Deciphering infected cell types, hub gene networks and cell-cell communication in infectious bronchitis virus via single-cell RNA sequencing.

Infectious bronchitis virus (IBV) is a coronavirus that infects chickens, which exhibits a broad tropism for epithelial cells, infecting the tracheal mucosal epithelium, intestinal mucosal epithelium, and renal tubular epithelial cells. Utilizing single-cell RNA sequencing (scRNA-seq), we systematically examined cells in renal, bursal, and tracheal tissues following IBV infection and identified tissue-specific molecular markers expressed in distinct cell types. We evaluated the expression of viral RNA in diverse cellular populations and subsequently ascertained that distal tubules and collecting ducts within the kidney, bursal mucosal epithelial cells, and follicle-associated epithelial cells exhibit susceptibility to IBV infection through immunofluorescence. Furthermore, our findings revealed an upregulation in the transcription of proinflammatory cytokines IL18 and IL1B in renal macrophages as well as increased expression of apoptosis-related gene STAT in distal tubules and collecting duct cells upon IBV infection leading to renal damage. Cell-to-cell communication unveiled potential interactions between diverse cell types, as well as upregulated signaling pathways and key sender-receiver cell populations after IBV infection. Integrating single-cell data from all tissues, we applied weighted gene co-expression network analysis (WGCNA) to identify gene modules that are specifically expressed in different cell populations. Based on the WGCNA results, we identified seven immune-related gene modules and determined the differential expression pattern of module genes, as well as the hub genes within these modules. Our comprehensive data provides valuable insights into the pathogenesis of IBV as well as avian antiviral immunology.

The pseudogene GBP1P1 suppresses influenza A virus replication by acting as a protein decoy for DHX9.

Recently, substantial evidence has demonstrated that pseudogene-derived long noncoding RNAs (lncRNAs) as regulatory RNAs have been implicated in basic physiological processes and disease development through multiple modes of functional interaction with DNA, RNA, and proteins. Here, we report an important role for GBP1P1, the pseudogene of guanylate-binding protein 1, in regulating influenza A virus (IAV) replication in A549 cells. GBP1P1 was dramatically upregulated after IAV infection, which is controlled by JAK/STAT signaling. Functionally, ectopic expression of GBP1P1 in A549 cells resulted in significant suppression of IAV replication. Conversely, silencing GBP1P1 facilitated IAV replication and virus production, suggesting that GBP1P1 is one of the interferon-inducible antiviral effectors. Mechanistically, GBP1P1 is localized in the cytoplasm and functions as a sponge to trap DHX9 (DExH-box helicase 9), which subsequently restricts IAV replication. Together, these studies demonstrate that GBP1P1 plays an important role in antagonizing IAV replication.IMPORTANCELong noncoding RNAs (lncRNAs) are extensively expressed in mammalian cells and play a crucial role as regulators in various biological processes. A growing body of evidence suggests that host-encoded lncRNAs are important regulators involved in host-virus interactions. Here, we define a novel function of GBP1P1 as a decoy to compete with viral mRNAs for DHX9 binding. We demonstrate that GBP1P1 induction by IAV is mediated by JAK/STAT activation. In addition, GBP1P1 has the ability to inhibit IAV replication. Importantly, we reveal that GBP1P1 acts as a decoy to bind and titrate DHX9 away from viral mRNAs, thereby attenuating virus production. This study provides new insight into the role of a previously uncharacterized GBP1P1, a pseudogene-derived lncRNA, in the host antiviral process and a further understanding of the complex GBP network.

Irpetones A and B, Anti-Osteoclastic Heptaketides from a Marine Mesophotic Zone Ircinia Sponge-Associated Fungus Irpex sp. NBUF088.

