The total number of spikelets (TSPN) and the number of fertile spikelets (FSPN) affect the final number of grains per spikelet in wheat. This study constructed a high-density genetic map using 55K ...single nucleotide polymorphism (SNP) arrays from a population of 152 recombinant inbred lines (RIL) from crossing the wheat accessions 10-A and B39. Twenty-four quantitative trait loci (QTLs) for TSPN and 18 QTLs for FSPN were localized based on the phenotype in 10 environments in 2019-2021. Two major QTLs,
(34.43-47.43 Mb) and
(32.97-34.43 Mb), explained 13.97%-45.90% of phenotypic variation. Linked kompetitive allele-specific PCR (KASP) markers further validated these two QTLs and revealed that
had less effect on TSPN than
in 10-A×BE89 (134 RILs) and 10-A×Chuannong 16 (192 RILs) populations, and one population of Sichuan wheat (233 accessions). The alleles combination haplotype 3 with the allele from 10-A of
and the allele from B39 of
resulted in the highest number of spikelets. In contrast, the allele from B39 for both loci resulted in the lowest number of spikelets. Using bulk-segregant analysis-exon capture sequencing, six SNP hot spots that included 31 candidate genes were identified in the two QTLs. We identified
from B39 and
from 10-A and further analyzed
variation in wheat. These results identified loci and molecular markers with potential utility for wheat breeding and laid a foundation for further fine mapping and cloning of the two loci.
M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) ...transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.
A subpathway is defined as the local region of a biological pathway with specific biological functions. With the generation of large-scale sequencing data, there are more opportunities to study the ...molecular mechanisms of cancer development. It is necessary to investigate the potential impact of DNA methylation, copy number variation (CNV), and gene-expression changes in the molecular states of oncogenic dysfunctional subpathways. We propose a novel method, Identification of Cancer Dysfunctional Subpathways (ICDS), by integrating multi-omics data and pathway topological information to identify dysfunctional subpathways. We first calculated gene-risk scores by integrating the three following types of data: DNA methylation, CNV, and gene expression. Second, we performed a greedy search algorithm to identify the key dysfunctional subpathways within pathways for which the discriminative scores were locally maximal. Finally, a permutation test was used to calculate the statistical significance level for these key dysfunctional subpathways. We validated the effectiveness of ICDS in identifying dysregulated subpathways using datasets from liver hepatocellular carcinoma (LIHC), head-neck squamous cell carcinoma (HNSC), cervical squamous cell carcinoma, and endocervical adenocarcinoma. We further compared ICDS with methods that performed the same subpathway identification algorithm but only considered DNA methylation, CNV, or gene expression (defined as ICDS_M, ICDS_CNV, or ICDS_G, respectively). With these analyses, we confirmed that ICDS better identified cancer-associated subpathways than the three other methods, which only considered one type of data. Our ICDS method has been implemented as a freely available R-based tool (https://cran.r-project.org/web/packages/ICDS).
The core function of a manufacturing system is to consistently and efficiently output a specified number of qualified products that can meet production demands. However, the imperfect inspection can ...sometimes bring disturbances to the work-in-process (WIP) quality and the processing machine degradation in the function realization process, and this aspect has not been paid due attention in existing research on manufacturing system health evaluation researches. Therefore, a functional healthy state evaluation approach for manufacturing systems considering imperfect inspection based on extended stochastic flow network (ESFN) is proposed in this paper. First, a function realization-oriented operational mechanism is expounded from the systematic perspective. On this basis, the connotation of the functional healthy state of the manufacturing system considering imperfect inspection is further defined. Second, an ESFN model is established to describe the relationship among processing machines, WIPs, and inspection machines in a running manufacturing system. Third, a functional healthy state evaluation approach for a manufacturing systems considering imperfect inspection is proposed. Finally, the effectiveness of the approach is verified by an illustrative example.
