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Myocardial infarction (MI) is the leading cause of premature death. The death of cardiomyocytes (CMs) and the dysfunction of the remaining viable CMs are the main pathological factors contributing to heart failure (HF) following MI. This study aims to determine the transcriptional profile of CMs and investigate the heterogeneity among CMs under hypoxic conditions. Single-cell atlases of the heart in both the sham and MI groups were developed using single-cell data (GSE214611) downloaded from Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/). The heterogeneity among CMs was explored through various analyses including enrichment, pseudo time, and intercellular communication analysis. The marker gene of C5 was identified using differential expression analysis (DEA). Real-time polymerase chain reaction (RT-PCR), bulk RNA-sequencing dataset analysis, western blotting, immunohistochemical and immunofluorescence staining, Mito-Tracker staining, TUNEL staining, and flow cytometry analysis were conducted to validate the impact of the marker gene on mitochondrial function and cell apoptosis of CMs under hypoxic conditions. We identified a cell subcluster named C5 that exhibited a close association with mitochondrial malfunction and cellular apoptosis characteristics, and identified Slc25a4 as a significant biomarker of C5. Furthermore, our findings indicated that the expression of Slc25a4 was increased in failing hearts, and the downregulation of Slc25a4 improved mitochondrial function and reduced cell apoptosis. Our study significantly identified a distinct subcluster of CMs that exhibited strong associations with ventricular remodeling following MI. Slc25a4 served as the hub gene for C5, highlighting its significant potential as a novel therapeutic target for MI. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis is a persistent disease of the lung interstitium for which there is no efficacious pharmacological therapy. Protodioscin, a steroidal saponin, possesses diverse pharmacological properties; however, its function in pulmonary fibrosis is yet to be established. Hence, in this investigation, it was attempted to figure out the anti-pulmonary fibrosis influences of protodioscin and its pharmacological properties related to oxidative stress. Methods: A mouse lung fibrosis model was generated using tracheal injections of bleomycin, followed by intraperitoneal injection of different concentrations of protodioscin, and the levels of oxidative stress and fibrosis were detected in the lungs. Multiple fibroblasts were treated with TGF-β to induce their transition to myofibroblasts. It was attempted to quantify myofibroblast markers' expression levels and reactive oxygen species levels as well as Nrf2 activation after co-incubation of TGF-β with fibroblasts and different concentrations of protodioscin. The influence of protodioscin on the expression and phosphorylation of p62, which is associated with Nrf2 activation, were detected, and p62 related genes were predicted by STRING database. The effects of Nrf2 inhibitor or silencing of the Nrf2, p62 and NBR1 genes, respectively, on the activation of Nrf2 by protodioscin were examined. The associations between p62, NBR1, and Keap1 in the activation of Nrf2 by protodioscin was demonstrated using a co-IP assay. Nrf2 inhibitor were used when protodioscin was treated in mice with pulmonary fibrosis and lung tissue fibrosis and oxidative stress levels were detected. Results: In vivo, protodioscin decreased the levels of fibrosis markers and oxidative stress markers and activated Nrf2 in mice with pulmonary fibrosis, and these effects were inhibited by Nrf2 inhibitor. In vitro, protodioscin decreased the levels of myofibroblast markers and oxidative stress markers during myofibroblast transition and promoted Nrf2 downstream gene expression, with reversal of these effects after Nrf2, p62 and NBR1 genes were silenced or Nrf2 inhibitors were used, respectively. Protodioscin promoted the binding of NBR1 to p62 and Keap1, thereby reducing Keap1-Nrf2 binding. Conclusion: The NBR1-p62-Nrf2 axis is targeted by protodioscin to reduce oxidative stress and inhibit pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Cold shock proteins (CSPs) are DNA/RNA binding proteins with crucial regulatory roles in plant growth, development, and stress responses. In this study, we employed bioinformatics tools to identify and analyze the physicochemical properties, conserved domains, gene structure, phylogenetic relationships, cis-acting elements, subcellular localization, and expression patterns of the cotton CSP gene family. A total of 62 CSP proteins were identified across four cotton varieties (Gossypium arboreum, Gossypium raimondii, Gossypium barbadense, Gossypium hirsutum) and five plant varieties (Arabidopsis thaliana, Brassica chinensis, Camellia sinensis, Triticum aestivum, and Oryza sativa). Phylogenetic analysis categorized cotton CSP proteins into three evolutionary branches, revealing similar gene structures and motif distributions within each branch. Analysis of gene structural domains highlighted the conserved CSD and CCHC domains across all cotton CSP families. Subcellular localization predictions indicated predominant nuclear localization for CSPs. Examination of cis-elements in gene promoters revealed a variety of elements responsive to growth, development, light response, hormones, and abiotic stresses, suggesting the potential regulation of the cotton CSP family by different hormones and their involvement in diverse stress responses. RT-qPCR results suggested that GhCSP.A1, GhCSP.A2, GhCSP.A3, and GhCSP.A7 may play roles in cotton's response to low-temperature stress. In conclusion, our findings underscore the significant role of the CSP gene family in cotton's response to low-temperature stress, providing a foundational basis for further investigations into the functional aspects and molecular mechanisms of cotton's response to low temperatures. [ABSTRACT FROM AUTHOR]

