Publications by authors named "Liang Wang"

3,405 Publications

  • Page 1 of 1

Actor and Action Modular Network for Text-based Video Segmentation.

IEEE Trans Image Process 2022 Jun 28;PP. Epub 2022 Jun 28.

Text-based video segmentation aims to segment an actor in video sequences by specifying the actor and its performing action with a textual query. Previous methods fail to explicitly align the video content with the textual query in a fine-grained manner according to the actor and its action, due to the problem of semantic asymmetry. The semantic asymmetry implies that two modalities contain different amounts of semantic information during the multi-modal fusion process. To alleviate this problem, we propose a novel actor and action modular network that individually localizes the actor and its action in two separate modules. Specifically, we first learn the actor-/action-related content from the video and textual query, and then match them in a symmetrical manner to localize the target tube. The target tube contains the desired actor and action which is then fed into a fully convolutional network to predict segmentation masks of the actor. Our method also establishes the association of objects cross multiple frames with the proposed temporal proposal aggregation mechanism. This enables our method to segment the video effectively and keep the temporal consistency of predictions. The whole model is allowed for joint learning of the actor-action matching and segmentation, as well as achieves the state-of-the-art performance for both single-frame segmentation and full video segmentation on A2D Sentences and J-HMDB Sentences datasets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TIP.2022.3185487DOI Listing
June 2022

Kaempferol-3-O-rutinoside exerts cardioprotective effects through NF-κB/NLRP3/Caspase-1 pathway in ventricular remodeling after acute myocardial infarction.

J Food Biochem 2022 Jun 27:e14305. Epub 2022 Jun 27.

State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, Anhui, People's Republic of China.

Ventricular remodeling (VR) after acute myocardial infarction (AMI) is the main pathogenesis of chronic heart failure (CHF). Kaempferol-3-O-rutinoside (KR) is the flavonoid glycoside with the highest content in Lu'an GuaPian tea, which has good pharmacological activities. However, the mechanism of KR against VR after AMI remains unclear. Molecular docking was used to predict the targets of KR on the NLRP3/Caspase-1 signaling pathway. Histological changes in the myocardium were visualized using HE staining, Masson staining. Cardiomyocyte apoptosis was detected using TUNEL. Immunohistochemistry was used to examine NLRP3, Caspase-1 p20, and GSDMD. IL-1β level in serum was detected using ELISA. Finally, the expressions of NF-κB p65, NLRP3, ASC, Caspase-1 p20, GSDMD, and IL-1β were measured using RT-PCR and Western blotting. Our results showed that KR had a good binding activity with NLRP3, Caspase-1, and GSDMD, significantly improved cardiac function, alleviated cardiac pathological changes, reduced the excessive deposition of myocardial interstitial collagen, and inhibited cardiomyocyte apoptosis in AMI rats. Furthermore, KR could decrease the IL-1β level and inhibit the expressions of NF-κB p65, NLRP3, ASC, Caspase-1 p20, GSDMD, and IL-1β. Our study suggests that KR can prevent and treat VR after AMI, and the protective effect is related to its regulatory NF-κB/NLRP3/Caspase-1 signaling pathway. PRACTICAL APPLICATIONS: Kaempferol-3-O-rutinoside is present in Carthamus tinctorius L., Nymphaea candida, Afgekia mahidoliae and green tea, which has good pharmacological activities against liver injury, cerebral ischemia/reperfusion injury, dementia, hyperglycemia, and myocardial infarction. Our previous study found that kaempferol-3-O-rutinoside had an obvious anti-inflammatory effect, and could significantly improve the cell survival rate of H9c2 myocardium inflammatory injury induced by LPS. In this study, kaempferol-3-O-rutinoside significantly improved cardiac function, alleviated cardiac pathological changes, reduced the excessive deposition of myocardial interstitial collagen, and inhibited cardiomyocyte apoptosis in AMI rats. Furthermore, kaempferol-3-O-rutinoside could decrease the IL-1β level and inhibit the expressions of NF-κB p65, NLRP3, ASC, Caspase-1, GSDMD and IL-1β, suggesting that kaempferol-3-O-rutinoside could regulate NF-κB/NLRP3/Caspase-1 signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jfbc.14305DOI Listing
June 2022

Inference for partially observed competing risks model for Kumaraswamy distribution under generalized progressive hybrid censoring.

J Appl Stat 2022 23;49(8):2064-2092. Epub 2021 Feb 23.

School of Mathematics, Yunnan Normal University, Kunming, People's Republic of China.

In this paper, inference for a competing risks model is studied when latent failure times follow Kumaraswamy distribution and causes of failure are partially observed. Under generalized progressive hybrid censoring, existence and uniqueness of maximum likelihood estimators of model parameters are established. The confidence intervals are obtained by using asymptotic distribution theory. We further compute Bayes estimators along with credible intervals. In addition, inference is also discussed when there is order restricted shape parameters. The performance of all estimates is investigated using Monte-Carlo simulations. Finally, analysis of a real data set is presented for illustration purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/02664763.2021.1889999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225323PMC
February 2021

Rab22a Promotes Epithelial-Mesenchymal Transition in Papillary Thyroid Carcinoma by Activating PI3K/AKT/mTOR Signaling Pathway.

Biomed Res Int 2022 15;2022:1874550. Epub 2022 Jun 15.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.

