This study was aimed to evaluate the therapeutic effects and potent mechanisms of a novel GLP-1/GIP dual agonist on hyperglycemia and myocardial injury in diabetic mice. Novel dual-receptor agonists were designed and then evaluated via in vitro receptor activation assays. Acute hypoglycemic effects were assessed in diabetic mice induced by intraperitoneal injection of streptozotocin. Chronic effects of dual-receptor agonists on diabetes as well as diabetic cardiomyopathy were investigated in DCM model mice. Effects of the in vitro coculture of dual-receptor agonists with or without signaling pathway inhibitors on the cell viability and apoptosis of primary cardiomyocytes under a high-glucose state were assessed via MTT and western blotting methods to investigate the probable mechanism. AP5 exhibited balanced activities of dual-receptor activation in vitro and improved hypoglycemic ability in diabetic mice. Moreover, chronic treatment of AP5 achieved the prominently improved efficacy in reversing the deteriorative diabetic disorders and reducing the myocardial injury markers in DCM mice. Moreover, AP5 also inhibited the apoptosis and improved the survival rate of primary cardiomyocytes under a high-glucose state via increasing the expression levels of antiapoptotic proteins and inhibiting the release of apoptotic proteins, respectively, as well as activating the AMPK/PI3K/Akt signaling pathway. In conclusion, the dual GLP-1/GIP receptor agonist, AP5, can effectively improve diabetic symptoms and exert therapeutic effects on DCM via activating the AMPK/PI3K/Akt pathway, reducing the ROS production, oxidative stress and inflammatory markers in the rodent DCM model.Abbreviation: Diabetes mellitus, DM; diabetic cardiomyopathy, DCM; streptozotocin, STZ; glucagon-like peptide-1, GLP-1; malondialdehyde, MDA; glucose-dependent insulinotropic polypeptide, GIP; creatine kinase, CK; diabetic cardiomyopathy, DCM; serum superoxide dismutase; SOD; total superoxide disumutase, T-SOD; Methyl Thiazolyl Tetrazolium, MTT; lactate dehydrogenase; LDH; Adenosine Monophosphate-Activated Protein Kinase, AMPK; Dulbecco's modified Eagle medium, DMEM; Fetal Bovine Serum, FBS; Reactive Oxygen Species, ROS; Glyceraldehyde-phosphate dehydrogenase, GAPDH; Surface Plasmon Resonance, SPR; Ethylene Diamine Tetraacetic Acid, EDTA; Interleukin-1β, IL-1β; Phosphoinositol 3-kinase, PI3K; Tumor necrosis factor, TNF-α; Renin-angiotensin-aldosterone system, RAAS; Glucose transporter, GLUT; Dipeptidyl peptidase-IV, DPP-IV; oxygen free radicals, OFR.

Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by memory and cognitive dysfunction, as well as abnormal changes in behavior and personality. The research focused on how machine learning classified AD became a recent hotspot. In this study, we proposed a novel voxel-based feature detection framework for AD. Specifically, using 649 voxel-based morphometry (VBM) methods obtained from MRI in Alzheimer's Disease Neuroimaging Initiative (ADNI), we proposed a feature detection method according to the Random Survey Support Vector Machines (RS-SVM) and combined the research process based on image-, gene-, and pathway-level analysis for AD prediction. Particularly, we constructed 136, 141, and 113 novel voxel-based features for EMCI (early mild cognitive impairment)-HC (healthy control), LMCI (late mild cognitive impairment)-HC, and AD-HC groups, respectively. We applied linear regression model, least absolute shrinkage and selection operator (Lasso), partial least squares (PLS), SVM, and RS-SVM five methods to test and compare the accuracy of these features in these three groups. The prediction accuracy of the AD-HC group using the RS-SVM method was higher than 90%. In addition, we performed functional analysis of the features to explain the biological significance. The experimental results using five machine learning indicate that the identified features are effective for AD and HC classification, the RS-SVM framework has the best classification accuracy, and our strategy can identify important brain regions for AD.

This study aimed to investigate the association between trimethylamine N-oxide (TMAO) and the prognosis and association between high-sensitivity C-reactive protein (hsCRP) and TMAO-associated cardiovascular risk in patients with acute myocardial infarction (AMI) complicated by heart failure (HF).

