Aligned grains and scattered light found in gaps of planet-forming disk.

Polarized (sub)millimetre emission from dust grains in circumstellar disks was initially thought to be because of grains aligned with the magnetic field1,2. However, higher-resolution multi-wavelength observations3-5 and improved models6-10 found that this polarization is dominated by self-scattering at shorter wavelengths (for example, 870 µm) and by grains aligned with something other than magnetic fields at longer wavelengths (for example, 3 mm). Nevertheless, the polarization signal is expected to depend on the underlying substructure11-13, and observations until now have been unable to resolve polarization in multiple rings and gaps. HL Tau, a protoplanetary disk located 147.3 ± 0.5 pc away14, is the brightest class I or class II disk at millimetre-submillimetre wavelengths. Here we show deep, high-resolution polarization observations of HL Tau at 870 µm, resolving polarization in both the rings and the gaps. We find that the gaps have polarization angles with a notable azimuthal component and a higher polarization fraction than the rings. Our models show that the disk polarization is due to both scattering and emission from the aligned effectively prolate grains. The intrinsic polarization of aligned dust grains is probably more than 10%, which is much higher than that expected in low-resolution observations (about 1%). Asymmetries and dust features that are not seen in non-polarimetric observations are seen in the polarization observations.

TransIntegrator: capture nearly full protein-coding transcript variants via integrating Illumina and PacBio transcriptomes.

Genes have the ability to produce transcript variants that perform specific cellular functions. However, accurately detecting all transcript variants remains a long-standing challenge, especially when working with poorly annotated genomes or without a known genome. To address this issue, we have developed a new computational method, TransIntegrator, which enables transcriptome-wide detection of novel transcript variants. For this, we determined 10 Illumina sequencing transcriptomes and a PacBio full-length transcriptome for consecutive embryo development stages of amphioxus, a species of great evolutionary importance. Based on the transcriptomes, we employed TransIntegrator to create a comprehensive transcript variant library, namely iTranscriptome. The resulting iTrancriptome contained 91 915 distinct transcript variants, with an average of 2.4 variants per gene. This substantially improved current amphioxus genome annotation by expanding the number of genes from 21 954 to 38 777. Further analysis manifested that the gene expansion was largely ascribed to integration of multiple Illumina datasets instead of involving the PacBio data. Moreover, we demonstrated an example application of TransIntegrator, via generating iTrancriptome, in aiding accurate transcriptome assembly, which significantly outperformed other hybrid methods such as IDP-denovo and Trinity. For user convenience, we have deposited the source codes of TransIntegrator on GitHub as well as a conda package in Anaconda. In summary, this study proposes an affordable but efficient method for reliable transcriptomic research in most species.

Risk factors for secondary epilepsy following febrile seizures in children: A meta-analysis.

OBJECTIVE: To systematically assess the risk factors for secondary epilepsy in children with febrile seizures, in order to promptly identify early signs of epilepsy and establish a reliable foundation for timely clinical intervention and improved prognosis. METHODS: The databases, including CNKI, WanFang, VIP, CBM, PubMed, Embase, Web of Science, and the Cochrane Library were searched for relevant studies, up to October 2023. Two researchers independently collected and extracted data from selected studies, adhering to predefined criteria. Statistical analysis was performed using Stata 15.0. RESULTS: A total of 23 studies included 714 cases in the case group and 5269 cases in the control group. The results of Meta-analysis showed that preterm birth (OR=3.30, P=0.02), history of perinatal asphyxia (OR=3.94, P=0.001), age at the first seizure < 12 months (OR=2.93, P=0.003), peak temperature < 39℃ (OR=2.51, P<0.001), onset of fever to seizure < 1 h (OR=5.61, P<0.001), Complex FS(OR=4.08, P<0.001), duration of the seizure > 15 min (OR=6.21, P<0.001), Multiple seizures (≥2/episode) in one attack (OR=2.92, P<0.001), focal seizures (OR=2.53, P=0.018), recurrent FS (≥2) (OR=3.49, P<0.001), neurodevelopmental abnormality(OR=8.68, P<0.001), developmental delay(OR=10.04, P<0.001), family history of epilepsy (OR=2.74, P=0.004), family history of FS (OR=2.07, P=0.022), electroencephalogram (EEG) abnormal(OR=4.06, P<0.001)and Brain imaging abnormalities (OR=2.84, P=0.002)were Risk factors for secondary epilepsy following FS in Children. Notably, gender (female) was not a significant factor. CONCLUSIONS: This study provides a comprehensive and systematic discussion of the risk factors associated with secondary epilepsy in children with febrile seizures. It actively formulates intervention measures for modifiable risk factors and conducts early detection and continuous follow-up observation for non-modifiable high-risk children, thereby reducing the risk of epilepsy.

