To explore more efficient treatments for chronic obstructive pulmonary disease (COPD), effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) and electroacupuncture were tested on rats with COPD, and silent information regulator transcript-1 (SIRT1)/nuclear factor-kappaB (NF-κB) signaling was further investigated to interpret the therapy.

Argonaute (Ago) proteins are programmable nucleases found in eukaryotes and prokaryotes. Prokaryotic Agos (pAgos) share a high degree of structural homology with eukaryotic Agos (eAgos), and eAgos originate from pAgos. Although eAgos exclusively cleave RNA targets, most characterized pAgos cleave DNA targets. This study characterized a novel pAgo, MbpAgo, from the psychrotolerant bacterium Mucilaginibacter paludis which prefers to cleave RNA targets rather than DNA targets. Compared to previously studied Agos, MbpAgo can utilize both 5'phosphorylated(5'P) and 5'hydroxylated(5'OH) DNA guides (gDNAs) to efficiently cleave RNA targets at the canonical cleavage site if the guide is between 15 and 17 nt long. Furthermore, MbpAgo is active at a wide range of temperatures (4-65°C) and displays no obvious preference for the 5'-nucleotide of a guide. Single-nucleotide and most dinucleotide mismatches have no or little effects on cleavage efficiency, except for dinucleotide mismatches at positions 11-13 that dramatically reduce target cleavage. MbpAgo can efficiently cleave highly structured RNA targets using both 5'P and 5'OH gDNAs in the presence of Mg2+ or Mn2+. The biochemical characterization of MbpAgo paves the way for its use in RNA manipulations such as nucleic acid detection and clearance of RNA viruses.

Grain length (GL) directly affects the yield and quality of rice. Very few cloned GL-related genes are applied in production because their yield-increasing effects are not obvious, and the overall regulatory networks underlying the associated processes remain poorly understood. DNA samples from two bulk DNA pools (L-pool and S-pool) and their parents (KJ01 and Huaye 3) were subjected to high-throughput sequencing. Using bulked segregant analysis (BSA), qGL3.5 was mapped to a 0.34-Mb "hotspot" region on chromosome 3 that contains 37 genes related to various traits. Then, qGL3.5 was mapped to the genomic interval between the flanking markers M2 and M3 using 2786 BC4F2 individuals. Because the region from B5 to B6 was not the associated region under BSA-seq analysis, qGL3.5 was narrowed down to the interval between B6 and M3, which spanned 24.0-kb. Of all 37 genes with non-synonymous single-nucleotide polymorphisms (SNPs) between KJ01 and Huaye 3 based on BSA-seq analysis, only one complete annotated gene, ORF18 (Gene ID: LOC_Os03g42790.1) was found. ORF18 encodes an IBR-RING zinc-finger-related protein, with one really interesting new gene (RING) and two in between ring finger (IBR) domains. The knockout of ORF18 derived from Huaye 3 using clustered, regularly interspaced, short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) editing technology increased the GL of the mutant by approximately 2.2 mm. The novel locus qGL3.5 negatively regulated GL by promoting elongation of the longitudinal cell of the grain outer glume. These results provide a new genetic resource for rice grain shape breeding and a starting point for the functional characterization of the wild rice GL gene.

Uveal melanoma (UM) is the most frequent primary eye cancer in adults with a 50% mortality rate. Characterizing the fundamental signaling pathways that drive UM is of importance for the development of targeted therapy. This study aims to probe the impact of sclerostin (SOST) on malignant progression of UM and regulation of Wnt/β-catenin signaling.

Genomic prediction (GP) and genome-wide association (GWA) analyses are currently being employed to accelerate breeding cycles and to identify alleles or genomic regions of complex traits in forest trees species. Here, 1490 interior lodgepole pine (Pinus contorta Dougl. ex. Loud. var. latifolia Engelm) trees from four open-pollinated progeny trials were genotyped with 25,099 SNPs, and phenotyped for 15 growth, wood quality, pest resistance, drought tolerance, and defense chemical (monoterpenes) traits. The main objectives of this study were to: (1) identify genetic markers associated with these traits and determine their genetic architecture, and to compare the marker detected by single- (ST) and multiple-trait (MT) GWA models; (2) evaluate and compare the accuracy and control of bias of the genomic predictions for these traits underlying different ST and MT parametric and non-parametric GP methods. GWA, ST and MT analyses were compared using a linear transformation of genomic breeding values from the respective genomic best linear unbiased prediction (GBLUP) model. GP, ST and MT parametric and non-parametric (Reproducing Kernel Hilbert Spaces, RKHS) models were compared in terms of prediction accuracy (PA) and control of bias.