Chemical investigation of Irpex sp. NBUF088, associated with an Ircinia sp. sponge located at an 84 m deep mesophotic zone, led to the discovery of two new heptaketides, named irpetones A (1) and B (2). Their structures were identified by analysis of spectroscopic data and quantum-chemical calculations. Compound 1 exhibited inhibition against the receptor activator of NF-κB ligand-induced osteoclastogenesis in bone marrow monocytes with an IC50 of 6.3 ± 0.2 µM, causing no notable cytotoxicity. It was also determined that 1 inhibited the phosphorylation of ERK1/2-JNK1/2-p38 MAPKs and the nuclear translocation of NF-κB, consequently suppressing the activation of MAPK and NF-κB signaling pathways induced by the NF-κB ligand.

Long-term outcomes of anti-vascular endothelial growth factor therapy with and without posterior scleral reinforcement on myopic maculopathy in myopic choroidal neovascularization eyes.

BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapy is used for myopic choroidal neovascularization (mCNV). Patchy chorioretinal atrophy (pCRA) enlargement has been reported in mCNV cases associated with vision loss. Our aim was to compare the long-term effectiveness of anti-VEGF therapy alone versus anti-VEGF followed by posterior scleral reinforcement (PSR) in controlling myopic maculopathy in mCNV eyes. METHODS: We performed a retrospective review of the medical records of 95 high myopia patients (refractive error ≥ 6.00 diopters, axial length ≥ 26.0 mm) with mCNV. Patients were treated with anti-VEGF alone (group A) or anti-VEGF followed by PSR (group B). The following data were collected: refractive error, best corrected visual acuity (BCVA), ophthalmic fundus examination, ocular coherence tomography and ocular biometry at 12 and 24 months pre- and postoperatively. The primary outcomes were changes in pCRA and BCVA. RESULTS: In 26 eyes of 24 patients, the mean pCRA size significantly increased from baseline (0.88 ± 1.69 mm2) to 12 months (1.57 ± 2.32 mm2, t = 3.249, P = 0.003) and 24 months (2.17 ± 2.79 mm2, t = 3.965, P = 0.001) postoperatively. The increase in perilesional pCRA in group B (n = 12) was 98.2% and 94.2% smaller than that in group A (n = 14) at 12 and 24 months (Beta 0.57 [95% CI 0.01, 191 1.13], P = 0.048). In group B, 7 eyes (58.3%) gained more than 2 lines of BCVA compared with only 4 eyes (28.6%) in group A at 24 months. CONCLUSION: Anti-VEGF therapy followed by PSR achieved better outcomes than anti-VEGF therapy alone in controlling the development of myopic maculopathy in mCNV and may constitute a better treatment option by securing a better long-term VA outcome.

Associations of parental age at pregnancy with adolescent cognitive development and emotional and behavioural problems: a birth cohort in rural Western China.

BACKGROUND: The relationship between parental age at pregnancy and offspring development in low- and middle-income countries remains unclear. We aimed to examine the associations of parental age at pregnancy with adolescent development in rural China. METHODS: We conducted a prospective birth cohort study of offspring born to pregnant women who participated in an antenatal micronutrient supplementation trial in rural Western China. Adolescent cognitive development and emotional and behavioural problems were assessed by using the Wechsler Intelligence Scale for Children-IV and the Youth Self-Report-2001, respectively. After accounting for the possible nonlinear relationships, we examined the linear associations between parental age (in years) at pregnancy and scores of adolescent cognitive development and emotional and behavioural problems by performing generalized estimating equations. RESULTS: Among 1897 adolescents followed from birth to early adolescence, 59.5% were male with a mean age of 11.8 (standard deviation (SD): 0.8) years. The mean ages of mothers and fathers at pregnancy were 24.6 (SD: 4.4) and 27.9 (SD: 4.1) years old, respectively. All the P values of the nonlinear terms between parental age and adolescent development in all domains were greater than 0.05. Each one-year increase in maternal age at pregnancy was associated with a 0.29-point (95% confidence interval (CI) 0.06, 0.52) increase in the full-scale intelligence quotient in early adolescence. After parental age was categorized into quartiles, the total behavioural problem scores of adolescents with fathers with an age in the fourth quartile (Q4) were 6.71 (95% CI 0.86, 12.57) points higher than those of adolescents with fathers with an age in the first quartile (Q1), with a linear trend P value of 0.01. Similarly, higher scores (worse behavioural problems) were observed for internalizing behavioural problems and other emotional and behavioural symptoms related to anxiety, withdrawal, social problems, thought problems and aggressive behaviour. CONCLUSIONS: At conception, older maternal age was independently linked to better adolescent cognitive development, whereas advanced paternal age was independently associated with a greater risk of adolescent emotional and behavioral problems. These findings suggest that public health policies targeting an optimal parental age at pregnancy should be developed in the context of offspring developmental consequences.