Background: Rab22a is a member of the RAS superfamily, involved in early endosome formation and intracellular vesicle transport. Rab22a is significantly upregulated in a variety of malignant tumors. However, its function in thyroid cancer has never been addressed.

Methods: The expression of Rab22a in paraffin sections of 101 patients was detected by immunohistochemical staining. By upregulating and downregulating the expression of Rab22a in thyroid cancer cell lines, the effect of Rab22a on cell proliferation, invasion, and migration was analyzed. Co-IP was employed, and the interaction between Rab22a and PI3Kp85 was shown. The function of Rab22a on PI3K/AKT/mTOR signaling and epithelial-mesenchymal transition (EMT) was further studied by western blot analysis.

Results: Immunostaining showed that Rab22a was significantly overexpressed in thyroid cancer tissues but negative in adjacent normal tissues or nodular goiters. The proliferation, migration, invasion, and EMT in papillary thyroid carcinoma cell lines were enhanced upon Rab22a overexpression but inhibited after knocking down Rab22a. The co-IP assay demonstrated an interaction between Rab22a and PI3K85, an effector of PI3K. We further found that Rab22a can activate the PI3K/AKT/mTOR signaling pathway. However, the ability of Rab22a to promote the proliferation, invasion, migration, and EMT of papillary thyroid carcinoma cells was significantly inhibited after being treated with LY294002, a PI3K inhibitor.

Conclusions: Rab22a can promote the EMT process and enhance proliferation, migration, and invasion of papillary thyroid carcinoma cells by activating the PI3K/AKT/mTOR signaling pathway. Our study provides new pathological diagnosis clues and clinical treatment targets for thyroid cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2022/1874550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9217539PMC
June 2022

Karyotype of the Blastocoel Fluid Derived by Laser-Assisted Hatching Demonstrates a Low Agreement With the Trophectoderm.

Front Physiol 2022 8;13:827568. Epub 2022 Jun 8.

Center of Reproductive Medicine, Second Affiliated Hospital of Naval Medical University, Shanghai, China.

Objective: The aim of this study is to compare the amplification efficiency and the genomic profiles of blastocoel fluid (BF) derived by laser-assisted hatching and trophectoderm (TE) cells derived from the same blastocyst.

Methods: Fifty-four fresh blastocysts underwent shrinkage by laser-assisted hatching, and each BF sample was collected individually. BF and TE cells were retrieved from each blastocyst for chromosome analysis through multiple annealing and looping-based amplification cycles (MALBAC) and next-generation sequencing (NGS).

Results: Fifty-four BF samples and 32 TE samples were retrieved for this study. Out of the 54 BF samples, only 35 provided reliable NGS data for comprehensive chromosome analysis (64.8%), while all 32 TE samples did (100%). Finally, there were 23 pairs of BF and TE samples from the same blastocyst. Only 17.4% of the BF-DNA karyotypes were completely agreeable with the TE samples (4/23).

Conclusion: Blastocoel fluid derived by laser-assisted hatching is easy to operate, and BF-DNA can be successfully amplified and subjected to NGS. Due to the low amplification efficiency and increased discordance with TE, BF does not adequately represent the status of the rest of the blastocyst. The use of BF as a single source of DNA for preimplantation genetic screening (PGS) is not yet advised.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2022.827568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9216213PMC
June 2022

Effect of Structural Optimization of Scrubbing Cooling Rings on Vertical Falling Film Flow Characteristics.

ACS Omega 2022 Jun 9;7(24):21291-21305. Epub 2022 Jun 9.

Shanghai Engineering Research Center of Coal Gasification, Institute of Clean Coal Technology, East China University of Science and Technology, Shanghai 200237, China.

In order to study the influence of the structural optimization of the scrubbing cooling ring in the scrubbing cooling chamber on the flow characteristics of the vertical falling film, the flow characteristics of the turbulent falling film in the rising section of the development region at different internal platform heights of the scrubbing cooling ring and a high Reynolds number were studied by FLUENT software. First, the correctness of the model was verified by the maximum error of simulation and experimental results of no more than 9.836%. Then, the distribution of liquid film thickness (δ), velocity (), and turbulence intensity ( ) at 0° of the tube in the axial direction = 0-500 mm were calculated and obtained when the platform height () was 0-30 mm and the liquid film Reynolds number ( ) = 1.1541 × 10-3.4623 × 10. The results showed that δ in the entrance region increased sharply due to the "jet" effect with solid wall constraints formed by the structure of the water inlet pipe and the scrubbing cooling ring. On the contrary, the liquid film in the fully developed region showed a stable fluctuation trend due to the weakening of the "jet" effect. When = 30 mm, the change of δ was relatively stable and the change of was small, indicating that this platform height is conducive to the stable and uniform distribution of the liquid film. In addition, when < 1.1541 × 10, the liquid film was unstable due to the low flow rate and insufficient cohesion of the liquid film, but increased slightly. In addition, with the increase of , δ did not change significantly along the axial direction, that is, the Plateau-Rayleigh hindered the growth of δ. Finally, the empirical formula for δ applicable to = 1.1541 × 10-3.4623 × 10 at the axial fixed position was fitted for the first time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.2c02492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219060PMC
June 2022

Distribution and assessment of heavy metals in suspended particles in the Sundarban mangrove river, Bangladesh.