Chelerythrine induces apoptosis and ferroptosis through Nrf2 in ovarian cancer cells.

Ovarian cancer is a prevalent malignancy in the female reproductive system, representing a significantly fatal and incurable tumor. Chelerythrine (CHE), a natural benzopyridine alkaloid, has demonstrated a broad spectrum of anticancer activities. Nevertheless, the ovarian cancer inhibitory impact of CHE remains unclear. In this study, we investigated the cytotoxic mechanism and potential targets of CHE on in vitro cultures of A2780 and SKOV3 cells derived from ovarian cancer. Additionally, in vivo experiments were conducted to confirm the suppressive impact of CHE on tumor growth in nude mice. The findings revealed that CHE impeded the growth of A2780 and SKOV3 cells in a concentration-time-dependent manner and significantly suppressed the development of tumors in nude mice. CHE elevated the level of oxidative stress in tumor cells, prompted cell cycle halt in the S phase, and increased their mitochondrial membrane potential. Western blotting results demonstrated that CHE could modulate the expression of proteins associated with apoptotic and ferroptosis processes in A2780 and SKOV3 cells. Nrf2 was verified to be an upstream key target mediating the inhibitory impact of CHE on ovarian cancer cells. In summary, CHE exerts its anti-cancer effects on ovarian cancer by modulating Nrf2, inhibiting cellular proliferation, and promoting apoptosis and ferroptosis.

Elucidating Anomalous Intensity Ratios in Chlorine L-Edge X-ray Absorption Spectroscopy: Multiplet Effects and Core Rydberg Transitions.

A relativistic core-valence-separated equation-of-motion coupled cluster (CVS-EOM-CC) study of chlorine L2,3-edge X-ray absorption near-edge structure (XANES) spectra using CH3Cl and CH2ICl as representative molecules is reported. The nearly identical intensity for the main features in the L2- and L3-edge XANES spectra is attributed to multiplet effects and the overlap between core-valence and core Rydberg transitions. The multiplet effects originating from the interaction between the core hole and the C-Cl σ* orbitals account for around half of the deviation of the L3 and L2 intensity ratio from the 2:1 ratio of the numbers of 2p3/2 and 2p1/2 electrons. The 2p3/2 → 4s core Rydberg transitions are shown to overlap with the 2p1/2 → σ* transitions and contribute to the other half of the intensity anomaly. We demonstrate that triple excitations in CVS-EOM-CC calculations play important roles in accurate simulation of the overlap between the 2p1/2 → σ* and 2p3/2 → 4s transitions.

A Bayesian inference model can predict the effects of attention on the serial dependence in heading estimation from optic flow.

It has been demonstrated that observers can accurately estimate their self-motion direction (i.e., heading) from optic flow, which can be affected by attention. However, it remains unclear how attention affects the serial dependence in the estimation. In the current study, participants conducted two experiments. The results showed that the estimation accuracy decreased when attentional resources allocated to the heading estimation task were reduced. Additionally, the estimates of currently presented headings were biased toward the headings of previously seen headings, showing serial dependence. Especially, this effect decreased (increased) when the attentional resources allocated to the previously (currently) seen headings were reduced. Furthermore, importantly, we developed a Bayesian inference model, which incorporated attention-modulated likelihoods and qualitatively predicted changes in the estimation accuracy and serial dependence. In summary, the current study shows that attention affects the serial dependence in heading estimation from optic flow and reveals the Bayesian computational mechanism behind the heading estimation.

