Chronic heart failure (CHF) is the final outcome of many cardiovascular diseases, and is a severe health issue faced by the elderly population. Mixed lineage kinase 3 (MLK3), a member of MAP3K ...family, is associated with aging, inflammation, oxidative stress, and related diseases, such as CHF. MLK3 has also been reported to play an important role in protecting against cardiomyocyte injury; however, its function in myocardial fibrosis is unknown. To investigate the role of MLK3 in myocardial fibrosis, we inhibited the expression of MLK3, and examined cardiac function and remodeling in TAC mice. In addition, we assessed the expression of MLK3 protein in ventricular cells and its downstream associated protein. We found that MLK3 mainly regulates NF-κB/NLRP3 signaling pathway-mediated inflammation and that pyroptosis causes myocardial fibrosis in the early stages of CHF. Similarly, MLK3 mainly regulates the JNK/p53 signaling pathway-mediated oxidative stress and that ferroptosis causes myocardial fibrosis in the advanced stages of CHF. We also found that promoting the expression of miR-351 can inhibit the expression of MLK3, and significantly improve cardiac function in mice subjected to TAC. These results suggest the pyroptosis and ferroptosis induced by MLK3 signaling in cardiomyocytes are essential for adverse myocardial fibrosis, in response to pressure overload. Furthermore, miR-351, which has a protective effect on ventricular remodeling in heart failure caused by pressure overload, may be a key target for the regulation of MLK3.
Background
Artificial intelligence and computer vision have revolutionized laparoscopic surgical video analysis. However, there is no multi-center study focused on deep learning-based laparoscopic ...cholecystectomy phases recognizing. This work aims to apply artificial intelligence in recognizing and analyzing phases in laparoscopic cholecystectomy videos from multiple centers.
Methods
This observational cohort-study included 163 laparoscopic cholecystectomy videos collected from four medical centers. Videos were labeled by surgeons and a deep-learning model was developed based on 90 videos. Thereafter, the performance of the model was tested in additional ten videos by comparing it with the annotated ground truth of the surgeon. Deep-learning models were trained to identify laparoscopic cholecystectomy phases. The performance of models was measured using precision, recall, F1 score, and overall accuracy. With a high overall accuracy of the model, additional 63 videos as an analysis set were analyzed by the model to identify different phases.
Results
Mean concordance correlation coefficient for annotations of the surgeons across all operative phases was 92.38%. Also, the overall phase recognition accuracy of laparoscopic cholecystectomy by the model was 91.05%. In the analysis set, there was an average surgery time of 2195 ± 896 s, with a huge individual variance of different surgical phases. Notably, laparoscopic cholecystectomy in acute cholecystitis cases had prolonged overall durations, and the surgeon would spend more time in mobilizing the hepatocystic triangle phase.
Conclusion
A deep-learning model based on multiple centers data can identify phases of laparoscopic cholecystectomy with a high degree of accuracy. With continued refinements, artificial intelligence could be utilized in huge data surgery analysis to achieve clinically relevant future applications.
Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to cardiac fibrosis and heart failure (HF). Recent studies have demonstrated that EndMT is regulated by autophagy, and we ...previously showed suppression of excessive autophagy and alleviation of cardiac fibrosis in HF mice with inactivated receptor for advanced glycation end products (RAGE). Thus, we investigated whether reduced cardiac fibrosis due to RAGE knockout occurred by inhibiting EndMT mediated by excessive autophagy. We found a decrease in endothelial cells (CD31
/VE-Cadherin
) and an increase in cells co-expressing CD31 and α-smooth muscle actin (α-SMA, myofibroblast marker) at 8 weeks in heart tissue of mice subjected to transverse aortic constriction (TAC), which implied EndMT. Knockout RAGE decreased EndMT accompanied by decreased expression of autophagy-related proteins (LC3BII/I and Beclin 1), and alleviated cardiac fibrosis and improved cardiac function in TAC mice. Moreover, 3-methyladenine (3-MA) and chloroquine (CQ), inhibitors of autophagy, attenuated EndMT, and cardiac fibrosis in TAC mice. Importantly, EndMT induced by AGEs could be blocked by autophagy inhibitor in vivo and in vitro. These results suggested that AGEs/RAGE-autophagy-EndMT axis involved in the development of cardiac fibrosis and knockout RAGE ameliorated cardiac fibrosis through decreasing EndMT regulated by autophagy, which could be a promising therapeutic strategy for HF.