Plasma exosomal microRNAs (miRNAs) have been used as potential biomarkers for various diseases and have been investigated for their possible involvement in the pathogenesis of vitiligo. However, the miRNA expression profile of plasma exosomes in patients with non-segmental vitiligo (NSV) has not been determined yet. To screen differentially expressed microRNAs in plasma exosomes derived from patients with NSV and explore their roles in the pathogenesis of NSV. High-throughput sequencing was performed to determine the expression profiles of exosomal miRNAs in NSV. The effect of upregulated miR-1469 in NSV circulating exosomes on natural killer (NK) cells was further investigated using various molecular biological techniques. MiR-1469 was identified as a candidate biomarker whose expression was significantly increased in circulating exosomes of NSV patients. Circulating exosomes were internalized by NK cells and increased NK cell proliferation viability and IFN-γ secretion capacity delivering miR-1469. Further studies revealed that the upregulation of CD122, the predicted target of miR-1469, could partially reverse the effect of miR-1469 on natural killer cells. Alterations in plasma exosomal cargo occur in NSV and appear to contribute to NK cell dysfunction. Exosomal miR-1469 may be a biomarker of disease activity and could be used as a therapeutic drug target against innate immunity in NSV patients. The present study provides new insights into the role of exosomal miRNAs in NSV and suggests a novel miR-1469-CD122-IFN-γ pathway of NK cell underlying pathogenesis of NSV. • MiR-1469 derived from plasma exosomes of patients with non-segmental vitiligo is significantly elevated. • MiR-1469 is negatively correlated with the frequency of IFN-γ+ natural killer cells in non-segmental vitiligo. • MiR-1469 downregulates proliferation viability and IFN-γ secretion of natural killer cells by inhibiting CD122. [ABSTRACT FROM AUTHOR]

Exploring herbs and their compounds for potential drugs is a significant research focus due to the incurable nature of Sjögren's syndrome (SS), a prevalent chronic inflammatory autoimmune disease. Dendrobium officinale polysaccharide (DOP) has demonstrated diverse biological effects, particularly in immunomodulation. Nonetheless, limited research has been conducted on DOP concerning the treatment of SS. This research aims to examine the impacts of DOP on experimental SS (ESS) mice and its possible mechanisms. An ESS animal model was established using the immune induction method. Besides the control group, ESS mice were randomly assigned to the model (distilled water), the HCQ (60 mg/kg), the DOP (43 mg/kg), the DOP (130 mg/kg), and the DOP (390 mg/kg) groups. Drugs were treated for three weeks. The findings indicated that DOP enhanced saliva production of ESS mice and diminished lymphocyte infiltration and foci in the submandibular gland (SMG). DOP also significantly downregulated the mRNA content of proinflammatory factors (TNF-α, IL-1β, and IL-17) and the expression of genes and proteins of apoptotic factors (Bax and Caspase-3). Furthermore, DOP downregulated the BAFF and BAFF receptor (BAFFR) as well as Fas and Fas ligand (Fas-L) expressions in the SMG. Our study demonstrates that DOP may reduce inflammation and apoptosis by inhibiting BAFF/BAFFR and Fas/Fas-L signaling, thus producing therapeutic effects in ESS mice. [ABSTRACT FROM AUTHOR]

