Deep Learning-Based Dynamic Region of Interest Autofocus Method for Grayscale Image.

In the field of autofocus for optical systems, although passive focusing methods are widely used due to their cost-effectiveness, fixed focusing windows and evaluation functions in certain scenarios can still lead to focusing failures. Additionally, the lack of datasets limits the extensive research of deep learning methods. In this work, we propose a neural network autofocus method with the capability of dynamically selecting the region of interest (ROI). Our main work is as follows: first, we construct a dataset for automatic focusing of grayscale images; second, we transform the autofocus issue into an ordinal regression problem and propose two focusing strategies: full-stack search and single-frame prediction; and third, we construct a MobileViT network with a linear self-attention mechanism to achieve automatic focusing on dynamic regions of interest. The effectiveness of the proposed focusing method is verified through experiments, and the results show that the focusing MAE of the full-stack search can be as low as 0.094, with a focusing time of 27.8 ms, and the focusing MAE of the single-frame prediction can be as low as 0.142, with a focusing time of 27.5 ms.

Sirt1 Deficiency Promotes Age-Related AF Through Enhancing Atrial Necroptosis by Activation of RIPK1 Acetylation.

BACKGROUND: Aging is one of the most potent risk determinants for the onset of atrial fibrillation (AF). Sirts (sirtuins) have been implicated in the pathogenesis of cardiovascular disease, and their expression declines with aging. However, whether Sirts involved in age-related AF and its underlying mechanisms remain unknown. The present study aims to explore the role of Sirts in age-related AF and delineate the underlying molecular mechanisms. METHODS: Sirt1 levels in the atria of both elderly individuals and aging rats were evaluated using quantitative real-time polymerase chain reaction and Western blot analysis. Mice were engineered to specifically knockout Sirt1 in the atria and right ventricle (Sirt1mef2c/mef2c). Various techniques, such as echocardiography, atrial electrophysiology, and protein acetylation modification omics were employed. Additionally, coimmunoprecipitation was utilized to substantiate the interaction between Sirt1 and RIPK1 (receptor-interacting protein kinase 1). RESULTS: We discerned that among the diverse subtypes of sirtuin proteins, only Sirt1 expression was significantly diminished in the atria of elderly people and aged rats. The Sirt1mef2c/mef2c mice exhibited an enlarged atrial diameter and heightened vulnerability to AF. Acetylated proteomics and cell experiments identified that Sirt1 deficiency activated atrial necroptosis through increasing RIPK1 acetylation and subsequent pseudokinase MLKL (mixed lineage kinase domain-like protein) phosphorylation. Consistently, necroptotic inhibitor necrosulfonamide mitigated atrial necroptosis and diminished both the atrial diameter and AF susceptibility of Sirt1mef2c/mef2c mice. Resveratrol prevented age-related AF in rats by activating atrial Sirt1 and inhibiting necroptosis. CONCLUSIONS: Our findings first demonstrated that Sirt1 exerts significant efficacy in countering age-related AF by impeding atrial necroptosis through regulation of RIPK1 acetylation, highlighting that the activation of Sirt1 or the inhibition of necroptosis could potentially serve as a therapeutic strategy for age-related AF.

Infant age inversely correlates with gut carriage of resistance genes, reflecting modifications in microbial carbohydrate metabolism during early life.

