The role of Ca2+ signalling and InsP3R in the pathogenesis of intrahepatic cholestasis of pregnancy.

BACKGROUND: In order to contribute new insights for future prevention and treatment of intrahepatic cholestasis of pregnancy (ICP), and to promote positive pregnancy outcomes, we evaluated serum Ca2+ levels and inositol 1,4,5-trisphosphate receptor (InsP3R) expression in the liver tissue of a rat ICP model. METHODS: After establishing the model by injection of oestradiol benzoate and progesterone into pregnant rats, animals were divided into normal control (n = 5) and ICP model groups (n = 5). The expression of InsP3R protein in the liver, and serum levels of Ca2+, glycocholic acid and bile acid were detected. RESULTS: InsP3R mRNA and protein were significantly lower in the ICP model group compared to the normal group, as determined by qPCR and immunohistochemistry, respectively. Serum enzyme-linked immunosorbent assay results revealed significantly higher levels of glycocholic acid and bile acid in the ICP model group compared to the normal group, while Ca2+ levels were significantly lower. The levers of Ca2+ were significantly and negatively correlated with the levels of glycocholic acid. The observed decrease in Ca2+ was associated with an increase in total bile acids, but there was no significant correlation. CONCLUSIONS: Our results revealed that the expression of InsP3R and serum Ca2+ levels was significantly decreased in the liver tissue of ICP model rats. Additionally, Ca2+ levels were found to be negatively correlated with the level of glycocholic acid.

This study investigated the relationship between serum Ca²⁺ levels, inositol 1,4,5-trisphosphate receptor (InsP3R) expression and intrahepatic cholestasis of pregnancy (ICP) in a rat model. The results indicated a significant decrease in InsP3R expression and Ca²⁺ in the disease group compared to the control group, alongside elevated levels of glycocholic acid and bile acid. The levels of Ca²⁺ exhibited a negative correlation with the levels of glycocholic acid. These findings indicated that the decrease of InsP3R expression and Ca²⁺ levels may be related to the pathogenesis of ICP. The study provides further insight into the treatment of this disease.

CircPUM1 promotes hepatocellular carcinoma progression through the miR-1208/MAP3K2 axis.

Hepatocellular carcinoma (HCC) is a common disease with a significant mortality, and there is no effective treatment for advanced patients. Growing evidence indicates that circRNAs are closely related to HCC progression, may be used as biomarkers and targets for the diagnosis and treatment of HCC. Recent researches have shown that circPUM1 may play an oncogene role in a variety of human cancers, but its role in HCC development has not been reported. Our study found that circPUM1 could promote the proliferation, migration and invasion of HCC cells in vitro. In addition, in vivo studies showed that circPUM1 could increase the development of HCC tumours and regulate the expression of EMT-related proteins. Furthermore, we demonstrated that circPUM1 could promote the development of HCC by up-regulating the expression of MAP3K2 via sponging miR-1208. Our study suggested that circPUM1 may be a potential therapeutic target for HCC.

Role of Different CD40 Polymorphisms in Graves' Disease and Hashimoto's Thyroiditis.

Genome-wide association studies have led to the discovery of several susceptibility genes related to autoimmune thyroid diseases (AITDs). However, controversial results have been reported regarding the role of single-nucleotide polymorphism (SNP) of CD40 in the disease susceptibility. The objective of this study was to identify the relationship of the polymorphisms of three sites of CD40 with the susceptibility to AITD in the Chinese population. We genotyped three polymorphisms of CD40: C/T -1 SNP, 58038T site of the third exon and C64610G site of the ninth exon in 196 GD cases, 121 HT cases and 122 control subjects. The three putative polymorphism sites were amplified by PCR for sequencing and analysis. The genotype frequencies of CD40 -1 C/C genotype and C allele were significantly higher in the GD group than those in normal control. For the C64610G polymorphism, the C/G genotype was significantly more frequent in HT group than in control group, and the G allele frequencies in the GD and HT group were both higher than those in control group. These results indicated that there exist different susceptibility loci for AITD within CD40, each contributing a different effect in the onset and development of AITDs.