Penicillium expansum is the most popular post-harvest pathogen and causes blue mold disease in pome fruit and leads to significant economic losses worldwide every year. However, the fundamental regulation mechanisms of growth in P. expansum are unclear. Recently, non-coding RNAs (ncRNAs) have attracted more attention due to critical roles in normalizing gene expression and maintaining cellular genotypes in organisms. However, the research related to ncRNAs in P. expansum have not been reported. Therefore, to provide an overview of ncRNAs on composition, distribution, expression changes, and potential targets in the growth process, a comparative transcriptomic analysis was performed on spores and mycelia of P. expansum in the present study. A total of 2595 novel mRNAs, 3362 long non-coding RNAs (lncRNAs), 10 novel microRNAs (miRNAs), 86 novel small interfering RNAs (siRNAs), and 11,238 circular RNAs (circRNAs) were predicted and quantified. Of these, 1482 novel mRNAs, 5987 known mRNAs, 2047 lncRNAs, 40 miRNAs, 38 novel siRNAs, and 9235 circRNAs were differentially expressed (DE) in response to the different development stages. Afterward, the involved functions and pathways of DE RNAs were revealed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database enrichment analysis. The interaction networks between mRNAs, lncRNAs, and miRNAs were also predicted based on their correlation coefficient of expression profiles. Among them, it was found that miR168 family members may play important roles in fungal growth due to their central location in the network. These findings will contribute to a better understanding on regulation machinery at the RNA level on fungal growth and provide a theoretical basis to develop novel control strategies against P. expansum. [ABSTRACT FROM AUTHOR]

Rosa roxburghii Tratt is a traditional Chinese plant that has been used to treat different inflammatory diseases. The purpose of this study was to investigate the mechanism of action of Rosa roxburghii Tratt extract (RRTE) against ulcerative colitis (UC) using network pharmacology and experimental validation. HPLC-Q/Orbitrap MS was used to rapidly identify the substances contained in RRTE after extracting the active components from the fruit. Then, network pharmacology combined with molecular docking was used to explore the critical target and potential mechanism of RRTE against UC using the active ingredients in RRTE as the research object. Data are presented in a visual manner. Finally, the pharmacological effects of RRTE in alleviating UC were further verified using a DSS-induced UC model of NCM460. The results showed that 25 components in RRTE were identified. A total of 250 targets of the active components and 5376 targets associated with UC were collected. Furthermore, a systematic analysis of the Protein–Protein Interaction (PPI) networks suggests that epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), and serine/threonine kinase 1 (AKT1) are critical targets for RRTE in the treatment of UC. A comprehensive regulatory network analysis showed that RRTE alleviated UC through the EGFR-mediated PI3K/Akt pathway, and molecular docking showed that active components could strongly bind to EGFR, PIK3R1, and AKT1. In addition, RRTE alleviated dextran sulfate sodium salt (DSS)-induced cell injury and significantly decreased the protein expression levels of EGFR, PIK3R1, and p-AKT in NCM460 cells in vitro. Furthermore, RRTE significantly regulated the expression of the apoptosis-related proteins Apoptotic protease-activating factor 1 (Apaf1), cleaved caspase-3, B-cell lymphoma-2 (Bcl2), and Bcl2 associated X protein (Bax). In conclusion, the components of RRTE are complex, and RRTE can relieve UC through the EGFR-mediated PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON) is one of the most prevalent mycotoxin contaminants, which posing a serious health threat to animals and humans. Previous studies have found that individually supplemented probiotic or glycyrrhinic acid (GA) could degrade DON and alleviate DON-induced cytotoxicity. The present study investigated the effect of combining GA with Saccharomyces cerevisiae (S. cerevisiae) and Enterococcus faecalis (E. faecalis) using orthogonal design on alleviating IPEC-J2 cell damage induced by DON. The results showed that the optimal counts of S. cerevisiae and E. faecalis significantly promoted cell viability. The optimal combination for increasing cell viability was 400 µg/mL GA, 1 × 106 CFU/mL S. cerevisiae and 1 × 106 CFU/mL E. faecalis to make GAP, which not only significantly alleviated the DON toxicity but also achieved the highest degradation rate of DON (34.7%). Moreover, DON exposure significantly increased IL-8, Caspase3 and NF-κB contents, and upregulated the mRNA expressions of Bax, Caspase 3, NF-κB and the protein expressions of Bax, TNF-α and COX-2. However, GAP addition significantly reduced aforementioned genes and proteins. Furthermore, GAP addition significantly increased the mRNA expressions of Claudin-1, Occludin, GLUT2 and ASCT2, and the protein expressions of ZO-1, Claudin-1 and PePT1. It was inferred that the combination of GA, S. cerevisiae, and E. faecalis had the synergistic effect on enhancing cell viability and DON degradation, which could protect cells from DON-induced damage by reducing DON cytotoxicity, alleviating cell apoptosis and inflammation via inhibiting NF-κB signaling pathway, improving intestinal barrier function, and regulating nutrient absorption and transport. These findings suggest that GAP may have potential as a dietary supplement for livestock or humans exposed to DON-contaminated food or feed. [ABSTRACT FROM AUTHOR]