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, the 5-year survival rate of patients with HNSCC is still about 50% due to frequent metastasis and recurrence. Circular RNAs (circRNAs) have been characterized as key regulators of gene expression in numerous malignancies. However, the role of circRNA in HNSCC metastasis remains largely unknown. Here, we demonstrated that the circRFWD3 was significantly upregulated in HNSCC tissues and cell lines by circRNA microarray analysis and qPCR. Notably, high expression of circRFWD3 is related to highly aggressive HNSCC cell lines and lymph node metastasis in HNSCC patients. After that, Sanger sequencing, RNase R, and actinomycin D assay were performed to verify the ring structure of circRFWD3. Then functional experiments found it could promote the metastasis of HNSCC cells both in vitro and in vivo. Mechanistically, a dual-luciferase reporter assay, FISH, RIP, RNA pull-down, RNA-seq, and western blot experiments were employed and found that circRFWD3 served as a miRNAs sponge for miR-27a/27b, leading to the upregulation of PPARγ, and then promoted HNSCC metastasis via NF-κB/MMP13 pathway. Finally, ISH and IHC were carried out to determine the expression levels and clinical significances of circRFWD3 and PPARγ in clinical cohorts of HNSCC. According to the analysis results from two independent HNSCC cohorts, upregulated expression of circRFWD3 and PPARγ were positively associated with worse survival in patients with HNSCC. Overall, our results uncover that circRFWD3 acts a critical role in promoting the aggressiveness of HNSCC cells and is a prognostic marker for the disease, indicating that circRFWD3 may act as a potential therapeutic target in HNSCC.

Mobile colistin resistance (mcr) gene mcr-10.1 has been distributed widely since it was initially identified in 2020. The aim of this study was to report the first mcr-10.1 in Africa and the first mcr in Sierra Leone; furthermore, we presented diverse modular structures of mcr-10.1 loci. Here, the complete sequence of one mcr-10.1-carrying plasmid in one clinical Enterobacter cloacae isolate from Sierra Leone was determined. Detailed genetic dissection and comparison were applied to this plasmid, together with a homologous plasmid carrying mcr-10.1 from GenBank. Moreover, a genetic comparison of 19 mcr-10.1 loci was performed. In this study, mcr-10.1 was carried by an IncpA1763-KPC plasmid from one Enterobacter cloacae isolate. A total of 19 mcr-10.1 loci displayed diversification in modular structures through complex transposition and homologous recombination. A site-specific tyrosine recombinase XerC was located upstream of mcr-10.1, and at least one insertion sequence element was inserted adjacent to a conserved xerC-mcr-10.1-orf336-orf177 region. Integration of mcr-10.1 into a different gene context and carried by various Inc plasmids contributed to the wide distribution of mcr-10.1 and enhanced the ability of bacteria to survive under colistin selection pressure. IMPORTANCE Colistin is used as one of the last available choices of antibiotics for patients infected by carbapenem-resistant bacterial strains, but the unrestricted use of colistin aggravated the acquisition and dissemination of mobile colistin resistance (mcr) genes. So far, 10 mcr genes have been reported in four continents around the world. This study presented one mcr-10.1-carrying Enterobacter cloacae isolate from Sierra Leone. The mcr-10.1 gene was identified on an IncpA1763-KPC plasmid. According to the results of genetic comparison of 19 mcr-10.1 loci, the mcr-10.1 gene was found to be located in a conserved xerC-mcr-10.1-orf336-orf177 region, and at least one insertion sequence element was inserted adjacent to this region. To our knowledge, this is the first report of identifying the mcr-10.1 gene in Africa and the mcr gene in Sierra Leone.

