biorefineries1,2. When chemically treated, lignin is compromised owing to detrimental intra- and intermolecular crosslinking that hampers downstream process3,4. The current valorization paradigms aim to avoid the formation of new C-C bonds, referred to as condensation, by blocking or stabilizing the vulnerable moieties of lignin5-7. Although there have been efforts to enhance biomass utilization through the incorporation of phenolic additives8,9, exploiting lignin's proclivity towards condensation remains unproven for valorizing both lignin and carbohydrates to high-value products. Here we leverage the proclivity by directing the C-C bond formation in a catalytic arylation pathway using lignin-derived phenols with high nucleophilicity. The selectively condensed lignin, isolated in near-quantitative yields while preserving its prominent cleavable ß-ether units, can be unlocked in a tandem catalytic process involving aryl migration and transfer hydrogenation. Lignin in wood is thereby converted to benign bisphenols (34-48 wt%) that represent performance-advantaged replacements for their fossil-based counterparts. Delignified pulp from cellulose and xylose from xylan are co-produced for textile fibres and renewable chemicals. This condensation-driven strategy represents a key advancement complementary to other promising monophenol-oriented approaches targeting valuable platform chemicals and materials, thereby contributing to holistic biomass valorization.

Low-Temperature Deposited Amorphous Poly(aryl ether ketone) Hierarchically Porous Scaffolds with Strontium-Doped Mineralized Coating for Bone Defect Repair.

In recent years, the demand for clinical bone grafting has increased. As a new solution for orthopedic implants, polyether ether ketone (PEEK, crystalline PAEK) has excellent comprehensive performance and is practically applied in the clinic. In this research, a noteworthy elevated scheme to enhance the performance of PEEK scaffolds is presented. The amorphous aggregated poly (aryl ether ketone) (PAEK) resin is prepared as the matrix material, which maintains high mechanical strength and can be processed through the solution. So, the tissue engineering scaffolds with multilevel pores can be printed by low-temperature deposited manufacturing (LDM) to improve biologically inert scaffolds with smooth surfaces. Also, the feature of PAEK's solution processing is profitable to uniformly add the functional components for bone repair. Ultimately, A system of orthopedic implantable PAEK material based on intermolecular interactions, surface topology, and surface modification is established. The specific steps include synthesizing PAEK that contain polar carboxyl structures, preparing bioinks and fabricating scaffolds by LDM, preparation of scaffolds with strontium-doped mineralized coatings, evaluation of their osteogenic properties in vitro and in vivo, and investigation on the effect and mechanism of scaffolds in promoting osteogenic differentiation. This work provides an upgraded system of PAEK implantable materials for clinical application.

zDHHC3-mediated S-palmitoylation of SLC9A2 regulates apoptosis in kidney clear cell carcinoma.

PURPOSE: Kidney clear cell carcinoma (KIRC) has a poor prognosis, high morbidity and mortality rates, and high invasion and metastasis rate, and effective therapeutic targets are lacking. zDHHC3 has been implicated in various cancers, but its specific role in KIRC remains unclear. METHODS: In this study, we performed a pan-cancer analysis, bioinformatics analysis, and cell experiment to detect the role of zDHHC3 in KIRC. RESULTS: zDHHC3 was significantly down-regulated in KIRC, and that its high expression was associated with favorable patient outcomes. We identified 202 hub genes that were most relevant to high zDHHC3 expression and KIRC, and found that they were involved mainly in ion transport and renal cell carcinoma. Among these hub genes, SLC9A2 was identified as a downstream gene of zDHHC3. zDHHC3 suppression led to decreased expression and S-palmitoylation of SLC9A2, which further inhibited the apoptosis of Caki-2 cells. CONCLUSION: Our findings suggest that zDHHC3 plays an important role in KIRC, due partly to its regulation of SLC9A2 S-palmitoylation. The targeting of the zDHHC3-SLC9A2 axis may provide a new option for the clinical treatment of KIRC.

-COOH & -OH Condensation Reaction Utilization for Biomass FDCA-based Polyesters.