Taming Two-Dimensional Polymerization by a Machine-Learning Discovered Crystallization Model.

Rapidly synthesizing high-quality two-dimensional covalent organic frameworks (2D COFs) is crucial to their practical applications. Here, we use a machine-learning approach that overcomes the challenges associated with bottom-up model derivation for the non-classical 2D COF crystallization processes. The resulting model, referred to as NEgen1, establishes correlations among the induction time, nucleation rate, growth rate, bond-forming rate constants, and common solution synthesis conditions for 2D COFs that grow by a nucleation-elongation mechanism. The results elucidate the detailed competition between the nucleation and growth dynamics in solution, which has been inappropriately described previously by classical, empirical models with assumptions invalid for 2D COF polymerization. By understanding the dynamic processes at play, the NEgen1 model reveals a simple strategy of gradually increasing monomer addition speed for growing large 2D COF crystals. This insight enables us to rapidly synthesize large COF-5 colloids, which could only be achieved previously by prolonged reaction times or by introducing chemical modulators. These results highlight the potential for systematically improving the crystal quality of 2D COFs, which has wide-reaching relevance for many of the applications for which 2D COFs are speculated to be valuable.

USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2.

RRM2 is the catalytic subunit of ribonucleotide reductase (RNR), which catalyzes de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) and plays critical roles in cancer cell proliferation. RRM2 protein level is controlled by ubiquitination mediated protein degradation system; however, its deubiquitinase has not been identified yet. Here we showed that ubiquitin-specific peptidase 12 (USP12) directly interacts with and deubiquitinates RRM2 in non-small cell lung cancer (NSCLC) cells. Knockdown of USP12 causes DNA replication stress and retards tumor growth in vivo and in vitro. Meanwhile, USP12 protein levels were positively correlated to RRM2 protein levels in human NSCLC tissues. In addition, high expression of USP12 was associated with poor prognosis in NSCLC patients. Therefore, our study reveals that USP12 is a RRM2 regulator and targeting USP12 could be considered as a potential therapeutical strategy for NSCLC treatment.

Structural-guided design to improve the catalytic performance of aldo-keto reductase KdAKR.

Aldo-keto reductases (AKRs) are important biocatalysts that can be used to synthesize chiral pharmaceutical alcohols. In this study, the catalytic activity and stereoselectivity of a NADPH-dependent AKR from Kluyveromyces dobzhanskii (KdAKR) toward t-butyl 6-chloro (5S)-hydroxy-3-oxohexanoate ((5S)-CHOH) were improved by mutating its residues in the loop regions around the substrate-binding pocket. And the thermostability of KdAKR was improved by a consensus sequence method targeted on the flexible regions. The best mutant M6 (Y28A/L58I/I63L/G223P/Y296W/W297H) exhibited a 67-fold higher catalytic efficiency compared to the wild-type (WT) KdAKR, and improved R-selectivity toward (5S)-CHOH (dep value from 47.6% to >99.5%). Moreover, M6 exhibited a 6.3-fold increase in half-life (t1/2 ) at 40°C compared to WT. Under the optimal conditions, M6 completely converted 200 g/L (5S)-CHOH to diastereomeric pure t-butyl 6-chloro-(3R, 5S)-dihydroxyhexanoate ((3R, 5S)-CDHH) within 8.0 h, with a space-time yield of 300.7 g/L/day. Our results deepen the understandings of the structure-function relationship of AKRs, providing a certain guidance for the modification of other AKRs.