Mar Pollut Bull 2022 Jun 24;181:113856. Epub 2022 Jun 24.

Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China; Analytical and Testing Center of Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China.

The suspended particulate matter (SPM) is an important carrier of heavy metals transportation from land to sea, so it is significant to study the heavy metal pollution in SPM. The distribution and assessment of five heavy metals (Mn, Cr, Ni, Cu, and Pb) in SPM collected from Passur River and its estuary in Sundarban were studied in combination with water temperature, salinity, and turbidity. The results show that the heavy metal content and distribution in SPM are mainly controlled by runoff input, hydrodynamic process and the interaction process of salt and fresh water in estuaries. The quality evaluation results of heavy metals in SPM show that pollution degree is light. Studies on the heavy metals in SPM are of great significance to comprehensively evaluate regional pollution status and carry out early warning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.marpolbul.2022.113856DOI Listing
June 2022

Involvement of LIN28A in Wnt-dependent regulation of hippocampal neurogenesis in the aging brain.

Stem Cell Reports 2022 Jun 3. Epub 2022 Jun 3.

Center of Stem Cell and Regenerative Medicine and Department of Neurology of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China. Electronic address:

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein LIN28A remained existent in neural progenitor cells and granule neurons in the adult hippocampus and that it decreased with aging. Lin28a knockout inhibited the responsiveness of neural progenitor cells to niche Wnt agonists and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that LIN28A regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis and related cognitive functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stemcr.2022.05.016DOI Listing
June 2022

Target Detection Based on Improved Hausdorff Distance Matching Algorithm for Millimeter-Wave Radar and Video Fusion.

Sensors (Basel) 2022 Jun 17;22(12). Epub 2022 Jun 17.

School of Electronics and Information Engineering, Changchun University of Science and Technology, Changchun 130022, China.

The intelligent transportation system (ITS) is inseparable from people's lives, and the development of artificial intelligence has made intelligent video surveillance systems more widely used. In practical traffic scenarios, the detection and tracking of vehicle targets is an important core aspect of intelligent surveillance systems and has become a hot topic of research today. However, in practical applications, there is a wide variety of targets and often interference factors such as occlusion, while a single sensor is unable to collect a wealth of information. In this paper, we propose an improved data matching method to fuse the video information obtained from the camera with the millimetre-wave radar information for the alignment and correlation of multi-target data in the spatial dimension, in order to address the problem of poor recognition alignment caused by mutual occlusion between vehicles and external environmental disturbances in intelligent transportation systems. The spatio-temporal alignment of the two sensors is first performed to determine the conversion relationship between the radar and pixel coordinate systems, and the calibration on the timeline is performed by Lagrangian interpolation. An improved Hausdorff distance matching algorithm is proposed for the data dimension to calculate the similarity between the data collected by the two sensors, to determine whether they are state descriptions of the same target, and to match the data with high similarity to delineate the region of interest (ROI) for target vehicle detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/s22124562DOI Listing
June 2022

Income Disparities in Obesity Trends among U.S. Adults: An Analysis of the 2011-2014 California Health Interview Survey.

Int J Environ Res Public Health 2022 Jun 11;19(12). Epub 2022 Jun 11.

School of Nursing and Health Studies, University of Miami, Coral Gables, FL 33146, USA.

The aim of this study was to examine income disparities in obesity trends among California adults. Data were obtained from the 2011-2014 California Health Interview Survey ( = 83,175 adults). Obesity for adults was defined as a body mass index of 30 kg/m or above. Family income was categorized as below 100%, 100% to 299%, or 300% and above of the federal poverty level (FPL). Weighted multiple logistic regression analyses were used to examine the association between family income and obesity across survey years after controlling for age, sex, race/ethnicity, smoking status, marital status, education, physical activity, and healthy diet. Obesity prevalence among California adults increased slightly from 25.1% in 2011 to 27.0% in 2014. Compared to 300% FPL or above, <100% FPL and 100-299% FPL were associated with increased odds of obesity, respectively (OR = 1.35, 95% CI = 1.22-1.50, for 100-299% FPL; OR = 1.18, 95% CI = 1.10-1.27, for 300% FPL or above). Each year, lower FPL was associated with higher odds of obesity, except for the year 2014. An inverse association between obesity and family income in each survey year was observed, with the magnitude of the income disparity decreasing from 2011 to 2014. The findings of this study show that family income was negatively associated with obesity among adults in California from 2011-2014, and the magnitude of the income disparity in obesity prevalence decreased over this period. Future studies need to examine potential risk factors associated with the decreasing trend.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph19127188DOI Listing
June 2022

Puerarin attenuates lipopolysaccharide-induced myocardial injury via the 14-3-3γ/PKCε pathway activating adaptive autophagy.

Int Immunopharmacol 2022 Jul 2;108:108905. Epub 2022 Jun 2.

Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China; Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University School of Pharmaceutical Science, Nanchang 330006, China. Electronic address:

Studies have confirmed that the heart is the main target organ of lipopolysaccharide (LPS) attacks, and 14-3-3γ and protein kinase C epsilon (PKCε) are the endogenous protective proteins. Puerarin (Pue) is the major bioactive ingredient isolated from the root of Pueraria lobata. It possesses many pharmacological properties, which has been widely used in the treatment and adjuvant therapy of cardio- and cerebrovascular diseases and cancer, etc. The study intended to explore the effects and mechanism of Pue pretreatment to protect myocardium against LPS injury. Adult mice and primary cultured neonatal rat cardiomyocytes were pretreated with Pue, and the injury model was made with LPS. Results showed that Pue pretreatment alleviated LPS-induced injury, as demonstrated by increased cell viability, decreased LDH activity and apoptosis, inhibited excess oxidative stress and the inflammatory cytokine release, and maintained mitochondrial function. Furthermore, Pue pretreatment upregulated 14-3-3γ expression, interacted with PKCε, which was phosphorylated and impelled migration to mitochondria, and then activated adaptive autophagy and protected the myocardium. However, pAD/14-3-3γ-shRNA or 3-MA (an autophagy inhibitor) could weaken the above effects of Pue pretreatment. Together, Pue pretreatment could activate adaptive autophagy by the 14-3-3γ/PKCε pathway and protect the myocardium against LPS injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.intimp.2022.108905DOI Listing
July 2022

Risk factors for acute respiratory distress syndrome in sepsis patients: a retrospective study from a tertiary hospital in China.

BMC Pulm Med 2022 Jun 21;22(1):238. Epub 2022 Jun 21.

Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.

Background: Less is known about the risk factors for acute respiratory distress syndrome (ARDS) in sepsis patients diagnosed according to sepsis 3.0 criteria. Moreover, the risk factors for ARDS severity remain unclear.

Methods: We retrospectively collected the characteristics of sepsis patients from the intensive care unit of the First Affiliated Hospital of China Medical University from January 2017 to September 2018. Logistic regression was used in determining the risk factors.

Results: 529 patients with sepsis were enrolled and 179 developed ARDS. The most common infection sites were acute abdominal infection (n = 304) and pneumonia (n = 117). Multivariate analysis showed that patients with pancreatitis with local infection (odds ratio [OR], 3.601; 95% confidence interval [CI], 1.429-9.073, P = 0.007), pneumonia (OR 3.486; 95% CI 1.890-6.430, P < 0.001), septic shock (OR 2.163; 95% CI 1.429-3.275, P < 0.001), a higher sequential organ failure assessment (SOFA) score (OR 1.241; 95% CI 1.155-1.333, P < 0.001) and non-pulmonary SOFA score (OR 2.849; 95% CI 2.113-3.841, P < 0.001) were independent risk factors for ARDS. Moreover, pneumonia is associated with increased severity of ARDS (OR 2.512; 95% CI 1.039-6.067, P = 0.041).

Conclusions: We determined five risk factors for ARDS in sepsis patients. Moreover, pneumonia is significantly associated with an increased severity of ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12890-022-02015-wDOI Listing
June 2022

Intelligent Extraction of Salient Feature From Electroencephalogram Using Redundant Discrete Wavelet Transform.

Front Neurosci 2022 1;16:921642. Epub 2022 Jun 1.

School of Aerospace Science and Technology, Xidian University, Xi'an, China.

At present, electroencephalogram (EEG) signals play an irreplaceable role in the diagnosis and treatment of human diseases and medical research. EEG signals need to be processed in order to reduce the adverse effects of irrelevant physiological process interference and measurement noise. Wavelet transform (WT) can provide a time-frequency representation of a dynamic process, and it has been widely utilized in salient feature analysis of EEG. In this paper, we investigate the problem of translation variability (TV) in discrete wavelet transform (DWT), which causes degradation of time-frequency localization. It will be verified through numerical simulations that TV is caused by downsampling operations in decomposition process of DWT. The presence of TV may cause severe distortions of features in wavelet subspaces. However, this phenomenon has not attracted much attention in the scientific community. Redundant discrete wavelet transform (RDWT) is derived by eliminating the downsampling operation. RDWT enjoys the attractive merit of translation invariance. RDWT shares the same time-frequency pattern with that of DWT. The discrete delta impulse function is used to test the time-frequency response of DWT and RDWT in wavelet subspaces. The results show that DWT is very sensitive to the translation of delta impulse function, while RDWT keeps the decomposition results unchanged. This conclusion has also been verified again in decomposition of actual EEG signals. In conclusion, to avoid possible distortions of features caused by translation sensitivity in DWT, we recommend the use of RDWT with more stable performance in BCI research and clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2022.921642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198366PMC
June 2022

Identification of SCRG1 as a Potential Therapeutic Target for Human Synovial Inflammation.

Front Immunol 2022 26;13:893301. Epub 2022 May 26.

Department of Orthopedics, Academy of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.

Synovial inflammation of joint tissue is the most important cause of tissue damage, joint destruction, and disability and is associated with higher morbidity or mortality. Therefore, this study aims to identify key genes in osteoarthritis synovitis tissue to increase our understanding of the underlying mechanisms of osteoarthritis and identify new therapeutic targets. Five GEO datasets with a total of 41 normal synovial membrane tissues and 45 osteoarthritis synovial membrane samples were used for analysis, and seven common differential genes were identified. The classification model constructed by LASSO analysis showed that six genes including CDKN1A, FOSB, STMN2, SLC2A3, TAC, and SCRG1 can be used as biomarkers of osteoarthritis, and the SCRG1 gene shows importance in osteoarthritis. Furthermore, drug database enrichment found that these six DEGs may be the drug targets of synovitis in osteoarthritis, and Valproic Acid CTD 00006977 may be a potential targeted therapeutic drug of SCRG1. Spearman correlation analysis was performed on the SCRG1 gene, and 27 genes with consistent expression were obtained. Functional analysis showed that 27 genes were mainly involved in metabolism, complement, antigen presentation, apoptosis, and regulation of immune pathways. The co-regulatory network of TFs-miRNA suggested that the SCRG1 gene may be regulated by hsa-miR-363-3p miRNA. In conclusion, SCRG1, as a diagnostic marker of osteoarthritis, co-regulates immune-related pathways through the interaction of related proteins, playing an important role in the occurrence and development of osteoarthritis, which may be a novel drug target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2022.893301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204521PMC
June 2022

Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ().