A green and sustainable -COOH & -OH condensation solution polymerization method was hereby reported for FDCA-based polyesters to avoid discoloration and toxic solvents. First, taking poly(ethylene 2,5-furandicarboxylate) (PEF) as the representative of FDCA-based polyester, enabling good white appearance PEF with Mn=6.51×103 g mol-1 from FDCA and ethylene glycol in green solvent γ-valerolactone (GVL), catalyzed by 4-dimethylaminopyridine (DMAP) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC). Additionally, the molecular weight of PEF was rapidly improved (Mn >2.5×104 g mol-1) via remelting polycondensation within minutes, with the dispersity still kept relatively low dispersity (D<1.40). Importantly, the -COOH & -OH condensation solution polymerization method was successfully applied for the synthesis of various FDCA-based polyesters, including diols with varying carbon chain lengths (3 to 11 carbons) and cycloalkyl diols, especially the applicability of this method to diols containing C=C double bonds, which was found to exhibit low heat resistance. Lastly, assisting with 13C labeled 1,4-succinic acid and in-situ 13C-NMR, an in-depth study of the possible catalytic mechanism was proposed, by which, EDC activated FDCA, and then DMAP catalyzed it with diol to yield macromolecular chain of polyester. Overall, the results provided a green and sustainable strategy for the synthesis of FDCA-based polyesters.

Synthesis of α,ω-End Functionalized Polydienes: Allylic-Bearing Heteroleptic Aluminums for Selective Alkylation and Transalkylation in Coordinative Chain Transfer Polymerization.

There are still challenges in the preparation of difunctional stereoregular polydienes, especially for the construction of initiating chain-end functionalization. Coordinative chain transfer polymerization (CCTP) provides a way to achieve the goal but usually requires sophisticated functionalized catalysts as well as expensive chain transfer agents (CTAs). In this work, heteroleptic aluminum with oligo(dienyl) substituents (oligo-Al agents) were readily prepared by living anionic polymerization (LAP) technique. The oligo-Al agents used in Nd-mediated CCTPs of dienes exhibit highly selective alkylation and transalkylation features. Kinetics and transfer efficiency studies using 1 H NMR, 13 C NMR, 1 H-13 C HSQC, and Dosy NMR analyses revealed that the resulting polydienes possess substituents at the initiating chain-end that have transferred from the oligo-Al agents. The functionalization efficiency of the initiating chain-end is up to 99 %, and the molar mass regulation efficiency of heteroleptic aluminum is higher than that of the traditional CTA Ali Bu2 H (0.608 vs. 0.410). Based on the experimental results and density functional theory (DFT) calculations, we propose a mechanism in which allylic-Al acts as an efficient alkylating moiety in catalyst preformation and also as an effective transfer agent in polymerization. Taking advantage of these features, di-functionalized polyisoprene, polybutadiene, and poly(isoprene-co-butadiene) can be facilely synthesized.

Amorphous Poly (Aryl Ether Ketones) Containing Methylene Groups with Excellent Thermal Resistance, Dielectric Properties and Mechanical Performance.

Low-dielectric constant polymers are widely used in various microelectronic materials. With the development of 5G communication technology, there is an urgent need for polymer materials with low dielectric constant at high frequency, good thermal resistance, and mechanical properties. In this study, four novel poly (aryl ether ketone) (PAEK) containing different numbers of methylene groups were synthesized via nucleophilic polycondensation reaction. At 10 GHz, these polymer films exhibit excellent dielectric properties with dielectric constants as low as 2.76. The relationship between the dielectric constant and the number of methylene groups is illustrated by constructing the amorphous accumulation cell model. In addition, methylene groups provided the polymer with favorable mechanical performance, including Young's modulus in the range of 2.17-2.21 GPa, the tensile strength from 82.0 to 88.5 MPa and the elongation at the break achieved 7.94%, respectively. Simultaneously, the polymer maintains good thermal resistance with a glass transition temperature (Tg) reaching 216 °C. The result indicates that the obtained novel PAEK is potentially valuable in the field of high-frequency communications.

Alterations of gut microbiome and metabolism induced by inulin associated with weight loss in obese female mice.

Our previous work revealed the microbiota-dependent beneficial effects of inulin in obese male mice, but the effects in obese female mice were not determined. High-fat diet (HFD)-induced obese female mice were switched to normal diets and gavaged with normal saline or inulin for 10 weeks. Inulin supplementation significantly accelerated weight loss and reversed HFD-induced gut microbiota dysbiosis in obese female mice, and also reduced the ratio of Firmicutes/Bacteroidetes and enriched the abundance of norank_f_Muribaculaceae and Alistipes. In addition, 52 key serum metabolites were distinctly altered after inulin supplementation. Among them, andrographolide and monoacylglycerols (18:4) increased more than 9-fold and 14-fold, respectively, while phosphatidylcholine (PC) (18:1e/2:0), PC (20:1/20:2) and PC (19:1/19:1) decreased. In conclusion, gut microbiota and metabolites were closely associated with the beneficial effects of inulin in accelerating weight loss in obese female mice.