The infant gut microbiome is increasingly recognized as a reservoir of antibiotic resistance genes, yet the assembly of gut resistome in infants and its influencing factors remain largely unknown. We characterized resistome in 4132 metagenomes from 963 infants in six countries and 4285 resistance genes were observed. The inherent resistome pattern of healthy infants (N = 272) could be distinguished by two stages: a multicompound resistance phase (Months 0-7) and a tetracycline-mupirocin-ß-lactam-dominant phase (Months 8-14). Microbial taxonomy explained 40.7% of the gut resistome of healthy infants, with Escherichia (25.5%) harboring the most resistance genes. In a further analysis with all available infants (N = 963), we found age was the strongest influencer on the resistome and was negatively correlated with the overall resistance during the first 3 years (p < 0.001). Using a random-forest approach, a set of 34 resistance genes could be used to predict age (R 2 = 68.0%). Leveraging microbial host inference analyses, we inferred the age-dependent assembly of infant resistome was a result of shifts in the gut microbiome, primarily driven by changes in taxa that disproportionately harbor resistance genes across taxa (e.g., Escherichia coli more frequently harbored resistance genes than other taxa). We performed metagenomic functional profiling and metagenomic assembled genome analyses whose results indicate that the development of gut resistome was driven by changes in microbial carbohydrate metabolism, with an increasing need for carbohydrate-active enzymes from Bacteroidota and a decreasing need for Pseudomonadota during infancy. Importantly, we observed increased acquired resistance genes over time, which was related to increased horizontal gene transfer in the developing infant gut microbiome. In summary, infant age was negatively correlated with antimicrobial resistance gene levels, reflecting a composition shift in the gut microbiome, likely driven by the changing need for microbial carbohydrate metabolism during early life.

Robust Principal Component Analysis Based on Fuzzy Local Information Reservation.

Principal Component Analysis (PCA) aims to acquire the principal component space containing the essential structure of data, instead of being used for mining and extracting the essential structure of data. In other words, the principal component space contains not only information related to the essential structure of data but also some unrelated information. This frequently occurs when the intrinsic dimensionality of data is unknown or when it has complex distribution characteristics such as multi-modalities, manifolds, etc. Therefore, it is unreasonable to identify noise and useful information based solely on reconstruction error. For this reason, PCA is unsuitable as a preprocessing technique for most applications, especially in noisy environment. To solve this problem, this paper proposes robust PCA based on fuzzy local information reservation (FLIPCA). By analyzing the impact of reconstruction error on sample discriminability, FLIPCA provides a theoretical basis for noise identification and processing. This not only greatly improves its robustness but also extends its applicability and effectiveness as a data preprocessing technique. Meanwhile, FLIPCA maintains consistent mathematical descriptions with traditional PCA while having few adjustable hyperparameters and low algorithmic complexity. Finally, we conducted comprehensive experiments on synthetic and real-world datasets, which substantiated the superiority of our proposed algorithm.

MMCA-NET: A Multimodal Cross Attention Transformer Network for Nasopharyngeal Carcinoma Tumor Segmentation Based on a Total-Body PET/CT System.

Nasopharyngeal carcinoma (NPC) is a malignant tumor primarily treated by radiotherapy. Accurate delineation of the target tumor is essential for improving the effectiveness of radiotherapy. However, the segmentation performance of current models is unsatisfactory due to poor boundaries, large-scale tumor volume variation, and the labor-intensive nature of manual delineation for radiotherapy. In this paper, MMCA-Net, a novel segmentation network for NPC using PET/CT images that incorporates an innovative multimodal cross attention transformer (MCA-Transformer) and a modified U-Net architecture, is introduced to enhance modal fusion by leveraging cross-attention mechanisms between CT and PET data. Our method, tested against ten algorithms via fivefold cross-validation on samples from Sun Yat-sen University Cancer Center and the public HECKTOR dataset, consistently topped all four evaluation metrics with average Dice similarity coefficients of 0.815 and 0.7944, respectively. Furthermore, ablation experiments were conducted to demonstrate the superiority of our method over multiple baseline and variant techniques. The proposed method has promising potential for application in other tasks.

Fructo-oligosaccharide supplementation enhances the growth of nursing dairy calves while stimulating the persistence of Bifidobacterium and hindgut microbiome's maturation.

The colonization and development of the gut microbiome in dairy calves play a crucial role in their overall health and future productivity. Despite the widely proposed benefits of inulin-related products on the host, there is insufficient information about how supplementing fructo-oligosaccharides (FOS) affects the colonization and development of the gut microbiome in calves. In a randomized intervention trial involving newborn male Holstein dairy calves, we investigated the effect of FOS on the calf hindgut microbiome, short-chain fatty acids (SCFA), growth performance, and the incidence of diarrhea. The daily administration of FOS exhibited a time-dependent increase in the ADG and the concentration of SCFA. Concurrently, FOS delayed the natural decline of Bifidobacterium, promoting the maturation and stabilization of the hindgut microbiome. These findings not only contribute to a theoretical understanding of the judicious application of prebiotics but also hold significant practical implications for the design of early life dietary interventions in the rearing of dairy calves.