Chemical substances and their activities in sea cucumber Apostichopus japonicus: A review.

Apostichopus japonicus, also known as Stichopus japonicus, with medicinal and food homologous figures, is a globally recognized precious ingredient with extremely high nutritional value. There is no relevant review available through literature search, so this article selects the research articles through the keywords "sea cucumber" and "Apostichopus japonicus (Stichopus japonicus)" in six professional databases, such as Wiley, PubMed, ScienceDirect, ACS, Springer, and Web of Science, from 2000 to the present, summarizing the extraction, isolation, and purification methods for the four major categories (polysaccharides, proteins and peptides, saponins, and other components) of the A. japonicus chemical substances and 10 effective biological activities of A. japonicus. Included are anticoagulation, anticancer/antitumor activities, hematopoiesis, regulation of gut microbiota, and immune regulatory activities that correspond to traditional efficacy. Literature support is provided for the development of medicines and functional foods and related aspects that play a leading role in future directions.

Analysis of risk factors related to early implant failure: A retrospective study.

STATEMENT OF PROBLEM: Factors influencing early implant failure (failure during the healing period) in the rehabilitation and restoration of oral function in partially edentulous patients are unclear. PURPOSE: The purpose of this clinical study was to investigate several factors that may be associated with early implant failure. MATERIAL AND METHODS: This retrospective study was conducted on 3247 implants in 2061 patients between 2009 and 2022. Patient-related and surgery-related factors, including smoking; sex; diabetes; bone grafting; implant length, diameter, and design; adjacent teeth; and insertion torque, were manually retrieved and analyzed. Using univariate and multivariate analyses, a generalized estimating equation (GEE) model with chi-squared tests was employed to evaluate factors related to early implant failure (the failure before restoration) (α=.05). RESULTS: The mean ±standard deviation age of the study patients was 49.2 ±15.0 years (range 18 to 91). Ninety-nine implants (3.05%) failed during the healing period. Three factors were statistically significant regarding early implant failure: smoking (odds ratio [OR]=1.92, P=.008), implant design (tapered implants) (OR=1.84, P=.007), and implant length <10 mm (OR=2.98, P=.011). Factors including diabetes, bone grafting, anatomic location, adjacent teeth (endodontic therapy in the adjacent teeth and the distance between implant and adjacent teeth), healing method, and insertion torque did not exhibit a statistically significant higher early implant failure rate. Ninety-three sites with failed implants received new implants, and 6 of these 93 implants failed during the healing period. CONCLUSIONS: Within the limitation of sample size, smokers, implant length (<10 mm), and implant design (tapered implant) exhibited higher risk of early implant failure in this retrospective study. Implant insertion torque, healing method, adjacent teeth, and diabetes did not significantly influence the risk of early implant failure.

Hazel Leaf Polyphenol Extract Alleviated Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis through Inhibiting Hippo Signaling.