Polymorphisms of the endothelial nitric oxide synthase gene in preeclampsia in a Han Chinese population.

BACKGROUND/AIMS: The endothelial nitric oxide synthase (eNOS) gene has been enlisted by previous research as a candidate gene of preeclampsia predisposition. This study investigates the specific roles of 3 polymorphisms of the eNOS gene in a population of Chinese origin from mainland China. METHODS: We studied the association of 3 commonly studied polymorphisms of the eNOS gene, namely 4b/a, T-786C and Glu298Asp, in a case-controlled sample of 220 patients diagnosed with preeclampsia and 200 healthy controls. The association between eNOS polymorphisms and preeclampsia was evaluated by performing genotyping for the eNOS variants and calculating odds ratios (OR) and 95% confidence intervals. The plasma nitrite concentration in participants was determined to examine how 3 eNOS polymorphisms affect plasma nitric oxide (NO) concentrations in pregnant women. RESULTS: The frequencies of both the variant 298Asp allele and eNOS 4a allele were significantly lower in preeclamptic women than in the control group and had a significantly lower OR. The variant 298Asp allele and eNOS 4a are strongly associated with higher plasma NO concentrations in pregnant women. CONCLUSIONS: Polymorphisms in the eNOS gene may be protective against preeclampsia in a Chinese population, and this protective effect may be associated with NO formation in plasma in pregnant women.

The expression and clinical significance of cytokines Th1, Th2, and Th17 in ovarian cancer.

BACKGROUND: This study was to analyze the levels of Th1, Th2 and Th17 cytokines in peripheral blood samples from ovarian cancer (OC) patients. METHODS: Ninty-five OC patients including 45 OC and 50 benign ovarian disease (BOD) were selected at Zhejiang Cancer Hospital from October 2021 to March 2022; 46 healthy participants were simultaneously selected at Taizhou Municipal Hospital as healthy controls (HC). The expressions of Th1, Th2 and Th17 were compared in all participants. Marker levels were analyzed with age, histological type, tumor size, ovarian number and clinical stage of OC. RESULTS: The IL6 and IL8 levels were significantly higher in OC compared to BOD and HC (p <0.00). The IL-4 expression was significantly higher in OC compared to HC (p < 0.00). The expressions of IL2, IL6 and IL10 were significantly higher in pathological stage III-IV OC compared with pathological stage I-II OC (p <0.05). Meanwhile, the levels of IL-2 and IL-10 were significantly higher in OC with bilateral ovaries than in OC with single ovary (p < 0.05). AUCs of different markers were to diagnose OC. The findings also implied that the expressions of IL-6, IL-8 and IL-10 were significantly different between OC and control groups (p <0.05), while the levels of IL-2, IL-4, TNF-α, IFN-γ, IL-12p70, IL-1ß and IL-5 between the two groups were not different (p > 0.05). CONCLUSIONS: In peripheral blood from OC patients, the immune system was more dysregulated and immune cells produced more cytokines with contrasting actions. These data showed significant clinical implications for the diagnosis of OC.

Emergence of a clinical Klebsiella pneumoniae harboring an acrAB-tolC in chromosome and carrying the two repetitive tandem core structures for bla KPC-2 and bla CTX-M-65 in a plasmid.