To investigate the relationship between human immunodeficiency virus (HIV) infection and the risk of mortality among coronavirus disease 2019 (COVID-19) patients based on adjusted effect estimate by a quantitative meta-analysis. A random-effects model was used to estimate the pooled effect size (ES) with corresponding 95% confidence interval (CI). I2 statistic, sensitivity analysis, Begg's test, meta-regression and subgroup analyses were also conducted. This meta-analysis presented that HIV infection was associated with a significantly higher risk of COVID-19 mortality based on 40 studies reporting risk factors-adjusted effects with 131,907,981 cases (pooled ES 1.43, 95% CI 1.25-1.63). Subgroup analyses by male proportion and setting yielded consistent results on the significant association between HIV infection and the increased risk of COVID-19 mortality. Allowing for the existence of heterogeneity, further meta-regression and subgroup analyses were conducted to seek the possible source of heterogeneity. None of factors might be possible reasons for heterogeneity in the further analyses. Sensitivity analysis indicated the robustness of this meta-analysis. The Begg's test manifested that there was no publication bias (P = 0.2734). Our findings demonstrated that HIV infection was independently associated with a significantly increased risk of mortality in COVID-19 patients. Further well-designed studies based on prospective study estimates are warranted to confirm our findings.

This study aimed to explore the specific pathogenesis of lncRNA MALAT1 promoting the invasion and metastasis of hepatocellular carcinoma (HCC) through peripheral blood vessels by regulating the expression of miRNA-613 molecule.

Salt stress seriously restricts crop yield and quality, leading to an urgent need to understand its effects on plants and the mechanism of plant responses. Although phytohormones are crucial for plant responses to salt stress, the role of phytohormone signal transduction in the salt stress responses of stress-resistant species such as Sophora alopecuroides has not been reported. Herein, we combined transcriptome and metabolome analyses to evaluate expression changes of key genes and metabolites associated with plant hormone signal transduction in S. alopecuroides roots under salt stress for 0 h to 72 h. Auxin, cytokinin, brassinosteroid, and gibberellin signals were predominantly involved in regulating S. alopecuroides growth and recovery under salt stress. Ethylene and jasmonic acid signals may negatively regulate the response of S. alopecuroides to salt stress. Abscisic acid and salicylic acid are significantly upregulated under salt stress, and their signals may positively regulate the plant response to salt stress. Additionally, salicylic acid (SA) might regulate the balance between plant growth and resistance by preventing reduction in growth-promoting hormones and maintaining high levels of abscisic acid (ABA). This study provides insight into the mechanism of salt stress response in S. alopecuroides and the corresponding role of plant hormones, which is beneficial for crop resistance breeding.

Rhamnolipids are predominantly produced from the opportunistic pathogen Pseudomonas aeruginosa, which restricts their scaled-up production and biomedical applications. Moreover, the wound healing property of rhamnolipids is mainly focused on either mono- or di-rhamnolipid congeners, which are obtained after extensive and costly purification procedures. Here, crude rhamnolipids from non-pathogenic Acinetobacter calcoaceticus BU-03 have been prepared and characterized and their wound healing potency evaluated in vitro and in vivo. Rhamnolipid extract was produced in a bioreactor by batch fermentation at a concentration of 12.7 ± 1.4 g/L. Characterization of the extract by Fourier Transform Infrared spectroscopy and mass spectrometry revealed characteristic rhamnolipid peaks. Rha-C10-C10 and Rha-Rha-C10-C10 appeared as the predominant congeners along with minor quantities of six more congeners. The rhamnolipid extract obtained from A. calcoaceticus had no toxicity against mouse fibroblast L929 cells and accelerated their migration. Transforming growth factor beta 1 (TGF-β1) has been shown to promote fibroblast migration by activating Smad3. It was found that the rhamnolipid extract enhanced Smad3 phosphorylation in L929 cells. In vivo studies showed that it promoted wound healing in mice with excisional wounds. The protein levels of TGF-β1 and alpha smooth muscle actin (α-SMA), a highly contractile protein, were significantly increased by 2.56- and 1.51-fold, respectively, in extract-treated compared with vehicle control-treated wounds, indicating that the activation of TGF-β1 signaling is possibly involved in the wound healing effect. These results suggest that a rhamnolipid extract obtained from A. calcoaceticus has potential as a wound healing material for topical application in cutaneous wound treatment.

Multiple organ dysfunction syndrome (MODS) with secondary hemophagocytic lymphohistiocytosis (SHLH) causes significant mortality. We aimed to identify the predictor factors for death in pediatric patients with SHLH-associated MODS receiving continuous renal replacement therapy (CRRT).

The purpose of this study was to determine the prognostic role of hormone receptor (HR) on inflammatory breast cancer (IBC) to elucidate its aggressive biological behavior.