Zr-MOF membranes with ultra-fast water-selective permeation towards intensification of esterification reaction.

Well-intergrown polycrystalline UiO-66 membranes were successfully synthesized on a polymeric substrate under mild synthesis conditions of a lower temperature and short synthesis time. The resulted UiO-66 membranes with fast water selective transport channels exhibited unprecedentedly high solvent dehydration performance with a permeation flux of ∼6100 g m-2 h-1 and a separation factor of ∼7500, showing great potential for intensification of esterification reaction.

Design and synthesis of novel poly (aryl ether ketones) containing trifluoromethyl and trifluoromethoxy groups.

The high-frequency and high-speed communication in the 5 G era puts forward requirements for the dielectric properties of polymers. Introducing fluorine into poly(ary ether ketone) can improve its dielectric properties. In this work, by introducing the fluorine group strategy, we successfully designed and synthesized three novel trifluoromethyl (-CF3) or trifluoromethoxy (-OCF3)-containing bisphenol monomers and their F-substitution PEK-based polymers (PEK-Ins). All these PEK-Ins exhibited good thermal, mechanical and dielectric properties. The T d5% of the three polymers is all higher than 520℃. The free volume fraction of novel polymers increased from 3.75% to 5.72%. Among the three polymers, exhibited the lowest dielectric constant of the films is 2.839, and the dielectric loss is 0.0048, ascribing to the increasing free volume. The Young's modulus of the polymer film is as high as 2.9 GPa and the tensile strength is as high as 84 MPa. PEK-Ins reduced the dielectric constant by introducing a low fluorine content. This study provides a new way to design PEK to synthesize low dielectric constant polymers.

Co-profiling reveals distinct patterns of genomic chromatin accessibility and gene expression in pulmonary hypertension caused by chronic hypoxia.

INTRODUCTION: Aberrant gene expression is a key mechanism underlying pulmonary hypertension (PH) development. The alterations of genomic chromatin accessibility and their relationship with the aberrant gene expressions in PH are poorly understood. We used bulk Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing (RNA-seq) in pulmonary artery smooth muscle cells (PASMCs) of chronic hypoxia-exposed rats mimicking group 3 human PH. METHODS: Adult Sprague Dawley rats were commercially obtained from Hunan SJA (Hunan SJA Laboratory Animal Co., Changsha, China) and randomizedly allocated into four groups exposing to nomobaric hypoxia or normoxia for 1 or 28 days respectively. After the assessment of pulmonary hemodynamics, smooth muscle cells were isolated from intralobular arteries and simultaneously subjected to bulk Assay of ATAC-seq and RNA-seq. RESULTS: Hypoxic exposure for continuous 28-days, but not for 1-day, induced established PH phenotypes in rats. ATAC-seq revealed a major distribution of differential accessibility regions (DARs) annotated to the genome in out-of-promoter regions, following 1-day or 28-days hypoxia. 1188 DAR-associated genes and 378 differentially expressed genes (DEGs) were identified in rats after exposure to 1-day hypoxia, while 238 DAR-associated genes and 452 DEGs for 28-days hypoxia. Most of the DAR-associated genes or DEGs in 1-day did not overlap with that of 28-days hypoxia. A Pearson correlation analysis indicated no significant correlation between ATAC-seq and RNA-seq. CONCLUSIONS: The alterations in genomic chromatin accessibility and genes expression of PASMCs in the initial stage of hypoxia are distinct from the established stage of hypoxia-induced PH. The genomic differential accessibility regions may not be the main mechanisms directly underlying the differentially expressed genes observed either in the initial or established stages of PH. Thus the time-course alterations of gene expression and their possible indirect link with genomic chromatin accessibility warrant more attention in mechanistic study of pulmonary hypertension.

Long-term divergent selection for residual feed intake in Chinese broiler chickens.