Fecal microbial gene transfer contributes to the high-grain diet-induced augmentation of aminoglycoside resistance in dairy cattle.

A high-grain (HG) diet can rapidly lower the rumen pH and thus modify the gastrointestinal microbiome in dairy cattle. Although the prevalence of antibiotic resistance is strongly linked with the gut microbiome, the influences of HG diet on animals' gut resistome remain largely unexplored. Here, we examined the impact and mechanism of an HG diet on the fecal resistome in dairy cattle by metagenomically characterizing the gut microbiome. Eight lactating Holstein cattle were randomly allocated into two groups and fed either a conventional (CON) or HG diet for 3 weeks. The fecal microbiome and resistome were significantly altered in dairy cattle from HG, demonstrating an adaptive response that peaks at day 14 after the dietary transition. Importantly, we determined that feeding an HG diet specifically elevated the prevalence of resistance to aminoglycosides (0.11 vs 0.24 RPKG, P < 0.05). This diet-induced resistance increase is interrelated with the disproportional propagation of microbes in Lachnospiraceae, indicating a potential reservoir of aminoglycosides resistance. We further showed that the prevalence of acquired resistance genes was also modified by introducing a different diet, likely due to the augmented frequency of lateral gene transfer (LGT) in microbes (CON vs HG: 254 vs 287 taxa) such as Lachnospiraceae. Consequently, we present that diet transition is associated with fecal resistome modification in dairy cattle and an HG diet specifically enriched aminoglycosides resistance that is likely by stimulating microbial LGT.IMPORTANCEThe increasing prevalence of antimicrobial resistance is one of the most severe threats to public health, and developing novel mitigation strategies deserves our top priority. High-grain (HG) diet is commonly applied in dairy cattle to enhance animals' performance to produce more high-quality milk. We present that despite such benefits, the application of an HG diet is correlated with an elevated prevalence of resistance to aminoglycosides, and this is a combined effect of the expansion of antibiotic-resistant bacteria and increased frequency of lateral gene transfer in the fecal microbiome of dairy cattle. Our results provided new knowledge in a typically ignored area by showing an unexpected enrichment of antibiotic resistance under an HG diet. Importantly, our findings laid the foundation for designing potential dietary intervention strategies to lower the prevalence of antibiotic resistance in dairy production.

Evolocumab prevents atrial fibrillation in rheumatoid arthritis rats through restraint of PCSK9 induced atrial remodeling.

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is implicated in the pathogenesis and progression of autoimmune disease. Patients with rheumatoid arthritis (RA) are at high risk of developing atrial fibrillation (AF), while whether PCSK9 is involved in the onset of AF among RA patients remains unclear. OBJECTIVES: To explore the role of PCSK9 in the occurrence of AF in RA patients and decipher the underlying mechanism. METHODS: We established a rat model of collagen-induced arthritis (CIA) by immunization with type II collagen in Freund's incomplete adjuvant. Atrial electrophysiological test was used to evaluate AF susceptibility. We performed a clinical study to examine the correlation between PCSK9 level and AF, which recruited healthy control, RA patients and RA patients complicated with AF. Evolocumab (a monoclonal antibody of PCSK9) is administered via intraperitoneal injection in CIA rats to assess the role of PCSK9 in RA-related AF. LPS-RS (LPS inhibitor), clodronate liposomes (depletion of macrophages), and cell co-culture model were used to dissect the mechanism underlying PCSK9 promotes AF. RESULTS: AF inducibility and duration were higher in CIA rats, accompanied by elevated plasma and atrial PCSK9. Interestingly, compared with healthy control subjects, patients with RA showed an increase in PCSK9, and the PCSK9 is much higher in RA patients complicated with AF. The level of PCSK9 was independently associated with AF risk in RA patients. In the in vivo experiment, evolocumab reduced AF susceptibility, and ameliorated atrial structural remodeling of CIA rats. Mechanistically, augmented LPS in CIA rats led to an increase in PCSK9, which exacerbated fibrosis of cardiac fibroblasts and apoptosis of cardiac myocytes by enhancement of M1 macrophages polarization and inflammation, thereby contributing to AF. CONCLUSION: This study suggests that elevated PCSK9 causes atrial structural remodeling by enhancement of M1 macrophages polarization in atria, and evolocumab can effectively protects CIA rats from AF.