Derived from hazelnuts, hazel leaf has been utilized in traditional folk medicine for centuries in countries such as Portugal, Sweden, and Iran. In our previous investigations, we conducted a preliminary assessment of the hazel leaf polyphenol extract (referred to as ZP) and identified nine compounds, such as kaempferol and chlorogenic acid, in its composition. ZP has shown promising properties as an antioxidant and anti-inflammatory agent. Our research has revealed that ZP has protective effects against cisplatin-induced acute kidney injury (AKI). We conducted a comprehensive examination of both the pathological and ultrastructural aspects and found that ZP effectively ameliorated renal tissue lesions and mitigated mitochondrial damage. Moreover, ZP significantly suppressed malondialdehyde levels while increasing glutathione and catalase concentrations in the kidneys of AKI-induced mice. ZP decreased the number of apoptotic cells and decreased pro-apoptotic protein expression in the kidneys of mice and human renal tubular epithelial cells (HK-2). Furthermore, treatment with ZP increased the levels of proteins marking anti-ferroptosis, such as GPX4, FTH1, and FSP1, in experiments both in vivo and in vitro. We elucidated the underlying mechanisms of ZP's actions, revealing its inhibitory effect on Yap phosphorylation and its regulation of Lats expression, which exert a protective influence on the kidneys. Furthermore, we found that inhibiting the Hippo pathway compromised ZP's nephroprotective effects in both in vitro and in vivo studies. In summary, this research shows that ZP exhibits renoprotective properties, effectively reducing oxidative damage, apoptosis, and ferroptosis in the kidneys by targeting the Hippo pathway.

Analysis of Polyphenol Extract from Hazel Leaf and Ameliorative Efficacy and Mechanism against Hyperuricemia Zebrafish Model via Network Pharmacology and Molecular Docking.

Hazel leaf, a by-product of hazelnuts, is commonly used in traditional folk medicine in Portugal, Sweden, Iran and other regions for properties such as vascular protection, anti-bleeding, anti-edema, anti-infection, and pain relief. Based on our previous studies, the polyphenol extract from hazel leaf was identified and quantified via HPLC fingerprint. The contents of nine compounds including kaempferol, chlorogenic acid, myricetin, caffeic acid, p-coumaric acid, resveratrol, luteolin, gallic acid and ellagic acid in hazel leaf polyphenol extract (ZP) were preliminary calculated, among which kaempferol was the highest with 221.99 mg/g, followed by chlorogenic acid with 8.23 mg/g. The inhibition of ZP on α-glucosidase and xanthine oxidase activities was determined via the chemical method, and the inhibition on xanthine oxidase was better. Then, the effect of ZP on hyperuricemia zebrafish was investigated. It was found that ZP obviously reduced the levels of uric acid, xanthine oxidase, urea nitrogen and creatinine, and up-regulated the expression ofOAT1 and HPRT genes in hyperuricemia zebrafish. Finally, the targeted network pharmacological analysis and molecular docking of nine polyphenol compounds were performed to search for relevant mechanisms for alleviating hyperuricemia. These results will provide a valuable basis for the development and application of hazel leaf polyphenols as functional ingredients.

Genomic Characteristics of Emerging Intraerythrocytic Anaplasma capra and High Prevalence in Goats, China.

Anaplasma capra is an emerging tickborne human pathogen initially recognized in China in 2015; it has been reported in ticks and in a wide range of domestic and wild animals worldwide. We describe whole-genome sequences of 2 A. capra strains from metagenomic sequencing of purified erythrocytes from infected goats in China. The genome of A. capra was the smallest among members of the genus Anaplasma. The genomes of the 2 A. capra strains contained comparable G+C content and numbers of pseudogenes with intraerythrocytic Anaplasma species. The 2 A. capra strains had 54 unique genes. The prevalence of A. capra was high among goats in the 2 endemic areas. Phylogenetic analyses revealed that the A. capra strains detected in this study were basically classified into 2 subclusters with those previously detected in Asia. Our findings clarify details of the genomic characteristics of A. capra and shed light on its genetic diversity.

Expressing Parasitoid Venom Protein VRF1 in an Entomopathogen Beauveria bassiana Enhances Virulence toward Cotton Bollworm Helicoverpa armigera.