This study centers on automatic sleep staging with a single channel electroencephalography (EEG), with some significant findings for sleep staging. In this study, we proposed a deep learning-based ...network by integrating attention mechanism and bidirectional long short-term memory neural network (AT-BiLSTM) to classify wakefulness, rapid eye movement (REM) sleep and non-REM (NREM) sleep stages N1, N2 and N3. The AT-BiLSTM network outperformed five other networks and achieved an accuracy of 83.78%, a Cohen's kappa coefficient of 0.766 and a macro F1-score of 82.14% on the PhysioNet Sleep-EDF Expanded dataset, and an accuracy of 81.72%, a Cohen's kappa coefficient of 0.751 and a macro F1-score of 80.74% on the DREAMS Subjects dataset. The proposed AT-BiLSTM network even achieved a higher accuracy than the existing methods based on traditional feature extraction. Moreover, better performance was obtained by the AT-BiLSTM network with the frontal EEG derivations than with EEG channels located at the central, occipital or parietal lobe. As EEG signal can be easily acquired using dry electrodes on the forehead, our findings might provide a promising solution for automatic sleep scoring without feature extraction and may prove very useful for the screening of sleep disorders.
Intra-abdominal adhesions have consistently posed a challenge for surgeons during procedures. This study aims to investigate the feasibility of utilizing indocyanine green (ICG) in conjunction with ...near-infrared imaging for the detection of intra-abdominal adhesions. In vitro, we analyzed factors affecting ICG fluorescence. We divided SD rats into groups to study ICG excretion in different digestive tract regions. Additionally, we reviewed surgical videos from previous cholecystectomy cases, categorizing them by ICG injection timing and assessing fluorescence imaging in various digestive tract regions. Finally, we preoperatively injected ICG into two cholecystectomized patients with abdominal adhesions, guiding intraoperative adhesiolysis with near-infrared fluorescence imaging. In vitro, we observed a significant influence of protein and ICG concentrations on ICG fluorescence intensity. Our rat experiments unveiled a strong and highly significant correlation (Kendall's tau-b = 1, P < 0.001) between the timing of ICG injection and the farthest point of intestinal fluorescence. A retrospective case analysis further validated this finding (Kendall's tau-b = 0.967, P < 0.001). Under the guidance of fluorescence navigation, two cholecystectomized patients with intra-abdominal adhesions successfully underwent adhesiolysis, and no postoperative complications occurred. The intraoperative combination of ICG with near-infrared fluorescence imaging effectively enhances the visibility of the liver, bile ducts, and various segments of the gastrointestinal tract while providing real-time navigation. This real-time fluorescence guidance has the potential to aid surgeons in the dissection of intra-abdominal adhesions.
Hard yet flexible coatings with multi‐functionalities are useful for foldable displays and marine industries but rare. In this study, a highly cross‐linked multifunctional hybrid coating with ...ceramic‐like hardness and polymer‐like flexibility is reported. The coating is prepared via a step‐by‐step strategy, where two types of epoxy‐oligosiloxane nanoclusters are first synthesized by sol‐gel chemistry, and amine‐terminated curing agents are used to cross‐link them at room temperature. The coating is highly transparent (>92% transmittance), hard (6‐7H), and flexible (10 mm bending diameter) because of the unique combination of siloxane nanoclusters and polymer networks. Meanwhile, since the coating contains fouling‐resistant telomer and low‐surface‐tension liquid lubricant polydimethylsiloxane (PDMS), it exhibits excellent anti‐biofouling and self‐cleaning properties. The results indicate that the mechanical and antifouling properties of the coating can be easily tuned and prove that the step‐by‐step strategy is a promising and universal method. The novel coatings can meet the needs of applications in foldable displays, marine industries, and other fields.
A novel multifunctional hard yet flexible coating via a universal step‐by‐step strategy has been developed. Such a coating exhibits high transparency, superior mechanical properties, and excellent anti‐fouling and self‐cleaning abilities. The coating is promising to find application in foldable displays, marine industries, and other fields.
While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired resistance is still inevitable in most ...cases. The introduction of antibody‒drug conjugates (ADCs) provides a novel alternative. ADCs are a new class of anticancer drugs comprising the coupling of antitumor mAbs with cytotoxic drugs. Compared with chemotherapeutic drugs, ADCs have the advantages of good tolerance, accurate target recognition, and small effects on noncancerous cells. ADCs occupy an increasingly important position in the therapeutic field. Currently, there are 13 Food and Drug Administration (FDA)‒approved ADCs and more than 100 ADC drugs at different stages of clinical trials. This review briefly describes the efficacy and safety of FDA-approved ADCs, and discusses the related problems and challenges to provide a reference for clinical work.
Positron emission tomography (PET) imaging of apoptosis can noninvasively detect cell death in vivo and assist in monitoring tumor response to treatment in patients. While extensive efforts have been ...devoted to addressing this important need, no apoptosis PET imaging agents have yet been approved for clinical use. This study reports an improved
18
F-labeled caspase-sensitive nanoaggregation tracer (
18
F-C-SNAT4) for PET imaging of tumor response to chemo- and immunotherapies in preclinical mouse models.