Effects of Fumarate and Nitroglycerin on In Vitro Rumen Fermentation, Methane and Hydrogen Production, and on Microbiota.

This study aimed to investigate the effects of fumarate and nitroglycerin on rumen fermentation, methane and hydrogen production, and microbiota. In vitro rumen fermentation was used in this study with four treatment groups: control (CON), fumarate (FA), nitroglycerin (NG) and fumarate plus nitroglycerin (FN). Real-time PCR and 16S rRNA gene sequencing were used to analyze microbiota. The results showed that nitroglycerin completely inhibited methane production and that this resulted in hydrogen accumulation. Fumarate decreased the hydrogen accumulation and improved the rumen fermentation parameters. Fumarate increased the concentration of propionate and microbial crude protein, and decreased the ratio of acetate to propionate in FN. Fumarate, nitroglycerin and their combination did not affect the abundance of bacteria, protozoa and anaerobic fungi, but altered archaea. The PCoA showed that the bacterial (Anosim, R = 0.747, p = 0.001) and archaeal communities (Anosim, R = 0.410, p = 0.005) were different among the four treatments. Compared with CON, fumarate restored Bacteroidetes, Firmicutes, Spirochaetae, Actinobacteria, Unclassified Ruminococcaceae, Streptococcus, Treponema and Bifidobacterium in relative abundance in FN, but did not affect Succinivibrio, Ruminobacter and archaeal taxa. The results indicated that fumarate alleviated the depressed rumen fermentation caused by the inhibition of methanogenesis by nitroglycerin. This may potentially provide an alternative way to use these chemicals to mitigate methane emission in ruminants.

The Endless World of Carotenoids-Structural, Chemical and Biological Aspects of Some Rare Carotenoids.

Carotenoids are a large and diverse group of compounds that have been shown to have a wide range of potential health benefits. While some carotenoids have been extensively studied, many others have not received as much attention. Studying the physicochemical properties of carotenoids using electron paramagnetic resonance (EPR) and density functional theory (DFT) helped us understand their chemical structure and how they interact with other molecules in different environments. Ultimately, this can provide insights into their potential biological activity and how they might be used to promote health. In particular, some rare carotenoids, such as sioxanthin, siphonaxanthin and crocin, that are described here contain more functional groups than the conventional carotenoids, or have similar groups but with some situated outside of the rings, such as sapronaxanthin, myxol, deinoxanthin and sarcinaxanthin. By careful design or self-assembly, these rare carotenoids can form multiple H-bonds and coordination bonds in host molecules. The stability, oxidation potentials and antioxidant activity of the carotenoids can be improved in host molecules, and the photo-oxidation efficiency of the carotenoids can also be controlled. The photostability of the carotenoids can be increased if the carotenoids are embedded in a nonpolar environment when no bonds are formed. In addition, the application of nanosized supramolecular systems for carotenoid delivery can improve the stability and biological activity of rare carotenoids.

Simple and Commercially Available 6-chloroimidazo[1,2-a]pyridine-2-carboxylic Acid-based Fluorescent Probe for Monitoring pH Changes.

Commercially available compounds that can be directly used as fluorescent probes will greatly promote the development of fluorescent imaging. Based on our previously work related to nitrogen bridgehead heterocycles, herein, a commercially available compound, 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid, has been detected for monitoring pH value (3.0-7.0). The probe proves to have high selectivity and sensitivity, brilliant reversibility, and extremely short response time. The real-time imaging of pH changes in yeast was also conducted.

Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation.

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure-activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, Rpred2 = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, Rpred2 = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors.

Platelet Desialylation Is a Novel Mechanism and Therapeutic Target in Daboia siamensis and Agkistrodon halys Envenomation-Induced Thrombocytopenia.