This study aimed to investigate the effects of heavy ion (12C6+) irradiation on the proliferation, apoptosis, cell cycle, migration, and epithelial-mesenchymal transition (EMT) of B16F10 cells.

Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with limited understanding and few effective therapeutic approaches. We aimed at providing a proteogenomic CCA characterization to inform biological processes and treatment vulnerabilities.

Hepatitis B virus (HBV) is a major risk factor for the development and progression of hepatocellular carcinoma (HCC). It has been reported that viral infection can interfere with the expression of cellular microRNA (miRNA) to affect oncogenesis. In this study, we showed that miR-520c-3p was upregulated in liver tumor specimens, and we revealed that HBV infection enhanced the expression of miR-520c-3p through the interaction of viral protein HBV X protein (HBx) with transcription factor CREB1. We further showed that miR-520c-3p induced by HBV transfection/infection caused epithelial-mesenchymal transition (EMT). Using the miRNA target prediction database miRBase and luciferase reporter assays, we identified PTEN as a novel target gene of miR-520c-3p and miR-520c-3p directly targeted PTEN's 3'-untranslated region. Moreover, we discovered that HBV promoted EMT via the miR-520c-3p-PTEN to activate AKT-NFκB signaling pathway, leading to increased HCC migration and invasion. Importantly, miR-520c-3p antagomir significantly represses invasiveness in HBx-induced hepatocellular xenograft models. Our findings indicate that miR-520c-3p is a novel regulator of HBV and plays an important role in HCC progression. It may serve as a new biomarker and molecular therapeutic target for HBV patients.

Detection of circulating tumor cells (CTCs) could be widely used for early diagnosis and real-time monitoring of tumor progression in liquid biopsy samples. Compared with normal cells, tumor cells exhibit relatively strong negative surface charges due to the high rate of glycolysis. In this study, a cationic fluorescence "turn-on" aggregation-induced emission (AIE) nanoprobe based on gold nanorods (GNRs) was designed and tested to detect tumor cells specifically. In brief, tetraphenylethene (TPE), an AIE dye, was conjugated to the cationic polymer polyethylenimine (PEI) yielding TPEI. TPEI-PEG-SH was obtained by further functionalizing TPEI with a thiol group. TPEI-PEG-SH was grafted to the surface of GNRs, yielding the cationic AIE nanoprobe, named as GNRs-PEG-TPEI. The nanoprobe was characterized to have a uniform particle size of 172 nm, a strong positive surface charge (+54.87 mV), and a surface modification load of ∼40%. The in vitro stability of GNRs-PEG-TPEI was verified. The cellular imaging results demonstrated that the nanoprobe could efficiently recognize several types of tumor cells including MCF-7, HepG2, and Caco-2 while exhibiting specific fluorescence signals only after interacting with tumor cells and minimal background interference. In addition, the study investigated the toxicity of the nanoprobe to the captured cells and proved the safety of the nanoprobe. In conclusion, a specific and efficient nanoprobe was developed for capture and detection of different types of tumor cells based on their unique metabolic characteristics. It holds great promise for achieving early diagnosis and monitoring the tumor progression by detecting the CTCs in clinical liquid biopsy samples.

Current rat model of rotator cuff (RC) tear could not mimic the suture anchor (SA) repair technique in the clinical practice. We designed a novel SA for RC repair of rats to establish a clinically relevant animal model. Small suture anchors that fit the rat shoulder were assembled. 60 rats were assigned to the transosseous (TO) repair group or SA repair group (n = 30/group). Micro-computed tomography (Micro-CT) scanning, biomechanical test and histological analysis were implemented at 2, 4, and 8-week post-repair. The failure load and stiffness in the SA group were significantly higher than those of TO group at 4-week post-repair. Micro-computed tomography analysis showed the bone mineral density and trabecular thickness of the SA group were significantly lower than those of TO group. The SA group showed a better insertion continuity at 4-week post-repair compared to TO group. No significant difference in gait parameters was found between groups. Therefore, SA repair is applicable for the rat model of RC tears. The SA repair achieved superior RC tendon healing, but more extensive initial bone damage compared to TO repair, while the shoulder function was comparable. This model could replicate the current repair technique in the clinical situation and be considered for future preclinical studies on healing enhancement for RC tears. Statement of Clinical Significance: With high clinical relevance, this model may facilitate the translation from an animal study into clinical trials.