Front Immunol 2022 2;13:915657. Epub 2022 Jun 2.

Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China.

To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp (), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of and relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including , , , and were significantly up-regulated in the LP+0.4% AKG group, and the relative expression levels of the pro-inflammatory factors and were significantly lower with the addition of 0.4%, 0.8%, and 1.2% AKG. Moreover, the abundance of in the LP+0.4% AKG group was lower than that in the LP group, and the abundance of and was higher at the phylum level. The abundance of in the LP+0.4% AKG group was decreased compared to the LP group, while the abundance of was increased at the genus level. In short, the effects of AKG on the intestinal health of the common carp were systematically and comprehensively evaluated from the perspectives of intestinal physical barrier, chemical barrier, biological barrier, and immune barrier. We found that an LP diet supplemented with 0.4% AKG was beneficial to the growth performance and intestinal health of common carp.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2022.915657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9200961PMC
June 2022

Proteogenomic, Epigenetic, and Clinical Implications of Recurrent Aberrant Splice Variants in Clear Cell Renal Cell Carcinoma.

Eur Urol 2022 Jun 16. Epub 2022 Jun 16.

Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Background: Alternative mRNA splicing can be dysregulated in cancer, resulting in the generation of aberrant splice variants (SVs). Given the paucity of actionable genomic mutations in clear cell renal cell carcinoma (ccRCC), aberrant SVs may be an avenue to novel mechanisms of pathogenesis.

Objective: To identify and characterize aberrant SVs enriched in ccRCC.

Design, Setting, And Participants: Using RNA-seq data from the Cancer Cell Line Encyclopedia, we identified neojunctions uniquely expressed in ccRCC. Candidate SVs were then checked for expression across normal tissue in the Genotype-Tissue Expression Project and primary tumor tissue from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and our institutional Total Cancer Care database.

Outcome Measurements And Statistical Analysis: Clinicopathologic, genomic, and survival data were available for all cohorts. Epigenetic data were available for the TCGA and CPTAC cohorts. Proteomic data were available for the CPTAC cohort. The association of aberrant SV expression with these variables was examined using the Kruskal-Wallis test, pairwise t test, Spearman correlation test, and Cox regression analysis.

Results And Limitations: Our pipeline identified 16 ccRCC-enriched SVs. EGFR, HPCAL1-SV and RNASET2-SV expression was negatively correlated with gene-specific CpG methylation. We derived a survival risk score based primarily on the expression of five SVs (RNASET2, FGD1, PDZD2, COBLL1, and PTPN14), which was consistent and applicable across multiple cohorts on multivariate analysis. The splicing factor RBM4, which modulates splicing of HIF-1α, exhibited significantly lower expression at the protein level in the high-risk group, as defined by our SV-based score.

Conclusions: We describe 16 aberrant SVs enriched in ccRCC, many of which are associated with disease biology and/or clinical outcomes. This study provides a novel strategy for identifying and characterizing disease-specific aberrant SVs.

Patient Summary: We describe a method to identify disease targets and biomarkers using transcriptomic analysis beyond somatic mutations or gene expression. Kidney tumors express unique splice variants that may provide additional prognostic information following surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2022.05.021DOI Listing
June 2022

Chemistry solutions to facilitate nanopore detection and analysis.

Biosens Bioelectron 2022 Jun 1;213:114448. Epub 2022 Jun 1.

Department of Chemistry, Illinois Institute of Technology, Chicago, IL, 60616, USA. Electronic address:

Characteristic ionic current modulations will be produced in a single molecule manner during the communication of individual molecules with a nanopore. Hence, the information regarding the length, composition, and structure of a molecule can be extracted from deciphering the electrical message. However, until now, achieving a satisfactory resolution for observation and quantification of a target analyte in a complex system remains a nontrivial task. In this review, we summarize the progress and especially the recent advance in utilizing chemistry solutions to facilitate nanopore detection and analysis. The discussed chemistry solutions are classified into several major categories, including covalent/non-covalent chemistry, redox chemistry, displacement chemistry, back titration chemistry, chelation chemistry, hydrolysis-chemistry, and click chemistry. Considering the significant success of using chemical reaction-assisted nanopore sensing strategies to improve sensor sensitivity & selectivity and to study various topics, other non-chemistry based methodologies can undoubtedly be employed by nanopore sensors to explore new applications in the interdisciplinary area of chemistry, biology, materials, and nanotechnology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bios.2022.114448DOI Listing
June 2022

Adherence to a healthy lifestyle in relation to colorectal cancer incidence and all-cause mortality after endoscopic polypectomy: a prospective study in three U.S. cohorts.