•A new connotation of the functional healthy state of the manufacturing system is proposed.•An ESFN model for manufacturing system is established.•A functional healthy state evaluation approach considering imperfect inspection is proposed.•A ferrite phase shifting unit manufacturing system healthy evaluation example is conducted.
Immunohistochemical (IHC) assay is a commonly used auxiliary technique in pathological diagnosis. Compared to the conventional manual scoring methods that are complicated and time-consuming, ...automated scoring methods have been playing a more and more important role in the development of digital medicine due to their adaptability and consistency. This study proposes an automatic scoring model for tumor IHC images, which mainly consists of a module for extracting the regions of interest (ROI) and a feature fusion scoring network. The former module extracts the effective tissue regions and the nuclear regions as prior knowledge to exclude cytoplasmic staining interference. The feature fusion network includes two branches. The main branch network combines the structure of cross-block stitching feature maps and the frequency channel attention networks (FcaNet) to extract the features of the effective tissue region images. The other branch network extracts the color representation vector of the cell nucleus region images. The fully-connected layers combine the features from both branches to give a comprehensive final score as the result. We performed experiments on IHC images of P53 protein in colorectal cancer. The results show that the proposed P53Net achieves better classification results than the commonly used classification models, with 94.21% accuracy, 89.24% F1-Score, and 0.9136 kappa coefficient.
•The TL1A/DR3 signaling pathway is aberrantly activated in sarcoidosis.•Anti-TL1A monoclonal antibody can attenuate granuloma formation in sarcoidosis.•Anti-TL1A monoclonal antibody can modulate the ...dysregulation of Th1/Th17 cells in sarcoidosis.•Anti-TL1A monoclonal antibody's impact in sarcoidosis might involve inhibiting the PI3K/AKT signaling pathway.
Sarcoidosis is a systemic granulomatous disease characterized by non-caseating epithelioid cell granulomas. One of its immunological hallmarks is the differentiation of CD4 + naïve T cells into Th1/Th17 cells, accompanied by the release of numerous pro-inflammatory cytokines. The TL1A/DR3 signaling pathway plays a crucial role in activating effector lymphocytes, thereby triggering pro-inflammatory responses. The primary aim of this investigation was to scrutinize the impact of anti-TL1A monoclonal antibody on the dysregulation of Th1/Th17 cells and granuloma formation in sarcoidosis. Initially, the abnormal activation of the TL1A/DR3 signaling pathway in pulmonary tissues of sarcoidosis patients was confirmed using qPCR and immunohistochemistry techniques. Subsequently, employing a murine model of sarcoidosis, the inhibitory effects of anti-TL1A monoclonal antibody on the TL1A/DR3 signaling pathway in sarcoidosis were investigated through qPCR, immunohistochemistry, and Western blot experiments. The influence of anti-TL1A monoclonal antibody on granulomas was assessed through HE staining, while their effects on sarcoidosis Th1/Th17 cells and associated cytokine mRNA levels were evaluated using flow cytometry and qPCR, respectively. Immunofluorescence and Western blot experiments corroborated the inhibitory effects of anti-TL1A monoclonal antibody on the aberrant activation of the PI3K/AKT signaling pathway in sarcoidosis. The findings of this study indicate that the TL1A/DR3 signaling pathway is excessively activated in sarcoidosis. Anti-TL1A monoclonal antibody effectively inhibit this abnormal activation in sarcoidosis, thereby alleviating the dysregulation of Th1/Th17 cells and reducing the formation of pulmonary granulomas. This effect may be associated with the inhibition of the downstream PI3K/AKT signaling pathway. Anti-TL1A monoclonal antibody hold promise as a potential novel therapeutic intervention for sarcoidosis.