Increased proliferation and migration of abnormal airway smooth muscle cells (ASMCs) are significantly associated with asthma. Recently, the function of long non-coding RNAs (lncRNAs) in ASMCs has been identified. Our research attempted to resolve the function of the lncRNA DGCR5 in ASMCs and focus on its in-depth mechanisms of proliferation and migration. Quantitative real-time PCR and western blotting were used to evaluate the expressions of RNA and proteins, respectively. The CCK-8 assay was used to detect cell proliferation. Transwell assays were used to assess migration. Luciferase and RNA pull-down assays were used to verify the targeting between miR-204-5p and lncRNA DGCR5 or SRSF7. LncRNA DGCR5 was upregulated in ASMCs stimulated with PDGF-BB. Knockdown of DGCR5 reversed the effect of platelet-derived growth factor BB (PDGF-BB) on the proliferation and migration of ASMCs. The results of this study showed that lncRNA DGCR5 binds to miR-204-5p, and SRSF7 is the target of miR-204-5p. Rescue experiments verified the interaction between miR-204-5p and DGCR5, as well as that between miR-204-5p and SRSF7. Overall, this study revealed that the lncRNA DGCR5/miR-204-5p/SRSF7 signalling axis has key regulatory effects on the proliferation and migration of ASMCs. [ABSTRACT FROM AUTHOR]

AtDjC5 belongs to the J-protein family in Arabidopsis thaliana. Its biological functions remain unclear. In this study, we examined the roles of AtDjC5 in resisting heat stress using reverse genetic analysis. After the seedlings were exposed directly to 44 °C for 90 min, AtDjC5 knockout seedlings displayed decreases in the survival rate, membrane system stability, and cell vitality compared to WT seedlings, indicating that AtDjC5 is involved in plant basal thermotolerance. The AtDjC5 knockout seedlings pre-exposed to 37 °C for 30 min exhibited decreases in the survival rate and total chlorophyll contents and increased cell death when they were subsequently exposed to 45 °C compared to the WT seedlings, indicating that AtDjC5 plays an important role in plant acquired thermotolerance. AtDjC5 was found to localize to the endoplasmic reticulum. The expression of the AtDjC5 gene was induced by heat and TM (an ER stress inducer) treatment. Furthermore, we found that the knockout of AtDjC5 inhibited ER stress-induced autophagy and the expression of ER stress-related genes. Taken together, these results suggest that AtDjC5 facilitates thermotolerance, likely by aiding in the ER stress response. [ABSTRACT FROM AUTHOR]