This study aimed to assess the effect of inbreeding on production traits using a long-term closed-line population recorded for residual feed intake (RFI). The study first used data from a previously reported population to determine the appropriate period of divergent selection for RFI. The results showed that RFI had similar moderate heritability estimates (0.28-0.34) during the fast-growing period (7-12 wk), and RFI at 7 to 10 wk had the highest heritability (0.34). Therefore, divergent selection was performed in a Chinese broiler population for RFI at 7 to 10 wk; the total sample size from generations zero (G0) to 13 was 9050. The divergence between the 2 lines increased steadily throughout generations, resulting in G13 with average RFI values of 304.55 in high RFI (HRFI) males, -160.31 in low RFI (LRFI) males, 296.30 in HRFI females and -157.55 in LRFI females. The feed intake (FI) and feed conversion ratio were almost higher in HRFI broilers than in LRFI broilers, and the magnitude of the difference in FI increased from approximately 4% for both sexes in G1 to approximately 33% in G13. Body weight gain was irregular from G1 to G13 and higher in LRFI broilers than in HRFI broilers after G10. Indeed, the HRFI broilers consumed more food, but they were lighter than LRFI broilers. In G13, LRFI males had heavier slaughter weight, longer cecum length, more white blood cells (WBC), red blood cells (RBC) and hemoglobin (HGB), but triglycerides, lower dressed percentage, percentage of half eviscerated yield, and eviscerated yield than HRFI males. LRFI females had a higher percentage of breast muscle and gizzard yield, longer cecum length, and more WBCs, RBCs and HGB but less abdominal fat and serum total cholesterol than HRFI females. This study was the first to verify that long-term divergent selection for RFI in Chinese broiler chickens is positive and beneficial.

Low-Temperature Printed Hierarchically Porous Induced-Biomineralization Polyaryletherketone Scaffold for Bone Tissue Engineering.

Polyetheretherketone (PEEK) as a popular orthopaedic implant is usually fabricated into a hierarchically porous structure for improving osteogenic activity. However, the applications are limited due to the excessively high processing temperature and uncontrollably tedious modification routes. Here, an amorphous polyaryletherketone with carboxyl groups (PAEK-COOH) is synthesized and fabricated to the hierarchically controllable porous scaffolds via a low-temperature 3D-printing process. The prepared PAEK-COOH scaffolds present controllable porous structures ranging from nano- to micro-scale, and their mechanical strengths are comparable to that of trabecular bone. More importantly, the in vitro experiments show that the nanoporous surface is conducive to promoting cellular adhesion, and carboxyl groups can induce hydroxyapatite mineralization via electrostatic interaction. The in vivo experiments demonstrate that the PAEK-COOH scaffolds offer much better osseointegration without additional active ingredients, compared to that of PEEK. Therefore, this work will not only develop a promising candidate for bone tissue engineering, but provide a viable method to design PAEK biomaterials.

Bio-effects of bio-based and fossil-based microplastics: Case study with lettuce-soil system.

Bio-based plastics have been developed as alternative materials to solve the energy crisis brought by plastic production, but their impacts on soil ecosystems (e.g. plant and microorganisms) remain largely unknown. Here, we conducted study on the impacts of polyethylene 2,5-furan-dicarboxylate (PEF), a new bio-based plastic, on the plant-soil ecosystem, with comparison of fossil-based plastic polyethylene terephthalate (PET). Our investigation showed that, after 21 days exposure to microplastics (MPs) at doses of 0.5%, 1% and 2%, both PEF and PET MPs inhibited the growth of lettuce, where chlorophyll was found to be the most sensitive index. According to the comprehensive stress resistance indicators, PET MPs showed more severe phytotoxicity than PEF MPs. Although both PEF and PET MPs could inhibit soil enzyme activities, PET MPs exhibited significantly reduction on the diversity of rhizosphere soil bacterial community and changed the relative abundance of dominant species. Our study gave insights into the effects of PEF and PET MPs on the plant-soil system, where bio-based PEF MPs showed more friendly interaction with plant and soil than fossil-based PET MPs. Our results provided scientific data for risk assessment and useful information for the prospective application of bio-based plastics.

Inhibition of KIF23 Alleviates IPAH by Targeting Pyroptosis and Proliferation of PASMCs.

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive vascular disease with high mortality and heritability. Pyroptosis is a novel form of programmed cell death, and it is closely associated with IPAH. However, the roles of pyroptosis-related genes (PRGs) in IPAH are still largely unknown. In this study, we identified KIF23 as the most relevant gene for IPAH and pyroptosis, and its expression was significantly increased in pulmonary arterial smooth muscle cells (PASMCs) of IPAH. Besides, the pyroptosis level of PASMCs was also considerably upregulated in IPAH. Knockdown of KIF23 in PASMCs could significantly suppress the PASMCs' pyroptosis and proliferation and then alleviate the increase in pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary vascular resistance in IPAH. KIF23 regulated the expression of Caspase3, NLRP3, and HMGB1, and they were all involved in the PI3K/AKT and MAPK pathways, indicating that PI3K/AKT and MAPK pathways might participate in regulating PASMCs pyroptosis by KIF23. In conclusion, our study suggests that KIF23 may be a new therapeutic target for IPAH, which can alleviate the symptoms of IPAH by inhibiting the pyroptosis and proliferation of PASMCs.