Effect of low-dose atropine eyedrops on pupil metrics: results after half a year of treatment and cessation.

PURPOSE: To evaluate the effect of low-dose atropine eyedrops on pupil metrics. METHODS: This study was based on a randomized, double-masked, placebo-controlled, and cross-over trial in mainland China. In phase 1, subjects received 0.01% atropine or placebo once nightly. After 1 year, the atropine group switched to placebo (atropine-placebo group), and the placebo group switched to atropine (placebo-atropine group). Ocular parameters were measured at the crossover time point (at the 12th month) and the 18th month. RESULTS: Of 105 subjects who completed the study, 48 and 57 children were allocated into the atropine-placebo and placebo-atropine groups, respectively. After cessation, the photopic pupil diameter (PD) and mesopic PD both decreased (- 0.46 ± 0.47 mm, P < 0.001; - 0.30 ± 0.74 mm, P = 0.008), and the constriction ratio (CR, %) increased (4.39 ± 7.54, P < 0.001) compared with values at the crossover time point of the atropine-placebo group; pupil metrics of the atropine-placebo group had no difference from the values at the crossover time point of the placebo-atropine group. After 6 months of treatment, the photopic PD and the mesopic PD increased (0.54 ± 0.67 mm, P < 0.001; 0.53 ± 0.89 mm, P < 0.001), the CR (%) decreased (- 2.53 ± 8.64, P < 0.001) compared with values at the crossover time point of the placebo-atropine group. There was no significant relationship between pupil metrics and myopia progression during 0.01% atropine treatment. CONCLUSION: Pupil metrics and the CR could return to pre-atropine levels after cessation. Pupil metrics had no significant effect on myopia progression during treatment.

Design, methodology, and preliminary results of the non-human primates eye study.

PURPOSE: To describe the normative profile of ophthalmic parameters in a healthy cynomolgus monkey colony, and to identify the characteristic of the spontaneous ocular disease non-human primates (NHP) models. METHODS: The NHP eye study was a cross-sectional on-site ocular examination with about 1,000 macaques held in Guangdong Province, southeastern China. The NHPs (Macaca fascicularis, cynomolgus) in this study included middle-aged individuals with a high prevalence of the ocular disease. The NHP eye study (NHPES) performed the information including systematic data and ocular data. Ocular examination included measurement of intraocular pressure (IOP), anterior segment- optical coherence tomography (OCT), slit-lamp examination, fundus photography, autorefraction, electroretinography, etc. Ocular diseases included measurement of refractive error, anisometropia, cataract, pterygium, etc. RESULTS: A total of 1148 subjects were included and completed the ocular examination. The average age was 16.4 ± 4.93 years. Compared to the male participants, the females in the NHPES had shorter axial length and the mean Average retinal nerve fiber layer (RNFL) thickness (except for the nasal quadrants). The mean IOP, anterior chamber depth, lens thickness, axial length, central corneal thickness, choroid thickness and other parameters were similar in each group. CONCLUSION: The NHPES is a unique and high-quality study, this is the first large macaque monkey cohort study focusing on ocular assessment along with comprehensive evaluation. Results from the NHPES will provide important information about the normal range of ophthalmic measurements in NHP.

[Analysis of FDA's Review Concerns for Premarket Pathways and Predicate Product Selection of Device-led Combination Products].

By discussing the relevant requirements of the Principles of Premarket Pathways for Combination Products Guidance, this study analyzes FDA's review concerns for premarket pathways and predicate product selection of device-led combination products' five typical situations, in order to provide reference for Chinese manufacturers and investigators in device-led combination products registration.