Int J Cancer 2022 Jun 18. Epub 2022 Jun 18.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

It remains unknown whether maintenance of a healthy lifestyle after endoscopic polypectomy could still confer benefit for colorectal cancer (CRC) incidence and mortality. In this study, we defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption, and diet (range, 0-5). We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of healthy lifestyle score and individual lifestyle factors with CRC incidence and all-cause mortality. During a median of 10 years of follow-up of 24668 participants who underwent endoscopic polypectomy, we documented 161 CRC cases and 4857 all-cause deaths. A higher healthy lifestyle score after endoscopic polypectomy was associated with lower risk of CRC and all-cause mortality. Compared to individuals with 0-1 healthy lifestyle factors, those with 2, 3, and 4-5 healthy lifestyle factors had a HR for CRC risk of 0.86 [95% confidence interval (CI), 0.60-1.24], 0.73 (95% CI, 0.47-1.14), and 0.52 (95% CI, 0.27-1.01), respectively (P =0.03). The corresponding HR (95% CI) for all-cause mortality was 0.83 (95% CI, 0.76-0.90), 0.63 (95% CI, 0.56-0.70), and 0.56 (95% CI, 0.48-0.65), respectively (P <0.0001). In the joint analysis of pre- and post-polypectomy periods, patients with a healthy post-polypectomy lifestyle had a lower incidence of CRC regardless of their pre-polypectomy exposure, whereas those with a healthy lifestyle in both periods had a lower mortality than those with an unhealthy lifestyle in either period. In conclusion, adherence to a healthy lifestyle after polypectomy may confer significant benefit for CRC prevention and reduction in all-cause mortality. This article is protected by copyright. All rights reserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.34176DOI Listing
June 2022

RF-Next: Efficient Receptive Field Search for Convolutional Neural Networks.

IEEE Trans Pattern Anal Mach Intell 2022 Jun 17;PP. Epub 2022 Jun 17.

Temporal/spatial receptive fields of models play an important role in sequential/spatial tasks. Large receptive fields facilitate long-term relations, while small receptive fields help to capture the local details. Existing methods construct models with hand-designed receptive fields in layers. Can we effectively search for receptive field combinations to replace hand-designed patterns? To answer this question, we propose to find better receptive field combinations through a global-to-local search scheme. Our search scheme exploits both global search to find the coarse combinations and local search to get the refined receptive field combinations further. The global search finds possible coarse combinations other than human-designed patterns. On top of the global search, we propose an expectationguided iterative local search scheme to refine combinations effectively. Our global-to-local search can be plugged into existing temporal action segmentation, object detection, instance segmentation, and speech synthesis methods to boost the performance. The source code is publicly available on http://mmcheng.net/rfnext.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TPAMI.2022.3183829DOI Listing
June 2022

The Potential Value of m6A RNA Methylation in the Development of Cancers Focus on Malignant Glioma.

Front Immunol 2022 30;13:917153. Epub 2022 May 30.

Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi'an, China.

N6-methyladenosine (m6A) RNA methylation is an epigenetic modification that has emerged in the last few years and has received increasing attention as the most abundant internal RNA modification in eukaryotic cells. m6A modifications affect multiple aspects of RNA metabolism, and m6A methylation has been shown to play a critical role in the progression of multiple cancers through a variety of mechanisms. This review summarizes the mechanisms by which m6A RNA methylation induced peripheral cancer cell progression and its potential role in the infiltration of immune cell of the glioblastoma microenvironment and novel immunotherapy. Assessing the pattern of m6A modification in glioblastoma will contribute to improving our understanding of microenvironmental infiltration and novel immunotherapies, and help in developing immunotherapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2022.917153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9196637PMC
June 2022

Clinical evaluation of transcatheter arterial embolization combined with propranolol orally treatment of infantile hepatic hemangioma.

Pediatr Surg Int 2022 Jun 16. Epub 2022 Jun 16.

Department of Vascular Anomalies and Interventional Radiology, Children's Hospital Affiliated to Shandong University Ji'nan Children's Hospital, Jinan, China.

Purpose: To assess the efficacy of transcatheter arterial embolization (TAE) plus propranolol treatment for infantile hepatic hemangioma (IHH).

Methods: A retrospective study of symptomatic IHH and hemodynamic changes in IHH was conducted between 2016 and 2019.

Results: There were five boys and seven girls with diffuse lesions (n = 7) and multifocal lesions (n = 5). Hepatomegaly and abdominal distension (n = 6) were the predominant clinical presentations. Seven patients (58.3%) had multiple cutaneous hemangiomas. Pulmonary arterial hypertension, heart failure (n = 4), and hypothyroidism (n = 4) were observed. A total of 17 TAE procedures were performed in 12 IHH cases, with a technical success rate of 100%. All patients received standard propranolol orally, and one patient was orally administered metacortandracin. Two patients died of heart failure and multiple organ dysfunction caused by an enlarged liver. In addition, one patient was not reexamined after discharge. Of the remaining nine children, the average follow-up time was 10.78 months (range 2-28 months), and they all responded well to TAE combined with oral propranolol.

Conclusion: TAE combined with propranolol is safe and effective for the treatment of IHH, demonstrating low complication rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00383-022-05143-wDOI Listing
June 2022

Criticality in reservoir computer of coupled phase oscillators.