Despite entomopathogenic fungi being used in various insect pest control, it is recognized that they could replace more chemical insecticides if they were more efficient. We have found that cotton bollworm Helicoverpa armigera responded to the infection of entomopathogenic fungus Beauveria bassiana by activating the Toll pathway. Koinobiont wasps also regulate host immunity and development to ensure the survival of their progeny. Previously, venom protein VRF1 was identified in Microplitis mediator. It enters H. armigera hemocytes, suppresses the expression of antimicrobial peptides (AMPs) by inhibiting the Toll pathway, and prevents parasite offspring from being encapsulated. With this in mind, we thought that it might be feasible to increase the virulence of B. bassiana by embedding VRF1 into its genome. Compared with that of wild-type (WT) B. bassiana, the median lethal dose (LD50) of the transformant expressing VRF1 (named BbVRF1) decreased approximately 2.36-fold, and the median time to lethality (LT50) was shortened to 84% when infecting H. armigera (a natural host of M. mediator). The AMP expression level of hemocytes in H. armigera infected with BbVRF1 strain was significantly downregulated compared to that in the control group infected with the WT. In addition, the LD50 of BbVRF1 against the fall armyworm Spodoptera frugiperda (an unnatural host of M. mediator) was decreased 3.45-fold and the LT50 was shortened to 73%, showing a greater virulence. Our research indicated that BbVRF1, an engineered strain of B. bassiana, has greater efficacy against pest insects both within and outside its host range (M. mediator), expanding the utilization of parasitoid wasp virulence effectors. IMPORTANCE Mycoinsecticides are essential for the development of integrated pest management as substitutes to chemical insecticides, but their usage is limited by their inferior virulence. Thus, genetically engineered bioinsecticides, including recombinant entomopathogenic fungi, have been regarded as a breakthrough to rapidly control pests. Deep knowledge of parasitoid wasps allows us to take advantage of this natural enemy of pest insects beyond raising them for field release. Our transformant BbVRF1 (Beauveria bassiana integrated with a venom protein VRF1 from Microplitis mediator) showed a higher virulence in H. armigera and S. frugiperda, demonstrating its potential for managing natural or unnatural hosts of M. mediator. This result provides a new strategy regarding which venom protein of parasitoid wasps can become part of the arsenal with which to equip entomopathogenic fungi. Utilizing parasitoid wasps with this approach could easily overcome the difficulties of artificial culture and enhance the virulence of other biocontrol agents.

Effective protocol for generating NOON states of resonator modes.

We propose a protocol for the generation of NOON states of resonator modes. The physical model is composed of two Kerr-nonlinear resonators and a four-level qudit. Using the off-resonant couplings between the resonators and the qudit, qudit-level-dependent frequency shifts on the two resonators are induced. The frequency shifts allow us to drive different resonators to the N-photon state when the qudit is in different intermediate levels. Consequently, the generation of NOON states with arbitrary photon number N can be completed in only three steps, i.e., driving the qudit to a superposition state of the two intermediate levels, driving one of the resonators to its N-photon state, and driving the qudit back to its ground level. Numerical simulations show that, in the regime of strong Kerr nonlinearity and coupling strengths, the protocol can produce the NOON state with high fidelity in the cases of different photon numbers. In addition, it is possible for the protocol to produce acceptable fidelity in the presence of systematic errors and decoherence factors. Therefore, the protocol may provide some useful perspectives for effective generation of photonic NOON states.

Serial dependence bias can predict the overall estimation error in visual perception.

Although visual feature estimations are accurate and precise, overall estimation errors (i.e., the difference between estimates and actual values) tend to show systematic patterns. For example, estimates of orientations are systematically biased away from horizontal and vertical orientations, showing an oblique illusion. Additionally, many recent studies have demonstrated that estimations of current visual features are systematically biased toward previously seen features, showing a serial dependence. However, no study examined whether the overall estimation errors were correlated with the serial dependence bias. To address this question, we enrolled three groups of participants to estimate orientation, motion speed, and point-light-walker direction. The results showed that the serial dependence bias explained over 20% of overall estimation errors in the three tasks, indicating that we could use the serial dependence bias to predict the overall estimation errors. The current study first demonstrated that the serial dependence bias was not independent from the overall estimation errors. This finding could inspire researchers to investigate the neural bases underlying the visual feature estimation and serial dependence.