Infant temperament characteristics play a critical role in children's developmental pathways and can predict adulthood psychopathology. The diversity and composition of the gut microbiota are associated with human temperament in both adults and young children. However, the relationship between the gut microbiota and temperament in 12-month-old infants is rarely studied; this developmental period is when temperament reaches a relatively stable stage. We used high-throughput sequencing methods to explore whether temperament characteristics were associated with gut microbiota diversity and composition. Infants' fecal samples were collected at 12 months of age for the gut microbiota analysis. Based on the primary caregivers' reports, infants' temperaments were measured using the Infant Behavior Questionnaire-revised (IBQ-R). This study included 51 infants, including 20 boys and 31 girls, with a mean age of 12.25 months. Results showed that soothability was positively correlated with maternal education level (β = 0.29, p = 0.043, adjust p = 0.025) and the abundance of Bifidobacterium genera (β = 0.62, p = 0.004, adjust p = 0.002). Conversely, cuddliness was negatively correlated with the abundance of Hungatella genera. There was no significant difference in temperament based on gender. This study demonstrated that gut microbiota composition was associated with temperament in 12-month-old infants. These results point to the importance of gut microbiota balance. Future studies on the mechanisms behind the gut microbiota affecting temperament are warranted.

Peer education has become a strategy for health promotion among high-risk groups for HIV infection worldwide. However, the extent to which peer education could have an impact on HIV prevention or the long-term effect of this impact is still unknown. This study thus quantifies the impact of peer education over time among high-risk HIV groups globally.

Psoriasis is a chronic inflammatory disorder of the skin, and genetic factors are reported to be involved in the disease pathogenesis. Many studies have named psoriasis candidate genes.

Mesoporous calcium-silicate nanoparticles (MCSNs) have good prospects in the medical field due to their great physicochemical characteristics, antibacterial activity and drug delivery capacity. This study was to analyze the antibiofilm activity and mechanisms of silver (Ag) and zinc (Zn) incorporated MCSNs (Ag/Zn-MCSNs) with different percentages of Ag and Zn.

Melt ponds (MPs), form as the result of thawing of snow and sea ice in the summer, have lower albedo than the sea ice and are thus partly responsible for the polar amplification of global warming. Knowing the community composition of MP organisms is key to understanding their roles in the biogeochemical cycles of nutrients and elements. However, the community composition of MP microbial eukaryotes has rarely been studied. In the present study, we assessed the microbial eukaryote biodiversity, community composition, and assembly processes in MPs and surface sea water (SW) using high throughput sequencing of 18S rRNA of size-fractionated samples. Alpha diversity estimates were lower in the MPs than SW across all size fractions. The community composition of MPs was significantly different from that of SW. The MP communities were dominated by members from Chrysophyceae, the ciliate classes Litostomatea and Spirotrichea, and the cercozoan groups Filosa-Thecofilosea. One open MP community was similar to SW communities, which was probably due to the advanced stage of development of the MP enabling the exchange of species between it and adjacent SW. High portions of shared species between MPs and SW may indicate the vigorous exchange of species between these two major types of environments in the Arctic Ocean. SW microbial eukaryote communities are mainly controlled by dispersal limitation whereas those of MP are mainly controlled by ecological drift.

Prostate cancer (PCa) remains a leading cause of mortality among men in the United States and Western Europe. The molecular mechanism of PCa pathogenesis has not been fully elucidated. In the present study, the expression profile of E2F transcription factor 7 (E2F7) in PCa was examined using immunohistochemistry and reverse transcription‑quantitative PCR, whilst cell cycle progression and apoptosis were determined using fluorescent cell activated sorting techniques. Cell viability was measured using Cell Counting Kit‑8 in loss‑ and gain‑of‑function studies. Dual‑luciferase reporter assay was used to verify if E2F7 was one of the potential targets of miR‑30c. The staining score of E2F7 of PCa tissues was found to be notably higher compared with that of adjacent normal tissues. Suppression of E2F7 expression in PCa cell lines led to significantly reduced proliferation rates, increased proportion of cells in the G1 phase of the cell cycle and higher apoptotic rates compared with those in negative control groups. Dual‑luciferase reporter assay revealed E2F7 to be one of the binding targets of microRNA (miR)‑30c. In addition, transfection of miR‑30c mimics into PCa cells resulted in reduced cell viability, increased proportion of cells in the G1 phase and higher apoptotic rates. By contrast, transfection with the miR‑30c inhibitor led to lower apoptosis rates of PCa cells compared with negative control groups, whilst E2F7 siRNA co‑transfection reversed stimulatory effects of miR‑30c inhibitors on cell viability. In addition, the expression of cyclin‑dependent kinase inhibitor p21 were found to be upregulated by transfection with either E2F7 siRNA or miR‑30c mimics into PCa cells. In conclusion, the present study suggested that E2F7 may be positively associated with PCa cell proliferation by inhibiting p21, whereas E2F7 is in turn under regulation by miR‑30c. These observations suggest the miR‑30c/E2F7/p21 axis to be a viable therapeutic target for PCa.