Objective: The emergence of clinical Klebsiella pneumoniae strains harboring acrAB-tolC genes in the chromosome, along with the presence of two repetitive tandem core structures for bla KPC-2 and bla CTX-M-65 genes on a plasmid, has presented a significant clinical challenge. Methods: In order to study the detailed genetic features of K. pneumoniae strain SC35, both the bacterial chromosome and plasmids were sequenced using Illumina and nanopore platforms. Furthermore, bioinformatics methods were employed to analyze the mobile genetic elements associated with antibiotic resistance genes. Results: K. pneumoniae strain SC35 was found to possess a class A beta-lactamase and demonstrated resistance to all tested antibiotics. This resistance was attributed to the presence of efflux pump genes, specifically acrAB-tolC, on the SC35 chromosome. Additionally, the SC35 plasmid p1 carried the two repetitive tandem core structures for bla KPC-2 and bla CTX-M-65, as well as bla TEM-1 with rmtB, which shared overlapping structures with mobile genetic elements as In413, Tn3, and TnAs3. Through plasmid transfer assays, it was determined that the SC35 plasmid p1 could be successfully transferred with an average conjugation frequency of 6.85 × 10-4. Conclusion: The structure of the SC35 plasmid p1 appears to have evolved in correlation with other plasmids such as pKPC2_130119, pDD01754-2, and F4_plasmid pA. The infectious strain SC35 exhibits no susceptibility to tested antibioticst, thus effective measures should be taken to prevent the spread and epidemic of this strain.

Expression of transforming growth factor beta 1 in lung tissue during cardiopulmonary bypass-induced lung injury in dogs.

BACKGROUND: Cardiopulmonary bypass (CPB) is a necessary technique for cardiac surgery and usually induces acute lung injury. Transforming growth factor ß1 (TGFß1) has been found to play a crucial role in the pathogenesis of inflammatory diseases; however, whether TGFß1 is also involved in CPB-induced lung injury has yet to be determined. Therefore, we aimed to investigate the TGFß1 expression in the lungs of dogs after CPB. METHODS: A total of 36 healthy mongrel dogs were randomly assigned to control and CPB groups. Six dogs in each group were killed before, 30 min after the operation, and 60 min after the operation (T0, T1, and T2). Lung injury was evaluated by hematoxylin and eosin staining. Respiratory index (RI), oxygenation index (OI), malondialdehyde (MDA) content in the lung, and pulmonary permeability index (PPI) were determined at each time point. TGFß1 expression was determined using real-time reverse transcription polymerase chain reaction and immunohistochemistry. RESULTS: There was a serious lung injury observed after CPB in dogs. RI increased and OI decreased in the dogs after CPB. The MDA content significantly increased after CPB; however, no significant change of MDA occurred in the control group. A significant increase of PPI was detected in CPB group at the T1 and T2 time points compared with that at the T0 time point. TGFß1 expression in the lung was increased after CPB on both the mRNA and protein levels. Positive correlations between TGFß1 mRNA level and MDA (r = 0.867, p < 0.01) and between TGFß1 mRNA and PPI (r = 0.821, p < 0.01) were detected by linear correlation. CONCLUSION: The upregulation of TGFß1 expression plays an important role in the development and progression of CPB-induced acute lung injury.

Perioperative cimetidine administration improves systematic immune response and tumor infiltrating lymphocytes in patients with colorectal cancer.

BACKGROUND/AIMS: Cimetidine has been shown to play an important role in the treatment of cancer and the regulation of the immune system. Therefore, we aimed to observe the effects of cimetidine on the systematic immune response in the perioperative period. METHODOLOGY: Sixty patients with colorectal cancer were enrolled from Jan 2005 to Dec 2005 from Taizhou Hospital. The patients were administrated with cimetidine (0.8 g.d-1 or 1.2 g.d-1) or saline from the day of admission to the 10th POD. Venous blood sample was collected and the T-, B- and NK-lymphocyte subsets were determined by flow cytometry. The specimens were subjected to tumor-infiltrating lymphocytes (TILs) response examination. RESULTS: The levels of CD3 and CD4 T-lymphocytes were increased significantly in both low and high dose cimetidine groups 10 days after operation. The number of CD19 B cells was also elevated by cimetidine. However, no significant changes were observed in the CD8, CD4/CD8 value. TIL responses in the cimetidine groups were also enhanced significantly. CONCLUSIONS: Cimetidine can alleviate systematic immunosuppression and improve the local immune function of the colorectal cancer patients in the perioperative period.

Characterization of the two tandem repeats for the KPC-2 core structures on a plasmid from hospital-derived Klebsiella pneumoniae.