Glioblastoma multiforme (GBM) is the most aggressive and highly vascularized brain tumor with poor prognosis. Endothelial cell-dependent angiogenesis and tumor cell-dependent Vasculogenic mimicry (VM) synergistically contribute to glioma vascularization and progression. However, the mechanism underlying GBM vascularization remains unclear. In this study, GBM stem cells (GSCs) were divided into high and low β8 integrin (ITGB8) subpopulations. Co-culture assays followed by Cell Counting Kit-8 (CCK-8), migration, Matrigel tube formation, and sprouting assays were conducted to assess the proliferative, migratory and angiogenic capacity of GBM cells and human brain microvascular endothelial cells (hBMECs). An intracranial glioma model was constructed to assess the effect of ITGB8 on tumor vascularization in vivo. Our results indicated that ITGB8 expression was elevated in GSCs and positively associated with stem cell markers in glioma tissues, and could be induced by hypoxia and p38 activation. ITGB8 in GSCs inhibited the angiogenesis of hBMECs in vitro, while it promoted the ability of network formation and expression of VM-related proteins. The orthotopic GBM model showed that ITGB8 contributed to decreased angiogenesis, meanwhile enhanced invasiveness and VM formation. Mechanistic studies indicated that ITGB8-TGFβ1 axis modulates VM and epithelial-mesenchymal transition (EMT) process via Smad2/3-RhoA signaling. Together, our findings demonstrated a differential role for ITGB8 in the regulation of angiogenesis and VM formation in GBM, and suggest that pharmacological inhibition of ITGB8 may represent a promising therapeutic strategy for treatment of GBM.

The association between gut microbiota and microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) remains unclarified. Hence, the microbiome analysis of patients with HCC might predict MVI development as an accurate, non-invasive, and convenient assessment. The aim of this study was to investigate the characteristics of gut microbiota in patients with HCC-MVI and establish a microbial prediction model of HCC-MVI based on a microbiome study.

Predictable DNA off-target effect is one of the major safety concerns for the application of cytosine base editors (CBEs). To eliminate Cas9-dependent DNA off-target effects, we designed a novel effective CBE system with dual guiders by combining CRISPR with transcription activator-like effector (TALE). In this system, Cas9 nickase (nCas9) and cytosine deaminase are guided to the same target site to conduct base editing by single-guide RNA (sgRNA) and TALE, respectively. However, if nCas9 is guided to a wrong site by sgRNA, it will not generate base editing due to the absence of deaminase. Similarly, when deaminase is guided to a wrong site by TALE, base editing will not occur due to the absence of single-stranded DNA. In this way, Cas9- and TALE-dependent DNA off-target effects could be completely eliminated. Furthermore, by fusing TALE with YE1, a cytidine deaminase with minimal Cas9-independent off-target effect, we established a novel CBE that could induce efficient C-to-T conversion without detectable Cas9- or TALE-dependent DNA off-target mutations.

Accurate delineation of individual teeth and alveolar bones from dental cone-beam CT (CBCT) images is an essential step in digital dentistry for precision dental healthcare. In this paper, we present an AI system for efficient, precise, and fully automatic segmentation of real-patient CBCT images. Our AI system is evaluated on the largest dataset so far, i.e., using a dataset of 4,215 patients (with 4,938 CBCT scans) from 15 different centers. This fully automatic AI system achieves a segmentation accuracy comparable to experienced radiologists (e.g., 0.5% improvement in terms of average Dice similarity coefficient), while significant improvement in efficiency (i.e., 500 times faster). In addition, it consistently obtains accurate results on the challenging cases with variable dental abnormalities, with the average Dice scores of 91.5% and 93.0% for tooth and alveolar bone segmentation. These results demonstrate its potential as a powerful system to boost clinical workflows of digital dentistry.

We present spatial-CITE-seq for high-plex protein and whole transcriptome co-mapping, which was firstly demonstrated for profiling 198 proteins and transcriptome in multiple mouse tissue types. It was then applied to human tissues to measure 283 proteins and transcriptome that revealed spatially distinct germinal center reaction in tonsil and early immune activation in skin at the COVID-19 mRNA vaccine injection site. Spatial-CITE-seq may find a range of applications in biomedical research.