Adjuvants that contain pathogen-associated molecular patterns (PAMPs) can enhance vaccination efficacy by binding to pattern recognition receptors (PRRs), thereby stimulating immune responses. Particularly effective may be the combination of multiple PAMPs that activate different PRRs, which occurs with natural pathogens. Here we hypothesized the enhanced effects would occur in two adjuvants that stimulate different PRRs: CpG oligodeoxynucleotide (CpG-ODN), which is Toll-like receptor 9 agonist; and 5'-triphosphate, short, double-stranded RNA (3pRNA), which activates retinoic acid-inducible gene I (RIG-I). The model antigen ovalbumin (OVA) was loaded and adjuvants were surface-adsorbed to aluminum hydroxide nanoparticles (hereafter NP-3pRNA-CpG) by electrostatic interaction with an average size of 120 nm and a negative surface charge for targeting lymph nodes. These nanoparticles were efficiently internalized by antigen-presenting cells (APCs) in the lymph nodes, and the resulting APC activation and antigen cross-presentation generated strong humoral immunity and cytotoxic T lymphocyte responses and IFN-γ secretion. NP-3pRNA-CpG significantly suppressed B16-OVA tumor growth and prolonged survival of tumor-bearing mice in therapeutic and prophylactic models, illustrating the enhanced effects of CpG-ODN and 3pRNA. Our study highlights the potential of combining multiple adjuvants for effective vaccine design.

The potential mechanism of neuroblastoma (NB) progression remains elusive. We intended to uncover the role and network of long noncoding RNA (lncRNA) double homeobox A pseudogene 8 (DUXAP8) in NB. Quantitative real time polymerase chain reaction (qRT-PCR) was performed to detect the levels of DUXAP8, microRNA-29 (miR-29) and nucleolar protein 4 like (NOL4L). The proliferation, colony formation, cell cycle and metastasis of NB cells were examined by (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, plate colony formation assay, flow cytometry and transwell assays. Western blot was conducted to detect the expression of metastasis and proliferation-associated proteins and NOL4L. The target relationship was predicted by StarBase software and was confirmed by dual-luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay. Nude mice bearing tumors were used to verify the role of DUXAP8 in vivo. We found the expression of DUXAP8 was positively related to the stage of NB tumors, and it was negatively associated with the survival rate of NB patients. DUXAP8 knockdown inhibited the proliferation, colony formation, cycle and motility of NB cells. MiR-29 could interact with DUXAP8, and DUXAP8 exacerbated NB via sponging miR-29. MiR-29 could bind to NOL4L, and the influence of NOL4L intervention on the functions of NB cells could be alleviated by the transfection of miR-29 inhibitor. NOL4L was regulated by DUXAP8/miR-29 axis in NB cells. DUXAP8 knockdown blocked the progression of NB in vivo. Collectively, DUXAP8 deteriorated NB through serving as a sponge for miR-29 to up-regulate the expression of NOL4L in vitro and in vivo.

A cocrystal of diosgenin with piperazine in 2:1 stoichiometry was successfully synthesized. The solid form was prepared by liquid assisted grinding, slurry and crystallization methods. The cocrystal was characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, and structure determined by single crystal X-ray diffraction, the hydrogen bonds formed into fish bone structure along the [010] direction and all the molecules packed into 3D layer structure along a axis. After formation of cocrystal, the solubility of diosgenin was improved, and the solubility value in 0.2% SDS solution was approximately 1.5 times as large as that of the parent material.