Genome-Wide Association Studies Provide Insight Into the Genetic Determination for Hyperpigmentation of the Visceral Peritoneum in Broilers.

Hyperpigmentation of the visceral peritoneum (HVP) has been becoming one of the most challenging problems in yellow-feathered chicken production, which seriously affected chicken carcass quality traits. Detecting which genes dominantly impact pigmentation in the peritoneum tissues is of great benefit to the genetic improvement of HVP. To investigate the genetic mechanism of HVP in yellow-feathered broilers, genome-wide association studies (GWASs) were conducted in the F2 generation of a cross broiler population with 395 birds. A total of 115,706 single-nucleotide polymorphisms (SNPs) of 122,415 were retained to identify quantitative trait loci (QTL) associated to HVP in chicken. The GWAS results based on the logistic mixed model (LMM) revealed that a narrow genomic location on chromosomes 1 (49.2-51.3 Mb) was significantly associated (p ≤ 4.32 × 10-7) with HVP, which contained 23 SNP makers related to 14 functional genes (MFNG, POLDIP3, POLR2F, PICK1, PDXP, SGSM3, RANGAP1, MYH9, RPL3, GALP3, LGALS1, MICALL1, ATF4, and CYP2D6). Four highly associated (p < 10-5) haplotype blocks of 0.80 kb (two SNPs), 0.06 kb (two SNPs), 0.95 kb (two SNPs), and 0.03 kb (two SNPs) were identified with two, two, four, and four distinct haplotypes, respectively. As a melanoma-associated gene, CYP2D6 were also possibly involved in the development of HVP occurring in chicken with two significant variations (rs314284996 and rs317955795) in the promoter regions. Further tests revealed that the expression of CYP2D6 was obviously higher in the visceral peritoneum tissue of chicken with HVP than that in the normal group (p < 0.05). Our results provide a novel clue to understand the genetic mechanism of HVP generation in chicken, and the mapped QTL or candidate genes might serve for genomic selection to improve carcass quality in the yellow-feathered chicken industry.

Unraveling SO2-tolerant mechanism over Fe2(SO4)3/TiO2 catalysts for NOx reduction.

Developing low-temperature SO2-tolerant catalysts for the selective catalytic reduction of NOx is still a challenging task. The sulfation of active metal oxides and deposition of ammonium bisulfate deactivate catalysts, due to the difficult decomposition of the as-formed sulfate species at low temperatures (<300 °C). In recent years, metal sulfate catalysts have attracted increasing attention owing to their good catalytic activity and strong SO2 tolerance at higher temperatures (>300°C); however, the SO2-tolerant mechanism of metal sulfate catalysts is still ambiguous. In this study, Fe2(SO4)3/TiO2 and Ce2(SO4)3/TiO2 catalysts were prepared using the corresponding metal sulfate salt as the precursor. These catalysts were tested for their low-temperature activity and SO2 tolerance activity. Compared to Ce2(SO4)3/TiO2, Fe2(SO4)3/TiO2 showed significantly better low-temperature activity and SO2 tolerance. It was demonstrated that less surface sulfate species formed on Fe2(SO4)3/TiO2 and Ce2(SO4)3/TiO2. However, the presence of NO and O2 could assist the decomposition of NH4HSO4 over Fe2(SO4)3/TiO2 at a lower temperature, endowing Fe2(SO4)3/TiO2 with better low-temperature SO2 tolerance than Ce2(SO4)3/TiO2. This study unraveled the SO2-tolerant mechanism of Fe2(SO4)3/TiO2 at lower temperatures (<300 °C), and a potential strategy is proposed for improving the low-temperature SO2-tolerance of catalysts with Fe2(SO4)3 as the main active component or functional promoter.

Alkali-Resistant Catalytic Reduction of NOx via Naturally Coupling Active and Poisoning Sites.