Numerical Analysis of Droplet Impact on the Convex Surface with Liquid Film.

Droplet impact on film is a common natural appearance in industrial production. The numerical simulation method is used to simulate the evolution process of droplet impact on different convex surfaces with liquid film to study the influence of various surface structures on the impact of droplets on the film. The mechanism of droplet impact on irregular wall is also explored. The effect of the height and width of the convex on the evolution of the interphase interface and the characteristic parameters of the crown and cavity are discussed. Based on the results, the convex has a great effect on the change form of droplets after impacting the liquid film. A region of high pressure will appear above the convex, and vortices will form around it. In terms of the characteristics of the crown, the growth rate of the crown height increases with the height of the convex. The spreading diameter of the crown increases with the height of the convex. The effect of convex width on the crown is less than that of convex height. The convex has a great influence on the evolution of the cavity, and the convex of different scales will affect the development shape of the cavity. The present finding provides theoretical guidance for the application of droplets impinging on liquid film.

Genus Suaeda: Advances in phytology, chemistry, pharmacology and clinical application (1895 - 2021).

More than 100 species of annual herb genus Suaeda widely distribute (Asia, North America, northern Africa and Europe), are rich in resources (about hundreds of millions of tons/Y) and have a long historical application. Most of them are mainly used for traditional food, feed and medicine. Recently, they have been employed to repair saline-alkali land and beautify the environment. So far, only 27 species have been reported on the bioactivity diversity, broad spectrum and effectiveness in clinical practice. Therefore, the in-depth and extensive research of Suaeda has become a research hotspot around the world. However, only one review summarized the nutritional, chemical and biological values of Suaeda. By searching the international authoritative databases (ACS Publications, ScienceDirect, PubMed, Springer, web of Science and Bing International etc.) and collecting 103 literatures closely related to Suaeda (1895-2021), herewith a comprehensive and systematic review was conducted on the phytology, chemistry, pharmacology and clinical application, enveloping the classification evolution between Amaranthaceae and Chenopodiaceae, distribution and common botanical characteristics; involving 9 chemical categories of 163 derivatives covering 14 new and 6 first-isolated ones, and appraising the content determination of 6 categories of components; mainly including the pharmacology of 13 species in vivo and vitro; estimating the clinical application of 16 species cured the related diseases of eight human physiological system except for the motor system. It is expected that this paper will provide forward-looking scientific ideas and literature support for the further modern research, development and utilization of the genus.

Effect of carbendazim on honey bee health: Assessment of survival, pollen consumption, and gut microbiome composition.

Gut microbiota and nutrition play major roles in honey bee health. Recent reports have shown that pesticides can disrupt the gut microbiota and cause malnutrition in honey bees. Carbendazim is the most commonly used fungicide in China, but it is not clear whether carbendazim negatively affects the gut microbes and nutrient intake levels in honey bees. To address this research gap, we assessed the effects of carbendazim on the survival, pollen consumption, and sequenced 16 S rRNA gene to determine the bacterial composition in the midgut and hindgut. Our results suggest that carbendazim exposure does not cause acute death in honey bees even at high concentrations (5000 mg/L), which are extremely unlikely to exist under field conditions. Carbendazim does not disturb the microbiome composition in the gut of young worker bees during gut microbial colonization and adult worker bees with established gut communities in the mid and hindgut. However, carbendazim exposure significantly decreases pollen consumption in honey bees. Thus, exposure of bees to carbendazim can perturb their beneficial nutrition homeostasis, potentially reducing honey bee immunity and increasing their susceptibility to infection by pathogens, which influence effectiveness as pollinators, even colony health.

Quercus salicina Blume: Research Progress in Chemistry and Pharmacodynamics (1959-2021).