Venom-induced thrombocytopenia (VIT) is one of the most important hemotoxic effects of a snakebite, which is often associated with venom-induced consumptive coagulopathy (VICC). Refractory thrombocytopenia without significant coagulation abnormalities has also been reported after envenomation by some viperid snakes; however, the mechanisms are not well understood and therapeutic strategies are lacking. Here, we found that patients injured by Daboia siamensis or Agkistrodon halys snakes, who were resistant to standard antivenom treatment, had developed coagulopathy-independent thrombocytopenia. Venoms from these viperid snakes, rather than from the elapid snake (Bungarus multicinctus), induced platelet surface expression of neuraminidase-1 (NEU-1), and significantly increased the desialylation of the glycoproteins on human platelets. The desialylated platelets caused by viperid snake venoms were further internalized by macrophages, which resulted in reduced platelet numbers in peripheral blood. Importantly, neuraminidase inhibitor significantly decreased viper venom-induced platelet desialylation, therefore inhibiting platelet phagocytosis by macrophages, and alleviating venom-induced thrombocytopenia. Collectively, these findings support an important role for desialylated platelet clearance in the progression of viper envenomation-induced, coagulopathy-independent thrombocytopenia. Our study demonstrates that the neuraminidase inhibitor may be a potential therapy or adjuvant therapy to treat snakebite-induced thrombocytopenia.

Atrial myocyte-derived exosomal microRNA contributes to atrial fibrosis in atrial fibrillation.

BACKGROUND: Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosomes are a promising cell-free therapeutic approach for the treatment of AF. The purposes of this study were to explore the mechanisms by which exosomes derived from atrial myocytes regulate atrial remodeling and to determine whether their manipulation facilitates the therapeutic modulation of potential fibrotic abnormalities during AF. METHODS: We isolated exosomes from atrial myocytes and patient serum, and microRNA (miRNA) sequencing was used to analyze exosomal miRNAs in exosomes derived from atrial myocytes and patient serum. mRNA sequencing and bioinformatics analyses corroborated the key genes that were direct targets of miR-210-3p. RESULTS: The miRNA sequencing analysis identified that miR-210-3p expression was significantly increased in exosomes from tachypacing atrial myocytes and serum from patients with AF. In vitro, the miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, miR-210-3p knock out (KO) reduced the incidence of AF and ameliorated atrial fibrosis induced by Ang II. The mRNA sequencing analysis and dual-luciferase reporter assay showed that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is a potential target gene of miR-210-3p. The functional analysis suggested that GPD1L regulated atrial fibrosis via the PI3K/AKT signaling pathway. In addition, silencing GPD1L in atrial fibroblasts induced cell proliferation, and these effects were reversed by a PI3K inhibitor (LY294002). CONCLUSIONS: Atrial myocyte-derived exosomal miR-210-3p promoted cell proliferation and collagen synthesis by inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be a novel target to ameliorate atrial fibrosis in patients with AF.

Fuzzy Sparse Deviation Regularized Robust Principal Component Analysis.

Robust principal component analysis (RPCA) is a technique that aims to make principal component analysis (PCA) robust to noise samples. The current modeling approaches of RPCA were proposed by analyzing the prior distribution of the reconstruction error terms. However, these methods ignore the influence of samples with large reconstruction errors, as well as the valid information of these samples in principal component space, which will degrade the ability of PCA to extract the principal component of data. In order to solve this problem, Fuzzy sparse deviation regularized robust principal component Analysis (FSD-PCA) is proposed in this paper. First, FSD-PCA learns the principal components by minimizing the square of l2 -norm-based reconstruction error. Then, FSD-PCA introduces sparse deviation on reconstruction error term to relax the samples with large bias, thus FSD-PCA can process noise and principal components of samples separately as well as improve the ability of FSD-PCA for retaining the principal component information. Finally, FSD-PCA estimates the prior probability of each sample by fuzzy weighting based on the relaxed reconstruction error, which can improve the robustness of the model. The experimental results indicate that the proposed model performs excellent robustness against different types of noise than the state-of-art algorithms, and the sparse deviation term enables FSD-PCA to process noise information and principal component information separately, so FSD-PCA can filter the noise information of an image and restore the corrupted image.