Background: DNA damage repair is an important mechanism of platinum resistance. HOXB7 is one member of HOX family genes, which are essential developmental regulators and frequently dysregulated in cancer. Recently, its relevance in chemotherapy resistance and DNA damage repair has also been addressed. However, little is known regarding the association between HOXB7 and chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Methods: The association between HOXB7 expression detected by immunohistochemisty and tumor regression grade (TRG) and long‐term survival was analyzed in 143 ESCC patients who underwent neoadjuvant chemotherapy. CCK8 assay was used to examine the effect of cisplatin in a panel of four ESCC cell lines. A stable cell strain with HOXB7 knockdown of KYSE150 and KYSE450 was established to explore the effect on cisplatin sensitivity. The interaction of HOXB7 with Ku70, Ku80 and DNA‐PKcs was determined by GST‐pull down, coimmunoprecipitation and immunofluorescent colocalization. Finally, we investigated whether disrupting HOXB7 function by a synthetic peptide HXR9 blocking the formation of HOXB7/PBX could enhance cisplatin sensitivity in vitro and in vivo. Results: High expression of HOXB7 was associated with cisplatin resistance and worse chemotherapy efficacy. HOXB7 knockdown reinforced cisplatin sensitivity. It was identified that HOXB7 interacts with Ku70, Ku80 and DNA‐PKcs. HOXB7 knockdown was related to the downregulation of Ku70, Ku80 and DNA‐PKcs as well as arrested cell cycle in S phase. HOXB7 inhibition by HXR9 had a synergistic effect to improve cisplatin sensitivity. Conclusion: HOXB7 may be a biomarker for the prediction of chemoresistance of ESCC and serves as a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Recently, CaMKIV has been identified as a potential regulator of skeletal muscle glucose metabolism, it can also affect insulin gene expression in pancreas. However, its effects on adipose insulin resistance have yet to be explored. Autophagy has been shown as a potential therapeutic target for ER (endoplasmic reticulum) stress and insulin resistance. The purpose of this study is to investigate the effects of CaMKIV on ER stress, autophagic function and insulin signaling in tunicamycin-treated adipocytes. Methods: In this study, mature 3 T3-L1 adipocytes were treated with tunicamycin to induce ER stress. Tunicamycin-treated 3 T3-L1 adipocytes were treated with recombinant CaMKIV in the presence or absence of targeted-siRNA mediated down-regulation of CREB and mTOR. The ER stress markers, autophagy activation, mTOR/CREB signaling and insulin sensitivity were analyzed by western blotting or electron microscopy. Results: Treatment with CaMKIV significantly reversed tunicamycin-induced expression of p-PERK, cleaved-ATF6, Atg7 and LC3II. It also reduced p62 expression. In addition, levels of p-Akt and p-IRS-1 were increased. Moreover, CaMKIV inhibited activated ER stress and insulin resistance in Atg7 siRNA transfected adipocytes. However, the protective effects of CaMKIV on ER stress, insulin signaling, and autophagy function were nullified by suppression of mTOR or CREB in tunicamycin-treated adipocytes. Conclusion: This study proves recombinant CaMKIV inhibits tunicamycin-induced ER stress and insulin resistance by regulating autophagy. The protective effect of CaMKIV in adipocytes is affected at least partly through mTOR/CREB signaling. Our finding may offer novel opportunities for treating obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Riboswitch can bind small molecules to regulate gene expression. Unlike other RNAs, riboswitch relies on its conformational switching for regulation. However, the understanding of the switching mechanism is still limited. Here, we focussed on the add A-riboswitch to illustrate the dynamical switching mechanism as an example. We performed molecular dynamics simulation, conservation and co-evolution calculations to infer the dynamical motions and evolutionary base pairings. The results suggest that the binding domain is stable for molecule recognition and binding, whereas the switching base pairings are co-evolutionary for translation. The understanding of the add A-riboswitch switching mechanism provides a potential solution for riboswitch drug design. Riboswitch can bind small molecules to regulate gene expression. However, the understanding of switching mechanism is very limited. We performed molecular dynamics simulation, conservation, and co-evolution calculations to infer the dynamical motions and evolutionary base pairings. The results suggest that the binding domain is stable for molecule recognition and binding while the switching base pairings are coevolutionary for translation. The understanding of the add A-riboswitch switching mechanism provides a potential solution for riboswitch drug design. [ABSTRACT FROM AUTHOR]

The advent of single-cell RNA-sequencing (RNA-Seq) technology has enabled transcriptome profiling of individual cells. Comprehensive gene expression analysis at the single-cell level has proven to be effective in characterizing the most fundamental aspects of cellular function and identity. This unbiased approach is revolutionary for small and/or heterogeneous tissues like oxygen-sensing cells in identifying key molecules. Here, we review the major methods of current single-cell RNA-Seq technology. We discuss how this technology has advanced the understanding of oxygen-sensing glomus cells in the carotid body and helped uncover novel oxygen-sensing cells and mechanisms in the mice olfactory system. We conclude by providing our perspective on future single-cell RNA-Seq research directed at oxygen-sensing cells. [ABSTRACT FROM AUTHOR]