Methods
We rationally designed and synthesized a new PET tracer
18
F-C-SNAT4 to detect cell death both in vitro and in vivo. In vitro radiotracer uptake studies were performed on drug-sensitive and -resistant NSCLC cell lines (NCI-H460 and NCI-H1299, respectively) treated with cisplatin at different doses. In vivo therapy response monitoring by
18
F-C-SNAT4 PET imaging was evaluated with two treatment modalities—chemotherapy and immunotherapy in two tumor xenografts in mice. Radiotracer uptake in the tumors was validated ex vivo using γ-counting and cleaved caspase-3 immunofluorescence.
Results
This
18
F-C-SNAT4 PET tracer was facilely synthesized and displayed improved serum stability profiles.
18
F-C-SNAT4 cellular update was elevated in NCI-H460 cells in a time- and dose-dependent manner, which correlated well with cell death. A significant increase in
18
F-C-SNAT4 uptake was measured in NCI-H460 tumor xenografts in mice. In contrast, a rapid clearance of
18
F-C-SNAT4 was observed in drug-resistant NCI-H1299 in vitro and in tumor xenografts. Moreover, in BALB/C mice bearing murine colon cancer CT26 tumor xenografts receiving checkpoint inhibitors,
18
F-C-SNAT4 showed its ability for monitoring immunotherapy-induced apoptosis and reporting treatment-responding mice from non-responding.
Conclusion
The uptake of
18
F-C-SNAT4 in tumors received chemotherapy and immunotherapy is positively correlated with the tumor apoptotic level and the treatment efficacy.
18
F-C-SNAT4 PET imaging can monitor tumor response to two different treatment modalities and predict the therapeutic efficacy in preclinical mouse models.
Abstract
Background
RNA
N
6
-methyladenosine (m
6
A) modification is critical for plant growth and crop yield. m
6
A reader proteins can recognize m
6
A modifications to facilitate the functions of m
...6
A in gene regulation. ECT2, ECT3, and ECT4 are m
6
A readers that are known to redundantly regulate trichome branching and leaf growth, but their molecular functions remain unclear.
Results
Here, we show that ECT2, ECT3, and ECT4 directly interact with each other in the cytoplasm and perform genetically redundant functions in abscisic acid (ABA) response regulation during seed germination and post-germination growth. We reveal that ECT2/ECT3/ECT4 promote the stabilization of their targeted m
6
A-modified mRNAs, but have no function in alternative polyadenylation and translation. We find that ECT2 directly interacts with the poly(A) binding proteins, PAB2 and PAB4, and maintains the stabilization of m
6
A-modified mRNAs. Disruption of
ECT2/ECT3/ECT4
destabilizes mRNAs of ABA signaling-related genes, thereby promoting the accumulation of ABI5 and leading to ABA hypersensitivity.
Conclusion
Our study reveals a unified functional model of m
6
A mediated by m
6
A readers in plants. In this model, ECT2/ECT3/ECT4 promote stabilization of their target mRNAs in the cytoplasm.
The multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 for DNA methylation maintenance during DNA replication. Here, we show that MOF (males absent ...on the first) acetylates UHRF1 at K670 in the pre-RING linker region, whereas HDAC1 deacetylates UHRF1 at the same site. We also identify that K667 and K668 can also be acetylated by MOF when K670 is mutated. The MOF/HDAC1-mediated acetylation in UHRF1 is cell-cycle regulated and peaks at G1/S phase, in line with the function of UHRF1 in recruiting DNMT1 to maintain DNA methylation. In addition, UHRF1 acetylation significantly enhances its E3 ligase activity. Abolishing UHRF1 acetylation at these sites attenuates UHRF1-mediated H3 ubiquitination, which in turn impairs DNMT1 recruitment and DNA methylation. Taken together, these findings identify MOF as an acetyltransferase for UHRF1 and define a mechanism underlying the regulation of DNA methylation maintenance through MOF-mediated UHRF1 acetylation.
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•MOF acetylates UHRF1 at K670, which is counteracted by HDAC1•Acetylation by MOF enhances UHRF1 E3 ubiquitin ligase activity•Abolishment of UHRF1 acetylation impairs histone H3 ubiquitination and DNMT1 recruitment•K670 acetylation of UHRF1 is required for proper function of DNA methylation maintenance
Wang et al. describe a regulatory mechanism of UHRF1 in DNA methylation maintenance. UHRF1 acetylation by MOF at lysine 670 is essential for efficient DNMT1 recruitment by facilitating histone H3 ubiquitination. These findings suggest that UHRF1 acetylation is important for its E3 ubiquitin ligase function in various biological processes.
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