Atomic Engineering Catalyzed Redox Kinetics of Nix Co1-x (OH)2 on Nanoporous Phosphide Electrode for Efficient Ni-Zn Batteries.

Aqueous nickel-zinc (Ni-Zn) batteries with excellent safety and environmental benignity are promising candidates for sustainable energy storage. However, the inferior conductivity and inevitable phase transition of trditional Ni-based cathodes limit the redox kinetics and lead to restricted electrode specific capacity and device energy density. Here, a Nix Co1-x (OH)2 electrode doped with Pd, Ag, and Au atoms is constructed for catalyzing the redox kinetics on the conductive nanoporous phosphide. Density functional theory calculations and experimental results reveal that the introduction of the Ag atomic dopants can effectively modulate the electron structure and optimize the OH- adsorption energy, thereby accelerating the catalyzed redox kinetics of Nix Co1-x (OH)2 by the facilitated charge transfer at the active sites around metal dopants. Consequently, the assembled Ni-Zn battery delivers an ultrahigh power density of 7.85 W cm-3 and energy density of 49.53 mW h cm-3 , with a long-term cycling stability. The cooperation of atomic catalysis and redox kinetics will inspire more exploration of efficient energy materials and devices.

Polymorphic Microsatellite Development, Genetic Diversity, Population Differentiation and Sexual State of Phytophthora capsici on Commercial Peppers in Three Provinces of Southwest China.

Pepper blight, caused by the oomycete pathogen Phytophthora capsici (P. capsici), is one of the most destructive soilborne diseases worldwide. Between 2019 and 2020, 235 single spore isolates of P. capsici were collected from 36 commercial pepper planting areas in Sichuan, Chongqing, and Guizhou provinces in China. A novel full set of 323 high-quality polymorphic microsatellites was obtained by resequencing 10 isolates. In total, 163 isolates with two alleles per microsatellite locus were used for population analysis and resulted in 156 genotypes on 10 microsatellite loci. The genetic diversity, population differentiation, principal component, genetic structure, and genetic relationships analyses showed an extensive variety of the P. capsici in Sichuan and Guizhou with clonal lineages, two shared genotypes, and no geographic differentiation. The population from Chongqing was differentiated from that of Sichuan and Guizhou and had the highest genetic diversity. There was no significant distinction between the populations of the two sampling years, but there was a small differentiation between the populations from bell peppers and hot peppers. The isolates from Southwest China were largely distant from the two reference isolates from the USA. The analysis of molecular variance showed that the major variance of the populations was within populations. The linkage equilibrium test, mating type composition, and oospore detection indicated that only P. capsici from the Jiulongpo district of Chongqing had appeared in sexual recombination. Overall, this study revealed that the high and complex genetic diversity population of P. capsici in Sichuan, Chongqing, and Guizhou with uneven geographic variation and limited sexual reproductive behavior in Chongqing, potentially driven by differences in the geographical environment, reproductive patterns, different cultivars, and artificial long-distance transfers. IMPORTANCE Phytophthora capsici, a notorious soilborne and rapidly evolving pathogen with a wide range of hosts, is a huge threat to pepper production worldwide. However, the detailed genetic structure and dynamics of P. capsici in most Chinese provinces are still unclear, even though China is the world's largest producer and consumer of peppers. Here, a novel full set of high-quality polymorphic microsatellites, obtained by genome resequencing data of 10 isolates from Southwest China, was provided for future population analyses. In this study, we further investigated and established the genetic structure, sexual recombination, geographic subdivisions, interannual stability, differentiation in different types of host peppers, and member relationships of P. capsici from three provinces in Southwest China. These results reveal the genetic structure and dynamics of P. capsici in three provinces of Southwest China and help us to execute more effective management strategies in the future.

Clinical outcomes of anterior tibiofibular ligament's distal fascicle transfer versus ligament reconstruction with InternalBrace™ for chronic ankle instability patients.