The crude extracts of different parts (leaves and shoots) of Quercus salicina Blume (QS) have shown considerable effect in urolithiasis. QS has been widely used in clinical practice and has attracted great research interest The relevant published literature, however, reveals only partial education of its chemical components and bio-active mechanisms, and only two review articles have summarized the QS research progress. In this review, a comprehensive and systematic review of chemistry and pharmacodynamics of QS was carried out using the international authoritative databases (1959-2021), focusing on phenols and flavonoids, and their effect such as urinary stone dissolution, anti-inflammatory, anti-diabetes, anti-bacterial, antioxidant, and anti-allergy activities as well as toxic effects. The aim of review is to provide the most recent and effective literature support for further basic research and application development.

Factors impacting new bone formation in transcrestal sinus floor elevation followed by implant placement: a cross-sectional study.

OBJECTIVES: This study aimed to evaluate factors related to new bone formation (NBF) following simultaneous implant placement with transcrestal sinus floor elevation (TSFE). MATERIALS AND METHODS: Between 2008 and 2020, 357 implants (276 patients) were placed with TSFE. Clinical and radiographic examinations were performed at the preoperative, postoperative, restoration, and follow-up stages. Marginal bone loss, during healing, and the survival rate were retrospectively analyzed. RESULTS: Implant protrusion lengths (IPL: 3-5 mm) significantly influenced NBF during the healing period (P-value = 0.026, Odds Ratio = 1.15, 95% confidence interval = 1.02- 1.30). Bone grafting was correlated with NBF (P-value = 0.001). The distance between the implant and lateral wall of the sinus (mesial: P-value = 0.041, distal: P-value = 0.019, buccal: P-value = 0.032, lingual: P-value = 0.043) and angle between the implant and sinus floor significantly influenced NBF in four directions (mesial: P-value = 0.041, distal: P-value = 0.02, buccal: P-value = 0.047, lingual: P-value = 0.005). Implant shape (cylindrical or conical), perforations, smoking, and diabetes did not significantly affect NBF during the healing period (P > 0.05). CONCLUSION: Increasing the distance and angle between the implant and lateral wall of the sinus floor corresponded with reduced NBF. IPL may be an important factor that should be considered. CLINICAL RELEVANCE: Our study analyzed new bone formation following transcrestal sinus floor elevation among patients who underwent this procedure with simultaneous implant placement, several factors (including angle and distance between sinus and lateral wall and implant protrusion length) were included in our study.

SNO-MLP (S-Nitrosylation of Muscle LIM Protein) Facilitates Myocardial Hypertrophy Through TLR3 (Toll-Like Receptor 3)-Mediated RIP3 (Receptor-Interacting Protein Kinase 3) and NLRP3 (NOD-Like Receptor Pyrin Domain Containing 3) Inflammasome Activation.

BACKGROUND: S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of SNO of MLP (muscle LIM protein) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload. METHODS: Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. SNO sites were further identified through liquid chromatography-tandem mass spectrometry. Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry and confirmed by coimmunoprecipitation. Recruitment of TLR3 (Toll-like receptor 3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA-transfected neonatal rat cardiomyocytes and in a TLR3 knockout mouse model. RESULTS: SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction. The level of SNO-MLP also increased in angiotensin II- or phenylephrine-treated neonatal rat cardiomyocytes. S-nitrosylated site of MLP at cysteine 79 was identified by liquid chromatography-tandem mass spectrometry and confirmed in neonatal rat cardiomyocytes. Mutation of cysteine 79 significantly reduced hypertrophic growth in angiotensin II- or phenylephrine-treated neonatal rat cardiomyocytes and transverse aortic constriction mice. Reducing SNO-MLP level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, SNO-MLP stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupted this interaction by downregulating TLR3-attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and RIP3 (receptor-interacting protein kinase 3). This interaction in turn induced NLRP3 (nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3) inflammasome activation, thereby promoting the development of myocardial hypertrophy. CONCLUSIONS: Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a therapeutic target for myocardial hypertrophy and heart failure.