Phys Rev E 2022 May;105(5):L052201

School of Physics and Information Technology, Shaanxi Normal University, Xi'an 710062, China.

Accumulating evidence shows that the cerebral cortex is operating near a critical state featured by power-law size distribution of neural avalanche activities, yet evidence of this critical state in artificial neural networks mimicking the cerebral cortex is still lacking. Here we design an artificial neural network of coupled phase oscillators and, by the technique of reservoir computing in machine learning, train it for predicting chaos. It is found that when the machine is properly trained, oscillators in the reservoir are synchronized into clusters whose sizes follow a power-law distribution. This feature, however, is absent when the machine is poorly trained. Additionally, it is found that despite the synchronization degree of the original network, once properly trained, the reservoir network is always developed to the same critical state, exemplifying the "attractor" nature of this state in machine learning. The generality of the results is verified in different reservoir models and by different target systems, and it is found that the scaling exponent of the distribution is independent of the reservoir details and the bifurcation parameters of the target system, but is modified when the dynamics of the target system is changed to a different type. The findings shed light on the nature of machine learning, and are helpful to the design of high-performance machines in physical systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1103/PhysRevE.105.L052201DOI Listing
May 2022

Probe Synthesis Reveals Eukaryotic Translation Elongation Factor 1 Alpha 1 as the Anti-Pancreatic Cancer Target of BE-43547A2.

Angew Chem Int Ed Engl 2022 Jun 15. Epub 2022 Jun 15.

Nankai University, College of Pharmacy, Weijin Road, Nankai district, 300071, Tianjin, CHINA.

The natural product, BE-43547A2, decreases pancreatic cancer cell stemness. However, its anticancer molecular mechanisms have not been fully established. Based on structure-activity relationships of BE-43547A2, we synthesized a probe and investigated its potential targets using an in situ click reaction. We found that BE-43547A2 exerts its anticancer effects by covalently binding the cysteine234 (C234) residue of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1). This binding mode was confirmed by a series of experiments including a xenograft mouse model. We also determined that eEF1A1 plays an important role in regulating pancreatic cancer cell stemness. Analyses of 99 clinical pancreatic cancer samples revealed that eEF1A1 expressions are closely correlated with clinicopathological grade and patient survival. In conclusion, eEF1A1 is involved in pancreatic cancer progression and is therefore, a promising novel covalent target for pancreatic cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202206953DOI Listing
June 2022

CASIA-E: A Large Comprehensive Dataset for Gait Recognition.

IEEE Trans Pattern Anal Mach Intell 2022 Jun 15;PP. Epub 2022 Jun 15.

Gait recognition plays a special role in visual surveillance due to its unique advantage, e.g., long-distance, cross-view and non-cooperative recognition. However, it has not yet been widely applied. One reason for this awkwardness is the lack of a truly big dataset captured in practical outdoor scenarios. Here, the "big" at least means: (1) huge amount of gait videos, (2) sufficient subjects, (3) rich attributes, and (4) spatial and temporal variations. Moreover, most existing large-scale gait datasets are collected indoors, which have few challenges from real scenes, such as the dynamic and complex background clutters, illumination variations, vertical view variations, etc. In this paper, we introduce a newly built big outdoor gait dataset, called CASIA-E. It contains more than one thousand people distributed over near one million videos. Each person involves 26 view angles and varied appearances caused by changes of bag carrying, dressing and walking styles. The videos are captured across five months and across three kinds of outdoor scenes. Soft biometric features are also recorded for all subjects including age, gender, height, weight and nationality. Besides, we report an experimental benchmark and examine some meaningful problems that have not been well studied previously, e.g., the influence of million-level training videos, vertical view angles, walking styles, and the thermal infrared modality. We believe that such a big outdoor dataset and the experimental benchmark will promote the development of gait recognition in both academic research and industrial applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TPAMI.2022.3183288DOI Listing
June 2022

High-efficiency photoreduction of CO in a low vacuum.

Phys Chem Chem Phys 2022 Jun 29;24(25):15389-15396. Epub 2022 Jun 29.

Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China.

Photoreduction of CO into CO, CH or hydrocarbons is attractive, due to environmental compatibility and economic feasibility. Optimizing the reaction engineering of CO reduction is an effective and general strategy that should be given special consideration. In this article, the photocatalytic CO reduction performances are originally investigated in a low vacuum in both dilute (10%) and pure CO. We discover that the CH yield increased above one hundred times as the vacuum degree increased from barometric pressure to -80 kPa in dilute CO. It also reveals long-term stability and good cycling performance in a low vacuum. The enhanced CO photoreduction performance in a low vacuum comes from better accumulation of photogenerated electrons, less intense Brownian movement of gas molecules in the environment and hindrance of the active site-blocking of gas molecules in the environment. Improved photocatalytic CO reduction in a low vacuum is further verified by Pt-TiO catalysts. This research presents a general route for producing clean fuels by photocatalytic CO reduction in a more effective way.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d2cp00269hDOI Listing
June 2022

A case of novel mutation of Cullin 3 gene in pseudohypoaldosteronism type II.

J Hypertens 2022 Jun;40(6):1239-1242

Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, China.