Releasing the poisoning effect of alkali metals over catalysts is still an intractable issue for selective catalytic reduction (SCR) of NOx with ammonia. The presence of K in fly ash always dramatically suppressed catalytic activity by impairing acidity and redox properties, leading to severe reduction of lifetime for SCR catalysts. Herein, alkali-resistant NOx reduction over TiO2-supported Fe2(SO4)3 catalysts was originally demonstrated via naturally coupling active and poisoning sites. Notably, TiO2-supported Fe2(SO4)3 catalysts expressed admirable NOx conversion and K resistance within a quite broad temperature window of 200-500 °C. The catalysts with more conserved sulfate species revealed that sulfate groups preferred to migrate from the bulk phase to surface, thus effectively binding with K poisons to release the damage on iron active sites. Because of protection effects of migrated sulfates and closely coupling effects with Fe active sites, NH3 and NO adsorption amounts and rates were well maintained. In this way, Fe metal sites and sulfate species closely coupled together on a self-preserved TiO2-supported Fe2(SO4)3 catalyst played essential roles as highly active sites and unique poisoning sites. This work paves a new way to design SCR catalysts with superior alkali resistance that are more reliable in practical deNOx application.

Neonatal Murine Model of Coxsackievirus A2 Infection for the Evaluation of Antiviral Therapeutics and Vaccination.

Coxsackievirus (CV) A2 has emerged as an important etiological agent in the pathogen spectrum of hand, foot, and mouth disease (HFMD). The symptoms of CVA2 infections are generally mild, but worsen rapidly in some people, posing a serious threat to children's health. However, compared with enterovirus 71 detected frequently in fatal cases, limited attention has been paid to CVA2 infections because of its benign clinical course. In the present study, we identified three CVA2 strains from HFMD infections and used the cell-adapted CVA2 strain HN202009 to inoculate 5-day-old BALB/c mice intramuscularly. These mice developed remarkably neurological symptoms such as ataxia, hind-limb paralysis, and death. Histopathological determination showed neuronophagia, pulmonary hemorrhage, myofiberlysis and viral myocarditis. Viral replication was detected in multiple organs and tissues, and CVA2 exhibited strong tropism to muscle tissue. The severity of illness was associated with abnormally high levels of inflammatory cytokines, including interleukin (IL)-6, IL-10, tumor necrosis factor α, and monocyte chemotactic protein 1, although the blockade of these proinflammatory cytokines had no obvious protection. We also tested whether an experimental formaldehyde-inactivated CVA2 vaccine could induce protective immune response in adult mice. The CVA2 antisera from the vaccinated mice were effective against CVA2 infection. Moreover, the inactivated CVA2 vaccine could successfully generate immune protection in neonatal mice. Our results indicated that the neonatal mouse model could be a useful tool to study CVA2 infection and to develop CVA2 vaccines.

Pathogenesis Study of Enterovirus 71 Using a Novel Human SCARB2 Knock-In Mouse Model.

Enterovirus 71 (EV71) can cause a severe hand-foot-mouth disease in children. However, the precise mechanism of EV71-associated disease, particularly the neuropathogenesis and pulmonary disorder, is still not fully understood because no suitable animal models are available. The human scavenger receptor class B, member 2 (hSCARB2), is a cellular receptor for EV71. Here, we generated a novel knock-in (KI) mouse model using the CRISPR/Cas9 system to insert the hSCARB2 gene into the mouse Rosa26 locus to study the pathogenesis of EV71. The hSCARB2 KI mice infected with clinical isolates of EV71 showed neurological symptoms, such as ataxia, paralysis, and death. Viral replication was detected in mainly astrocytes and a limited number of neurons and microglia, accompanied by gliosis. Vascular leakage and alveoli filled with erythrocytes were detected, suggesting that edema and hemorrhage, which are observed in human patients, also occurred in EV71-infected KI mice. In addition, proinflammatory cytokines and chemokines were significantly increased in the serum of infected KI mice. These pathological features of the KI mice after infection resembled those of EV71 encephalomyelitis in humans. Therefore, our KI mouse model is suitable to study the pathogenesis of EV71 and is of great significance for development of antiviral drugs and vaccines to treat or prevent EV71 infection.IMPORTANCE Enterovirus 71 (EV71) is associated with severe hand-foot-mouth disease. Recently, outbreaks of EV71 infection with high mortality have been reported in the Asia-Pacific region, posing a great challenge for global public health. To date, the precise mechanism of EV71-induced disease, particularly the neuropathogenesis and respiratory disorders, is still not fully understood because no suitable animal models are available. Human scavenger receptor class B, member 2 (hSCARB2), has been identified as a cellular receptor for EV71. Here, we introduce a novel CRISPR/Cas9-mediated hSCARB2 knock-in (KI) mouse model for the study of EV71 pathogenesis, which is of great significance for the development of antiviral drugs and vaccines.