Sphingosine-1-phosphate receptor 2 (S1PR2) was highly expressed in intestinal epithelial cells (IECs) and facilitated the proliferation of IECs. However, the specific function of S1PR2 in intestinal diseases, such as ulcerative colitis (UC), remains unclear. Accordingly, the current study set out to investigate the function of S1PR2 in maintaining intestinal barrier and inducing UC. S1PR2-overexpressed and knockdown Caco-2 cells were established to explore the function of S1PR2 on the permeability of IECs barrier. The UC-like mouse model in which UC is induced by dextran sulfate sodium (DSS) was established and utilized to investigate the role for S1PR2. The results showed that S1PR2 functioned as a maintainer of IECs permeability and a pathogenic factor for UC. A series of in vitro and in vivo experiments were conducted, and it was found that S1PR2 played an important role in intestinal epithelial cell proliferation and maintenance of intestinal epithelial cell barrier, possibly by the regulation on the expression level of SphK2, HDAC1, HDAC2, and ERK1/2 signaling pathway. The expression of S1PR2 was upregulated in UC mice and the colonic pathological damage in UC mice could be alleviated by the inhibition of S1PR2. Collectively, these results suggest that S1PR2 functions as a maintainer of IECs permeability and a pathogenic factor for UC. The research suggests S1PR2 may be an effective target for developing therapeutic strategies against UC.Abbreviations: S1PR2, Sphingosine-1-phosphate receptor 2; UC, ulcerative colitis; IECs, intestinal epithelial cells; DSS, dextran sulfate sodium; IBD, inflammation bowel disease; CD, Crohn's disease; S1P, sphingosin-1-phosphate; SphK, sphingosine kinase; HIECs, human IECs; siRNA, small interfering RNA; CCK-8, cell counting kit-8; TEER, transepithelial electrical resistance; TEM, transmission electron microscope; RT-PCR, real-time reverse transcriptase polymerase-chain reaction; ELISA, enzyme-linked immunosorbent assay; HE, hematoxylin and eosin.

O-GlcNAcylation is a highly dynamic, reversible and atypical glycosylation that regulates the activity, biological function, stability, sublocation and interaction of target proteins. O-GlcNAcylation receives and coordinates different signal inputs as an intracellular integrator similar to the nutrient sensor and stress receptor, which target multiple substrates with spatio-temporal analysis specifically to maintain cellular homeostasis and normal physiological functions. Our review gives a brief description of O-GlcNAcylation and its only two processing enzymes and HBP flux, which will help to better understand its physiological characteristics of sensing nutrition and environmental cues. This nutritional and stress-sensitive properties of O-GlcNAcylation allow it to participate in the precise regulation of skeletal muscle metabolism. This review discusses the mechanism of O-GlcNAcylation to alleviate metabolic disorders and the controversy about the insulin resistance of skeletal muscle. The level of global O-GlcNAcylation is precisely controlled and maintained in the "optimal zone", and its abnormal changes is a potential factor in the pathogenesis of cancer, neurodegeneration, diabetes and diabetic complications. Although the essential role of O-GlcNAcylation in skeletal muscle physiology has been widely studied and recognized, it still is underestimated and overlooked. This review highlights the latest progress and potential mechanisms of O-GlcNAcylation in the regulation of skeletal muscle contraction and structural properties.

With the advancement in machine learning (ML) and artificial neural networks as well as the development of portable electrocardiogram devices, artificial intelligence (AI) has been increasing in popularity over the years. In this study, we aimed to provide an overview of the research regarding the utilization of AI techniques to improve the diagnosis of arrhythmia.

An improved understanding of the molecular mechanism of colorectal adenocarcinoma is necessary to predict the prognosis and develop new target gene therapy strategies. This study aims to identify hub genes associated with colorectal adenocarcinoma and further analyze their prognostic significance. In this study, The Cancer Genome Atlas (TCGA) COAD-READ database and the gene expression profiles of GSE25070 from the Gene Expression Omnibus were collected to explore the differentially expressed genes between colorectal adenocarcinoma and normal tissues. The weighted gene co-expression network analysis (WGCNA) and differential expression analysis identified 82 differentially co-expressed genes in the collected datasets. Enrichment analysis was applied to explore the regulated signaling pathway in colorectal adenocarcinoma. In addition, 10 hub genes were identified in the protein-protein interaction (PPI) network by using the cytoHubba plug-in of Cytoscape, where five genes were further proven to be significantly related to the survival rate. Compared with normal tissues, the expressions of the five genes were both downregulated in the GSE110224 dataset. Subsequently, the expression of the five hub genes was confirmed by the Human Protein Atlas database. Finally, we used Cox regression analysis to identify genes associated with prognosis, and a 3-gene signature (CLCA1-CLCA4-GUCA2A) was constructed to predict the prognosis of patients with colorectal cancer. In conclusion, our study revealed that the five hub genes and CLCA1-CLCA4-GUCA2A signature are highly correlated with the development of colorectal adenocarcinoma and can serve as promising prognosis factors to predict the overall survival rate of patients.

To characterize nosocomial transmission and rearrangement of the resistance-virulence plasmid between two ST11-K64 carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) strains (JX-CR-hvKP-10 and JX-CR-hvKP-9) with low fitness.