Objective: To examine the impact of 5-Aza-2ʹ-deoxycytidine (5-AzadC) on methylation status of miR-124a genes in rheumatoid arthritis (RA) associated fibroblast-like synoviocytes (FLS) and its effect on RA-FLS proliferation and TNF-α expression. Materials and Methods: FLS were isolated from seven RA-derived synovial tissues and cultured in vitro. The expression of miR-124a was measured by real time quantitative polymerase chain reaction (PCR) in FLS with or without 5-AzadC treatment. MiR-124a gene methylation was detected by methylation-specific PCR. FLS were divided into three groups as control, IL-1β and IL-1β/5-AzadC, respectively. The cells in the IL-1β group were treated with 5 μg/L of IL-1β for 24 hours, whereas the cells in the IL-1β/5-AzadC group were first treated with IL-1β exactly as those in the IL-1β group for 24 h but further treated with 1μM 5-AzadC for additional 3 days. The cell growth was estimated based on absorbance at UV450nm. Secreted TNF-α from the cells was evaluated by enzyme-linked immunosorbent assay. After that, RA-FLS treated with IL-1β plus 5-AzadC were further transfected with miR-124a inhibitor or scrambled control. After culturing for 3 days, cell growth and TNF-α concentrations were measured. Results: After 5-AzadC treatment, the expression of miR-124a was significantly increased compared with the control group (1.545 ± 0.189 vs 0.836 ± 0.166, p = 0.001). On the other hand, 5-AzadC significantly reduced IL-1β-mediated cell proliferation by nearly 2.5 fold (p = 0.006). Also, the level of TNF-α secreted from the cells treated with IL-1β plus 5-AzadC was considerably less than that from the cells treated with IL-1β alone (324.99 ± 22.73 ng/L vs 387.91 ± 58.51 ng/L, p = 0.022). After transfection with miR-124a inhibitor in RA-FLS treated with IL-1β plus 5-AzadC, the cell proliferation was increased by 18.2% and the TNF-α expression was increased by 19.0% (p = 0.001 and 0.011, respectively). Conclusion: Methylation of miR-124a genes contributed to IL-1β-mediated RA-FLS proliferation and TNF-α expression. [ABSTRACT FROM AUTHOR]

Key points Carotid body (CB) glomus cells mediate acute oxygen sensing and the initiation of the hypoxic ventilatory response, yet the gene expression profile of these cells is not available., We demonstrate that the single cell RNA-Seq method is a powerful tool for identifying highly expressed genes in CB glomus cells., Our single cell RNA-Seq results characterized novel CB glomus cell genes, including members of the G protein-coupled receptor signalling pathway, ion channels and atypical mitochondrial electron transport chain subunits., A heterologous cell-based screening identified acetate (which is known to affect CB glomus cell activity) as an agonist for the most highly abundant G protein-coupled receptor (Olfr78) in CB glomus cells., These data established the first transcriptome profile of CB glomus cells, highlighting genes with potential implications in CB chemosensory function., Abstract The carotid body (CB) is a major arterial chemoreceptor containing glomus cells whose activities are regulated by changes in arterial blood content, including oxygen. Despite significant advancements in the characterization of their physiological properties, our understanding of the underlying molecular machinery and signalling pathway in CB glomus cells is still limited. To overcome this, we employed the single cell RNA­Seq method by performing next-generation sequencing on single glomus cell­derived cDNAs to eliminate contamination of genes derived from other cell types present in the CB. Using this method, we identified a set of genes abundantly expressed in glomus cells, which contained novel glomus cell-specific genes. Transcriptome and subsequent in situ hybridization and immunohistochemistry analyses identified abundant G protein-coupled receptor signalling pathway components and various types of ion channels, as well as members of the hypoxia-inducible factors pathway. A short-chain fatty acid olfactory receptor Olfr78, recently implicated in CB function, was the most abundant G protein-coupled receptor. Two atypical mitochondrial electron transport chain subunits (Ndufa4l2 and Cox4i2) were among the most specifically expressed genes in CB glomus cells, highlighting their potential roles in mitochondria-mediated oxygen sensing. The wealth of information provided by the present study offers a valuable foundation for identifying molecules functioning in the CB. [ABSTRACT FROM AUTHOR]

Perturbations in CREB binding protein (CREBBP) are associated with hematopoietic malignancies, including myelodysplastic syndrome (MDS). Mice hemizygous for Crebbp develop myelodysplasia with proliferative features, reminiscent of human MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U), and a proportion goes on to develop acute myeloid leukemia (AML). We have also shown that the Crebbp+/- non-hematopoietic bone marrow microenvironment induces excessive myeloproliferation of wild-type cells. We now report that transplantation of unfractionated Crebbp+/- bone marrow into wild-type recipients resulted in either early-onset AML or late-onset MDS and MDS/MPN-U. In contrast, purified Lin-Sca-1+c-Kit++ cells primarily gave rise to MDS with occasional transformation to AML. Furthermore, Crebbp+/- common myeloid progenitors and granulocyte/macrophage progenitors could trigger skewed myelopoiesis, myelodysplasia and late-onset AML. Surprisingly, the phenotypically abnormal cells were all of wild-type origin. MDS, MPN and AML can thus all be transferred from Crebbp+/- BM to wild-type hosts but fractionated bone marrow does not recapitulate the full disease spectrum of whole bone marrow, indicating that not only mutational status but also cellular context contribute to disease outcome. This has important consequences for structuring and interpreting future investigations into the underlying mechanisms of myeloid malignancies as well as for their treatment. [ABSTRACT FROM AUTHOR]