Today, Klebsiella pneumoniae strains are sophisticatedly associated with the transmission of KPC, and ST11 clones carrying KPC-2 are an important target for anti-infective clinical therapy, posing a very high threat to patients. To present the detailed genetic features of two KPC-2 core structures of F94_plasmid pA, the whole genome of K. pneumoniae strain F94 was sequenced by nanopore and illumina platform, and mobile genetic elements associated with antibiotic-resistance genes were analyzed with a series of bioinformatics methods. K. pneumoniae strain F94, identified as a class A carbapenemase-resistant Enterobacteriaceae, was resistant to most tested antibiotics, especially to low-levels of ceftazidime/avibactam (avibactam ≤ 4 mg/L), owing to overexpression of the two KPC-2 in F94_plasmid pA. However, strain F94 was sensitive to high-levels of ceftazidime/avibactam (avibactam ≥ 8 mg/L), which correlated with further inhibition of ceftazidime hydrolysis by the KPC-2 enzyme due to the multiplication of avibactam. Collinearity analysis indicated that multi-drug resistance (MDR) regions of plasmids with the tandam repeats of two or more KPC-2 core structures share highly similar structures. This study characterized the MDR region of the F94_ plasmid pA as homologous to plasmids pKPC2_090050, pKPC2_090374, plasmid unnamed 2, pC2414-2-KPC, pKPC2-020037, pBS1014-KPC2, pKPC-J5501, and pKPC2-020002, which contained the tandem repeats of one, two, or more KPC-2 core structures, providing insight into the evolution of multidrug resistance in K. pneumoniae. An alternative theoretical basis for exploring the tandem repeats of two or more KPC-2 core structures was developed by analyzing and constructing the homologous sequence of F94_ plasmid pA.

Characterization of Klebsiella pneumoniae carrying the blaNDM-1 gene in IncX3 plasmids and the rare In1765 in an IncFIB-IncHI1B plasmid.

Background: Today, the blaNDM gene is widely distributed on several plasmids from a variety of Gram-negative bacteria, primarily in transposons and gene cassettes within their multidrug-resistant (MDR) regions. This has led to the global dissemination of the blaNDM gene. Methods: The determination of class A beta-lactamase, class B and D carbapenemases was performed according to the recommendations of the Clinical and Laboratory Standards Institute (CLSI). Antimicrobial susceptibility testing was performed using both the BioMerieux VITEK2 system and antibiotic paper diffusion methods. Plasmid transfer was then evaluated by conjugation experiments and plasmid electroporation assays. To comprehensively analyze the complete genome of K. pneumoniae strain F11 and to investigate the presence of mobile genetic elements associated with antibiotic resistance and virulence genes, Nanopore and Illumina sequencing platforms were used, and bioinformatics methods were applied to analyze the obtained data. Results: Our findings revealed that K. pneumoniae strain F11 carried class A beta-lactamase and classes B+D carbapenemases, and exhibited resistance to commonly used antibiotics, particularly tigecycline and ceftazidime/avibactam, due to the presence of relevant resistance genes. Plasmid transfer assays demonstrated successful recovery of plasmids pA_F11 and pB_F11, with average conjugation frequencies of 2.91×10-4 and 1.56×10-4, respectively. However, plasmids pC_F11 and pD_F11 failed in both conjugation and electroporation experiments. The MDR region of plasmid pA_F11 contained rare In1765, TnAs2, and TnAs3 elements. The MDR2 region of plasmid pB_F11 functioned as a mobile genetic "island" and lacked the blaNDM-1 gene, serving as a "bridge" connecting the early composite structure of bleMBL and blaNDM-1 to the recent composite structure. Additionally, the MDR1 region of plasmid pB_F11 comprised In27, TnAs1, TnAs3, and Tn2; and plasmid pC_F11 harbored the recent composite structure of bleMBL and blaNDM-1 within Tn3000 which partially contained partial Tn125. Conclusion: This study demonstrated that complex combinations of transposons and integron overlaps, along with the synergistic effects of different drug resistance and virulence genes, led to a lack of effective therapeutic agents for strain F11, therefore its dissemination and prevalence should be strictly controlled.