Oxalamide/Amide Ligands: Enhanced and Copper-Catalyzed C-N Cross-Coupling for Triarylamine Synthesis.

Triarylamines are privileged core structures that are found in versatile optoelectronic materials. New methods are constantly being sought for their preparation. Herein, a new protocol for triarylamine synthesis is presented where a wide range of diarylamines couple smoothly with aryl bromides mediated by a copper oxalamide (or amide) catalytic system. Notably, a new non-C2-symmetric 1-isoquinolinamide-based N,N-/N,O-bidentate ligand was introduced that could tolerate bulky diarylamines. Plenty of known optoelectronic functional molecules could be synthesized in good to excellent yields. The practicality of this C-N cross-coupling was illustrated by the gram-scale synthesis of a patented thermally activated delayed fluorescence emitter for organic light-emitting diodes.

Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis.

BACKGROUND: Cold exposure is one of the most important risk factors for atrial fibrillation (AF), and closely related to the poor prognosis of AF patients. However, the mechanisms underlying cold-related AF are poorly understood. METHODS: Various techniques including 16S rRNA gene sequencing, fecal microbiota transplantation, and electrophysiological examination were used to determine whether gut microbiota dysbiosis promotes cold-related AF. Metabonomics were performed to investigate changes in fecal trimethylamine (TMA) and plasma trimethylamine N-oxide (TMAO) during cold exposure. The detailed mechanism underlying cold-related AF were examined in vitro. Transgenic mice were constructed to explore the role of pyroptosis in cold-related AF. The human cohort was used to evaluate the correlation between A. muciniphila and cold-related AF. FINDINGS: We found that cold exposure caused elevated susceptibility to AF and reduced abundance of Akkermansia muciniphila (A. muciniphila) in rats. Intriguingly, oral supplementation of A. muciniphila ameliorated the pro-AF property induced by cold exposure. Mechanistically, cold exposure disrupted the A. muciniphila, by which elevated the level of trimethylamine N-oxide (TMAO) through modulation of the microbial enzymes involved in trimethylamine (TMA) synthesis. Correspondingly, progressively increased plasma TMAO levels were validated in human subjects during cold weather. Raised TMAO enhanced the infiltration of M1 macrophages in atria and increased the expression of Casp1-p20 and cleaved-GSDMD, ultimately causing atrial structural remodeling. Furthermore, the mice with conditional deletion of caspase1 exhibited resistance to cold-related AF. More importantly, a cross-sectional clinical study revealed that the reduction of A. muciniphila abundance was an independent risk factor for cold-related AF in human subjects. INTERPRETATION: Our findings revealed a novel causal role of aberrant gut microbiota and metabolites in pathogenesis of cold-related AF, which raises the possibility of selectively targeting microbiota and microbial metabolites as a potential therapeutic strategy for cold-related AF. FUNDING: This work was supported by grants from the State Key Program of National Natural Science Foundation of China (No.81830012), and National Natural Science Foundation of China (No.82070336, No.81974024), Youth Program of the National Natural Science Foundation of China (No.81900374, No.81900302), and Excellent Young Medical Talents supporting project in the First Affiliated Hospital of Harbin Medical University (No. HYD2020YQ0001).

Bacteroides fragilis prevents aging-related atrial fibrillation in rats via regulatory T cells-mediated regulation of inflammation.

BACKGROUND: Aging plays a critical role in the genesis of atrial fibrillation (AF) and also changes the gut microbes. Whether the aging-associated gut dysbiosis contributes to the development of aging-related AF and whether the gut microbes can be a target to prevent aging-related AF remains unknown. METHODS AND RESULTS: 16S rRNA gene sequencing was performed to reveal the changes of gut microbes in elderly patients with AF, and the result showed that the intestinal abundance of B. fragilis was significantly decreased in elderly patients with AF. Subsequently, we examined the impact of B. fragilis supplementation on AF promotion, atrial structural remodeling and inflammation response in D-galactose induced aging rats. We found that oral administration of B. fragilis prevented AF inducibility and duration, which was associated with attenuation of atrial senescence, apoptosis and fibrosis. Furthermore, B. fragilis significantly diminished the systemic and atrial inflammation, which is accompanied by an increase in the number of Treg cells in the spleen and blood. More importantly, we found that the circulation level of polysaccharide A (PSA), the metabolite synthesized by B. fragilis, was reduced in elderly patients with AF and could predict the occurrence of AF, and B. fragilis increased the circulation concentration of PSA in D-galactose induced aging rats. CONCLUSIONS: The abundance of B. fragilis was lower in elderly patients with AF. Oral administration of B. fragilis significantly attenuated inflammatory response by increasing Treg cells, thereby preventing atrial structural remodeling and inhibiting AF promotion in D-galactose induced aging rats. This study provides experimental evidence for the effectiveness of targeting gut microbes in the prevention of aging-related AF.

Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome.

AIMS: Ageing is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-related diseases. However, whether the aged-associated dysbiosis contributes to age-related AF is still unknown. Direct demonstration that the aged gut microbiota is sufficient to transmit the enhanced AF susceptibility in a young host via microbiota-intestinal barrier-atria axis has not yet been reported. This study aimed to determine whether gut microbiota dysbiosis affects age-related AF. METHODS AND RESULTS: Herein, by using a faecal microbiota transplantation (FMT) rat model, we demonstrated that the high AF susceptibility of aged rats could be transmitted to a young host. Specially, we found the dramatically increased levels of circulating lipopolysaccharide (LPS) and glucose led to the up-regulated expression of NOD-like receptor protein (NLRP)-3 inflammasome, promoting the development of AF, which depended on the enhanced atrial fibrosis in recipient host. Inhibition of inflammasome by a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, resulted in a lower atrial fibrosis and AF susceptibility. Then, we conducted cross-sectional clinical studies to explore the effect of ageing on the altering trends with glucose levels and circulating LPS among clinical individuals in two China hospitals. We found that both of serum LPS and glucose levels were progressively increased in elderly patients as compared with those young. Furthermore, the ageing phenotype of circulating LPS and glucose levels, intestinal structure and atrial NLRP3-inflammasome of rats were also confirmed in clinical AF patients. Finally, aged rats colonized with youthful microbiota restored intestinal structure and atrial NLRP3-inflammasome activity, which suppressed the development of aged-related AF. CONCLUSIONS: Collectively, these studies described a novel causal role of aberrant gut microbiota in the pathogenesis of age-related AF, which indicates that the microbiota-intestinal barrier-atrial NLRP3 inflammasome axis may be a rational molecular target for the treatment of aged-related arrhythmia disease.

Lnc-C2orf63-4-1 Confers VSMC Homeostasis and Prevents Aortic Dissection Formation via STAT3 Interaction.

Emerging evidence indicates that long non-coding RNAs (lncRNAs) serve as a critical molecular regulator in various cardiovascular diseases. Here, we aimed to identify and functionally characterize lncRNAs as potential mediators in the development of thoracic aortic dissection (TAD). We identified that a novel lncRNA, lnc-C2orf63-4-1, was lowly expressed in aortic samples of TAD patients and angiotensin II (Ang II)-challenged vascular smooth muscle cells (VSMCs), which was correlated with clinically aortic expansion. Besides, overexpression of lnc-C2orf63-4-1 significantly attenuated Ang II-induced apoptosis, phenotypic switching of VSMCs and degradation of extracellular matrix both in vitro and in vivo. A customized transcription factor array identified that signal transducer and activator of transcription 3 (STAT3) functioned as the main downstream effector. Mechanistically, dual-luciferase report analysis and RNA antisense purification (RAP) assay indicated that lnc-C2orf63-4-1 directly decreased the expression of STAT3, which was depend on the reduced stabilization of STAT3 mRNA. Importantly, up-regulation of STAT3 efficiently reversed the protective role of lnc-C2orf63-4-1 against Ang II-mediated vascular remodeling. Therefore, lnc-C2orf63-4-1 negatively regulated the expression of STAT3 and prevented the development of aortic dissection. Our study revealed that lnc-C2orf63-4-1 played a critical role in vascular homeostasis, and its dysfunction exacerbated Ang II-induced pathological vascular remodeling.