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68–0.81, p = 3.08 × 10−11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26–1.60, p = 1.62 × 10−8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis -regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development. [Display omitted] We performed a large-scale genetic association study of nasopharyngeal carcinoma (NPC) followed by high-throughput profiling of cis -regulatory elements and experimental validation. We identified two NPC susceptibility genes, PHF2 at locus 9q22.33 and CDKN2B-AS1 at locus 9p21.3, which helps to uncover the genetic etiology of NPC development. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is an irreversible lung disease that severely affects human respiratory function. Traditionally, the natural plant Quzhou Fructus Arantii (QFA) has therapeutic effects on respiratory diseases. However, the effects and the mechanism of anti-fibrotic have not been elucidated. In this study, QFAE-nB was extracted from QFA, the aims of this study include understanding the correlation between Bleomycin (BLM)-induced PF and STING pathway in mice, as well as exploring the role and mechanisms of QFAE-nB in the treatment of PF. QFAE-nB was extracted from QFA, six main chemical components in QFAE-nB were identified by HPLC–QTOF–MS/MS, and quantitative analysis was conducted by HPLC. qPCR and Western blot were used to verify the molecular mechanism of QFAE-nB, and the anti-fibrotic effect of QFAE-nB was determined by hematoxylin-eosin (HE) staining and Masson staining as well as immunohistochemistry. TREX1-KO and STING-KO mice were used to verify the relationship between STING and PF and the important target action of QFAE-nB. Six main flavonoids in QFAE-nB were identified as eriocitrin (0.76%), neoeriocitrin (2.79%), narirutin (4.31%), naringin (35.41%), hesperidin (1.74%), and neohesperidin (27.18%). The results showed that BLM-induced PF was associated with its exacerbated release of proinflammatory factors and chemokines in lung tissues. In addition, QFAE-nB alleviated BLM-induced lung fibrosis in mice by inhibiting the activation of the STING signaling pathway and reducing the signal transduction of TBK1–IRF3 and TBK1–NF-κB pathways. Notably, knockout of the TREX1 gene caused massive inflammation and even induced PF in the lung tissues, whereas QFAE-nB effectively alleviated inflammation and reduced PF. The deletion of the STING gene suppressed BLM-induced PF and inflammation, but STING-KO mice treated with QFAE-nB showed even lower expression levels of proinflammatory factors and chemokine. The STING pathway plays an important role in PF, and QFAE-nB alleviates PF by mainly targeting the inhibition of the STING pathway to reduce inflammation. Together, the study paves the way for targeting the STING pathway in PF treatment. [Display omitted] • STING pathway plays an important role in the development of pulmonary fibrosis (PF). • Active ingredient from Quzhou Fructus Aurantii (QFAE-nB) efficiently alleviates PF. • QFAE-nB exerts anti-fibrotic effect mainly by inhibiting the STING pathway. • STING pathway is an effective target for treating PF. [ABSTRACT FROM AUTHOR]

• GMS line showing wrinkled-leaf as marker trait was developed for the first time. • GMS and wrinkled-leaf was governed by one gene or two genes in the same region. • BSA-Seq and fine mapping define a 182.6 kb fragment containing 92 candidate genes. • Five genes have important roles in sesame anther and leaf development. Genic male sterility (GMS) is a very important approach of heterosis exploitation in sesame (Sesamum indicum L.). Visible marker-trait linked to GMS is necessary since it can facilitate the breeding of new GMS lines and the production of F 1 hybrid seeds. We have successfully developed such a GMS line showing wrinkled-leaf (JQA) from a mutant identified in a multiple-cross population in sesame. However, the underlying genetic basis for this JQA line is unclear. To understand the inheritance patterns, near-isogenic line (NIL) together with F 2 and BC 1 populations segregating for both pollen-fertility and leaf-shape was constructed. Morphology investigation indicated that the JQA line was controlled by a single recessive gene, Sims5. By combining bulk-segregant analysis and next-generation sequencing technology (BSA-Seq) in the NIL population, seven and four chromosome regions putatively associated with traits variation were identified by SNP and InDel markers, respectively. A 1,817.6-kb consensus region on chromosome 12 was obtained by intersecting these intervals, which was most likely the target region containing the candidate gene(s) responsible for pollen-fertility and leaf-shape. The consensus region was further narrowed down to only 219.7 kb by fine mapping in a BC 1 population using SSR and InDel markers. Real-Time qRT-PCR analysis of genes within this region showed that four (XM_011097706.2, XM_011097714.2, XM_020698411.1 and XM_011097719.2) and one (XM_020698321.1) genes were highly suppressed in the anther and leaf of mutant plant, respectively, suggesting their important role in pollen and leaf development. These findings not only lay a solid foundation for the isolation and functional analysis of genes for pollen-fertility and wrinkled-leaf but also provided valuable genetic resources and molecular markers for the breeding of new sesame hybrid varieties. [ABSTRACT FROM AUTHOR]