Follistatin-like protein 3 (FSTL3) is a type of FSTLs. By interacting with a disintegrin and metalloproteinase 12 (ADAM12), transforming growth factor-β ligands (activin, myostatin and growth ...differentiation factor (GDF) 11), FSTL3 can either activate or inhibit these molecules in human non-tumor pathophysiologies and cancers. The FSTL3 gene was initially discovered in patients with in B-cell chronic lymphocytic leukemia, and subsequent studies have shown that the FSTL3 protein is associated with reproductive development, insulin resistance, and hematopoiesis. FSTL3 reportedly contributes to the development and progression of many cancers by promoting tumor metastasis, facilitating angiogenesis, and inducing stem cell differentiation. This review summarizes the current pathophysiological roles of FSTL3, which may be a putative prognostic biomarker for various diseases and serve as a potential therapeutic target.
The periosteum plays a vital role in repairing bone defects. Researchers have demonstrated the existence of electrical potential in the periosteum and native bone, indicating that electrical signals ...are essential for functional bone regeneration. However, the clinical use of external electrical treatments has been limited due to their inconvenience and inefficacy. As an alternative, low-intensity pulsed ultrasound (LIPUS) is a noninvasive form of physical therapy that enhances bone regeneration. Furthermore, the wireless activation of piezoelectric biomaterials through ultrasound stimulation would generate electric charges precisely at the defect area, compensating for the insufficiency of external electrical stimulation and potentially promoting bone regeneration through the synergistic effect of mechanical and electrical stimulation. However, the optimal integration of LIPUS with an appropriate piezoelectric periosteum is yet to be explored. Herein, the BaTiO3/multiwalled-carbon nanotubes/collagen (BMC) membranes have been fabricated, possessing physicochemical properties including improved surface hydrophilicity, enhanced mechanical performance, ideal piezoelectricity, and outstanding biocompatibility, all of which are conducive to bone regeneration. When combined with LIPUS, the endogenous electrical microenvironment of native bone was recreated. After that, the wireless-generated electrical signals, along with the mechanical signals induced by LIPUS, were transferred to macrophages and activated Ca2+ influx through Piezo1. Ultimately, the regenerative effect of the BMC membrane with LIPUS stimulation (BMC + L) was confirmed in a mouse cranial defect model. Together, this research presents a co-engineering strategy that involves fabricating a novel biomimetic periosteum and utilizing the synergistic effect of ultrasound to enhance bone regeneration, which is achieved through the reinforcement of the electrical environment and the immunomodulation of macrophage polarization.
This article delineates an ingenious strategy involving the synthesis of a BMC piezoelectric membrane. Under ultrasound stimulation, the synergistic interplay of mechanical and electrical signals activates macrophage Piezo1, augmenting calcium ion flux, thereby polarizing into M2 type and fostering bone defect repair. Display omitted
The primary object of this study is to analyze chromosomal abnormalities in miscarriages detected by copy number variants sequencing (CNV-Seq), establish potential pathways or genes related to ...miscarriages, and provide guidance for birth health in the following pregnancies.
This study enrolled 580 miscarriage cases with paired clinical information and chromosomal detection results analyzed by CNV-Seq. Further bioinformatic analyses were performed on validated pathogenic CNVs (pCNVs).
Of 580 miscarriage cases, three were excluded as maternal cell contamination, 357 cases showed abnormal chromosomal results, and the remaining 220 were normal, with a positive detection rate of 61.87% (357/577). In the 357 miscarriage cases, 470 variants were discovered, of which 65.32% (307/470) were pathogenic. Among all variants detected, 251 were numerical chromosomal abnormalities, and 219 were structural abnormalities. With advanced maternal age, the proportion of numerical abnormalities increased, but the proportion of structural abnormalities decreased. Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology analysis revealed that eleven pathways and 636 biological processes were enriched in pCNVs region genes. Protein-protein interaction analysis of 226 dosage-sensitive genes showed that TP53, CTNNB1, UBE3A, EP300, SOX2, ATM, and MECP2 might be significant in the development of miscarriages.
Our study provides evidence that chromosomal abnormalities contribute to miscarriages, and emphasizes the significance of microdeletions or duplications in causing miscarriages apart from numerical abnormalities. Essential genes found in pCNVs regions may account for miscarriages which need further validation.
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