PURPOSE: Treatment of chronic ankle instability (CAI) for ankle sprain patients remains a challenge. If initial treatments fail, surgical stabilization techniques including ligament reconstruction should be performed. Anterior tibiofibular ligament (ATiFL) distal fascicle transfer for CAI was recently introduced. The goal of the study is to assess the 1-year clinical effectiveness of ATiFL's distal fascicle transfer versus ligament reconstruction with InternalBrace™ (Fa. Arthrex, Naples). METHODS: Between October 2019 and February 2021, 25 patients (14 males and 11 females) scheduled for ligament reconstruction treatment of CAI were enrolled after propensity score matching. Twelve underwent ligament reconstruction with InternalBrace™ (InternalBrace™ group) and thirteen underwent ATiFL's distal fascicle transfer (ATiFL's distal fascicle transfer group). We recorded the American Orthopedic Foot & Ankle Society (AOFAS) score, Visual Analogue Scale (VAS), anterior drawer test grade, patient satisfaction and complications. All results of this study were retrospectively analyzed. RESULTS: Statistically significant (p = 0.0251, independent-samples t test) differences in the AOFAS can be found between the ATiFL's distal fascicle transfer group and the InternalBrace™ group. No substantial changes in the VAS (p = 0.1778, independent-samples t test), patient satisfaction (p = 0.1800, independent-samples t test) and anterior drawer test grade (p = 0.9600, independent-samples t test) were found between the two groups. There was one patient with superficial wound infection and one patient with sural nerve injury in the InternalBrace™ group and ATiFL's distal fascicle transfer group, respectively. CONCLUSION: This is the first study that assessed a cohort of CAI patients and suggests that the ATiFL's distal fascicle transfer operation has the potential to attain good-to-excellent clinical outcomes after 1-year recovery. The AOFAS scores were significantly higher for patients with ATiFL's distal fascicle transfer, indicating that this technique may be considered a viable option for both patients and their surgeon, while long-term outcomes should be investigated in the future.

Phage-based technologies for highly sensitive luminescent detection of foodborne pathogens and microbial toxins: A review.

Foodborne pathogens and microbial toxins are the main causes of foodborne illness. However, trace pathogens and toxins in foods are difficult to detect. Thus, techniques for their rapid and sensitive identification and quantification are urgently needed. Phages can specifically recognize and adhere to certain species of microbes or toxins due to molecular complementation between capsid proteins of phages and receptors on the host cell wall or toxins, and thus they have been successfully developed into a detection platform for pathogens and toxins. This review presents an update on phage-based luminescent detection technologies as well as their working principles and characteristics. Based on phage display techniques of temperate phages, reporter gene detection assays have been designed to sensitively detect trace pathogens by luminous intensity. By the host-specific lytic effects of virulent phages, enzyme-catalyzed chemiluminescent detection technologies for pathogens have been exploited. Notably, these phage-based luminescent detection technologies can discriminate viable versus dead microbes. Further, highly selective and sensitive immune-based assays have been developed to detect trace toxins qualitatively and quantitatively via antibody analogs displayed by phages, such as phage-ELISA (enzyme-linked immunosorbent assay) and phage-IPCR (immuno-polymerase chain reaction). This literature research may lead to novel and innocuous phage-based rapid detection technologies to ensure food safety.

[Overview of the Work Related to Regulatory Scientific Research of Combination Products].

Based on the research situation of the regulatory scientific research project of combination products technical evaluation in recent years, this study introduces the relevant research on how to optimize the supervision of combination products, summarizes the research progress and research results of the project, in order to promote the development of related industries.

[Thoughts on Improving Joint Review of Combination Products].

This article combines the joint review of combination products in recent years, sorts out the links and common problems in the joint review process, introduces the work carried out to optimize the joint review process of combination products, and puts forward relevant suggestions for improvement, aim to improving the work of joint review and providing reference for relevant product declaration.