Pseudohypoaldosteronism type II (PHA II) is a rare inherited disease characterized by hypertension, hyperkalemia and metabolic acidosis. With the development of gene sequencing technology, more genetic mutations underlying PHA II were reported and the understanding of its pathogenesis has gone deep into the molecular level. Here, we present a juvenile case of PHA II. A novel missense mutation (c.1376 A>T) located in exon 9 of Cullin 3 (CUL3) was found by whole-exome sequencing. The clinical manifestations were significantly improved after oral hydrochlorothiazide. This case enriches the genetic and clinical phenotype spectrum of PHA II and provides experience for diagnosing and treating the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HJH.0000000000003117DOI Listing
June 2022

Tissue-engineered bones with adipose-derived stem cells - composite polymer for repair of bone defects.

Regen Med 2022 Jun 15. Epub 2022 Jun 15.

Department of Hand & Reconstructive Surgery, Plastic & Reconstructive Surgery Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.

Development of alternative bone tissue graft materials based on tissue engineering technology has gradually become a research focus. Engineered bone composed of biodegradable, biosafe and bioactive materials is attractive, but also challenging. An adipose-derived stem cell/poly(L-glutamic acid)/chitosan composite scaffold was further developed for construction of biodegradable and bone-promoting tissue-engineered bone. A series of composite scaffold materials with different physical properties such as structure, pore size, porosity and pore diameter was developed. The composite scaffold showed good biodegradability and water absorption, and exhibited an excellent ability to promote bone differentiation. This type of biodegradable scaffold is expected to be applied to the field of bone repair or bone tissue engineering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/rme-2022-0044DOI Listing
June 2022

Regression of Bilateral Peripapillary Choroidal Neovascularization Associated with Idiopathic Intracranial Hypertension after Systemic Acetazolamide Treatment.

Case Rep Ophthalmol 2022 Jan-Apr;13(1):270-275. Epub 2022 Apr 19.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.

A rare occurrence of bilateral peripapillary choroidal neovascularization (CNV) in an 18-year-old idiopathic intracranial hypertension (IIH) patient regressed with systemic acetazolamide treatment alone. Multimodal imaging was done, including OCT angiography (OCTA), which showed CNV. No injections were given even though she had macular fluid in her left eye. Nonetheless, the subretinal fluid resolved, and visual acuity improved. This report shows that CNV secondary to IIH can be managed with systemic therapy alone. Moreover, we showed for the first time the ability to diagnose IIH-associated CNV using OCTA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000522143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9149341PMC
April 2022

An Improved Genetically Encoded Fluorescent cAMP Indicator for Sensitive cAMP Imaging and Fast Drug Screening.

Front Pharmacol 2022 12;13:902290. Epub 2022 May 12.

Guangdong Provincial Key Laboratory of Biomedical Optical Imaging Technology & Center for Biomedical Optics and Molecular Imaging & CAS Key Laboratory of Health Informatics, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.

Cyclic adenosine 3',5'-monophosphate (cAMP) is an important intracellular second messenger molecule downstream of many G protein-coupled receptors (GPCRs). Fluorescence imaging with bright and sensitive cAMP indicators allows not only dissecting the spatiotemporal dynamics of intracellular cAMP, but also high-content screening of compounds against GPCRs. We previously reported the high-performance circularly permuted GFP (cpGFP)-based cAMP indicator G-Flamp1. Here, we developed improved G-Flamp1 variants G-Flamp2 and G-Flamp2b. Compared to G-Flamp1, G-Flamp2 exhibited increased baseline fluorescence (1.6-fold) and larger fluorescence change (ΔF/F) (1,300% vs. 1,100%) in HEK293T cells, while G-Flamp2b showed increased baseline fluorescence (3.1-fold) and smaller ΔF/F (400% vs. 1,100%). Furthermore, live cell imaging of mitochondrial matrix-targeted G-Flamp2 confirmed cytosolic cAMP was able to enter the mitochondrial matrix. G-Flamp2 imaging also showed that adipose tissue extract activated the Gi protein-coupled orphan GPCR GPR50 in HEK293T cells. Taken together, our results showed that the high-performance of G-Flamp2 would facilitate sensitive intracellular cAMP imaging and activity measurement of compounds targeting GPCR-cAMP signaling pathway during early drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2022.902290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175130PMC
May 2022

AI based colorectal disease detection using real-time screening colonoscopy.

Precis Clin Med 2021 Jun 20;4(2):109-118. Epub 2021 May 20.

Department of Clinical Research Center, Dazhou Central Hospital, Dazhou 635000, China.

Colonoscopy is an effective tool for early screening of colorectal diseases. However, the application of colonoscopy in distinguishing different intestinal diseases still faces great challenges of efficiency and accuracy. Here we constructed and evaluated a deep convolution neural network (CNN) model based on 117 055 images from 16 004 individuals, which achieved a high accuracy of 0.933 in the validation dataset in identifying patients with polyp, colitis, colorectal cancer (CRC) from normal. The proposed approach was further validated on multi-center real-time colonoscopy videos and images, which achieved accurate diagnostic performance on detecting colorectal diseases with high accuracy and precision to generalize across external validation datasets. The diagnostic performance of the model was further compared to the skilled endoscopists and the novices. In addition, our model has potential in diagnosis of adenomatous polyp and hyperplastic polyp with an area under the receiver operating characteristic curve of 0.975. Our proposed CNN models have potential in assisting clinicians in making clinical decisions with efficiency during application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/pcmedi/pbab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982552PMC
June 2021
-->