Classical neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s are most commonly seen in older persons. The incidence rate increases as life expectancy increases. Even though neuronal loss, neuronal death and accumulated toxic proteins are well investigated, the mechanism(s) of neurodegenerative disorders is not yet fully understood. Versican is a large extracellular matrix proteoglycan. Its isoforms are aberrantly expressed in central nervous system injuries. Diverse lines of evidence suggest that versican isoforms play a vital role in regulating neuronal differentiation, maturation, neurite outgrowth, and synaptic transmission. Some toxic proteins may be increased and less sensitive to degeneration due to the chondroitin sulfate (CS) chains of versicans. We propose that the patterns of versican V1 and V2 isoforms act as a fine-tuned mechanism for guiding the change of neural microenvironment, and the unbalanced expression of V1 and V2 isoforms may contribute to the pathogenesis of neurodegenerative diseases. The emergence of versican isoforms indicates that it may explain the pathogenesis of the common sporadic forms of complex diseases. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. Depletion of Tregs results in the onset of a variety of autoimmune diseases. Tregs are defined based on expression of CD4, CD25, and the transcription factor, FoxP3. It is now clear that three inhibitory cytokines, IL-10, IL-35 and TGF-β, are key mediators of Tregs function. Tregs have been shown to be important contributors to the development of immune tolerance toward tumors and play a critical role in the induction of tolerance to tumor associated antigens and suppression of anti-tumor immunity. Increasing researches support the existence of elevated numbers of regulatory T cells in cancer patients. Poor prognosis and decreased survival rates are closely correlated with higher Treg cell frequencies. Depletion of Tregs or blockade of their immune inhibitory role can enhance anti-tumor effects. Recent evidence suggests that Tregs may be responsible for the failure of host anti-tumor immunity by suppressing cytotoxic T-cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of Tregs in tumor immunity. [ABSTRACT FROM AUTHOR]

To explore how Girdin/GIV is regulated by cyclic tension and propagates downstream signals to affect cell proliferation and migration. Human osteoblast-like MG-63 cells were exposed to cyclic tension force at 4000 μstrain and 0.5 Hz for 6 h, produced by a four-point bending system. Cyclic tension force upregulated Girdin and Akt expression and phosphorylation in cultured MG-63 cells. Girdin and Akt each promoted the phosphorylation of the other under stimulated tension. In vitro MTT and transwell assays showed that Girdin and Akt are required for cell proliferation and migration during cellular quiescence. Moreover, STAT3 was determined to be essential for Girdin expression under stimulated tension force in the physiological condition, as well as for osteoblast proliferation and migration during quiescence. These findings suggest that the STAT3/Girdin/Akt pathway activates in osteoblasts in response to mechanical stimulation and may play a significant role in triggering osteoblast proliferation and migration during orthodontic treatment. [ABSTRACT FROM AUTHOR]

Abstract: Bacillus amyloliquefaciens C06, an effective biological agent in controlling brown rot of stone fruit caused by Monilinia fructicola, was also found to produce extra-cellular mucilage and form mucoid colonies on semi-solid surfaces. This study aimed to characterize the extra-cellular mucilage produced by B. amyloliquefaciens C06 using transposon mutagenesis and biochemical and physical analyses. The mucilage production in B. amyloliquefaciens C06 was demonstrated to be associated with ywsC gene expression and characterized to be of high molecular weight, consisted of only glutamic acid and linked with non-peptide bonds, thus identified as γ-polyglutamic acid (γ-PGA). Compared with wild type B. amyloliquefaciens C06, its mutants deficient in producing γ-PGA, e.g. M106 and C06ΔywsC showed less efficiency in biofilm formation, surface adhesion and swarming ability. It was also demonstrated that γ-PGA was not essential for C06 to form colony on semi-solid surfaces, but was able to improve its colony structure. In vivo evaluation showed that disruption of γ-PGA production in C06ΔywsC impaired its efficiency of colonizing apple surfaces. [ABSTRACT FROM AUTHOR]