[Analysis on Focus of Clinical Evaluation of Dental Implants (Systems)].

From the perspective of technical evaluation, this article introduces the focus of clinical evaluation of dental implants (systems) in comparison with the comparable devices and discusses the clinical evaluation of such products，combined with the clinical evaluation review of dental implants (systems) products in recent years, in order to provide reference for the registration of these products.

Smart Responsive Quercetin-Conjugated Glycol Chitosan Prodrug Micelles for Treatment of Inflammatory Bowel Diseases.

The incidence and progression of inflammatory bowel disease are closely related to oxidative stress caused by excessive production of reactive oxygen species (ROS). To develop an efficacious and safe nanotherapy against inflammatory bowel diseases (IBD), we designed a novel pH/ROS dual-responsive prodrug micelle GC-B-Que as an inflammatory-targeted drug, which was comprised by active quercetin (Que) covalently linked to biocompatible glycol chitosan (GC) by aryl boronic ester as a responsive linker. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. Time-dependent NMR spectra traced the changes in the polymer structure in the presence of H2O2, confirming the release of the drug. The in vitro drug release studies indicated a low release rate (<20 wt %) in physiological conditions, but nearly complete release (>95 wt % after 72 h incubation) in a pH 5.8 medium containing 10 µM H2O2, exhibiting a pH/ROS dual-responsive property and sustained release behavior. Importantly, the negligible drug release in a simulated gastric environment in 1 h allowed us to perform intragastric administration, which has potential to achieve the oral delivery by mature enteric-coating modification in future. Further in vivo activities and biodistribution experiments found that the GC-B-Que micelles tended to accumulate in intestinal inflammation sites and showed better therapeutic efficacy than the free drugs (quercetin and mesalazine) in a colitis mice model. Typical inflammatory cytokines including TNF-α, IL-6, and iNOS were significantly suppressed by GC-B-Que micelle treatment. Our work promoted inflammatory-targeted delivery and intestinal drug accumulation for active single drug quercetin and improved the therapeutic effect of IBD. The current study also provided an alternative strategy for designing a smart responsive nanocarrier for a catechol-based drug to better achieve the target drug delivery.

S-Nitrosylation of Plastin-3 Exacerbates Thoracic Aortic Dissection Formation via Endothelial Barrier Dysfunction.

OBJECTIVE: Thoracic aortic dissection (TAD) is a fatal disease that leads to aortic rupture and sudden death. However, little is known about the effect and molecular mechanism of S-nitrosylation (SNO) modifications in TAD formation. Approach and Results: SNO levels were higher in aortic tissues from TAD patients than in those from healthy controls, and PLS3 (plastin-3) SNO was identified by liquid chromatography-tandem mass spectrometry analysis. Furthermore, tail vein administration of endothelial-specific adeno-associated viruses of mutant PLS3-C566A (denitrosylated form) suppressed the development of TAD in mice, but the wild-type PLS3 (S-nitrosylated form) virus did not. Mechanistically, Ang II (angiotensin II)-induced PLS3 SNO enhanced the association of PLS3 with both plectin and cofilin via an iNOS (inducible nitric oxide synthase)-dependent pathway in endothelial cells. The formation of PLS3/plectin/cofilin complex promoted cell migration and tube formation but weakened adherens junction formation in Ang II-treated endothelial cells. Interestingly, denitrosylated form of PLS3 partially mitigated Ang II-induced PLS3/plectin/cofilin complex formation and cell junction disruption. Additionally, the inhibition of iNOS attenuated PLS3 SNO and the association of PLS3 with plectin and cofilin, thereby modulating endothelial barrier function. CONCLUSIONS: Our data indicate that protein SNO modification in endothelial cells modulates the progression of aortic aneurysm and dissection. The iNOS-mediated SNO of PLS3 at the Cys566 site promoted its interaction with cofilin and plectin, thus contributing to endothelial barrier disruption and pathological angiogenesis in TAD.