Occurrence and characterization of plasmids carrying tmexCD1-toprJ1, blaDHA-1, and blaCTX-M-127, in clinical Klebsiella pneumoniae strains.

Objective: Today, the emergence of Klebsiella pneumoniae with the tmexCD1-toprJ1 gene cassette in patients has presented a significant clinical challenge. Methods: To present the detailed genetic features of the tmexCD1-toprJ1 gene cassette of K. pneumoniae strain F4_plasmid pA, the whole bacterial genome was sequenced by Illumina and nanopore platforms, and mobile genetic elements related to antibiotic resistance genes were analyzed with a series of bioinformatics methods. Results: K. pneumoniae strain F4 was determined to be a class A+C beta-lactamase, and was resistant to routinely used antibiotics, especially tigecycline, because of the oqxAB gene localized on the F4_chromosome and tmexCD1-toprJ1 on F4_plasmid A. After plasmid transfer assays, the F4_plasmid pA or F4_plasmid pB could be recovered with an average conjugation frequencies of 3.42×10-4 or 4.19×10-4. F4_plasmid pA carried tmexCD1-toprJ1 and bla DHA-1 accompanied by genetic intermixing of TnAs1, Tn5393, TnAs3, and In641, while F4_plasmid pB, bearing bla CTX-M-174, had structural overlap of TnAs3 and In641. Conclusions: We suggested that plasmids carrying tmexCD1- toprJ1 might be strongly related to IS26-integrated loop intermediates. This study showed that due to the structural evolution of F4 and related strains, their resistances were so strong that effective antibiotics were virtually unavailable, therefore their spread and prevalence should be strictly controlled.

Diagnostic roles of neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, C-reactive protein, and cancer antigen 125 for ovarian cancer.

OBJECTIVE: To compare the diagnostic value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP) level, and cancer antigen 125 (CA125) level for ovarian cancer (OC). METHODS: Data of 72 patients with OC, 50 patients with benign ovarian disease, and 46 healthy controls were retrospectively analyzed, and receiver operating characteristic analysis was performed. RESULTS: The platelet count was higher in patients with a tumor diameter of ≥10 vs. <10 cm. The absolute lymphocyte count was significantly higher in patients with stage I/II OC than in those with multiple and stage III/IV OC. The absolute monocyte count, NLR, MLR, and CA125 were significantly higher in patients with multiple and stage III/IV OC than in those with single and stage I/II OC. The NLR, PLR, MLR, fibrinogen, D-dimer, CRP, and CA125 were useful for distinguishing between the OC and healthy control groups. CONCLUSIONS: Our analysis showed that the following combinations have practical diagnostic value in OC: NLR + PLR + MLR + CA125, NLR + PLR + MLR + CA125 + CRP, NLR + MLR +PLR + CA125 + CRP + fibrinogen, and NLR + MLR + PLR + CA125 + CRP + fibrinogen + D-dimer.

Integrated Bioinformatics Analysis for the Identification of Key lncRNAs, mRNAs, and Potential Drugs in Clear Cell Renal Cell Carcinomas.

Purpose: The overall survival of clear cell renal cell carcinoma (ccRCC) is poor. Markers for early detection and progression could improve disease outcomes. This study aims to reveal the potential pathogenesis of ccRCC by integrative bioinformatics analysis and to further develop new therapeutic strategies. Patients and Methods: RNA-seq data of 530 ccRCC cases in TCGA were downloaded, and a comprehensive analysis was carried out using bioinformatics tools. Another 14 tissue samples were included to verify the expression of selected lncRNAs by qRT-PCR. DGIdb database was used to screen out potential drugs, and molecular docking was used to explore the interaction and mechanism between candidate drugs and targets. Results: A total of 58 differentially expressed lncRNAs (DElncRNAs) and 660 differentially expressed mRNAs (DEmRNAs) were identified in ccRCC. LINC02038, FAM242C, LINC01762, and PVT1 were identified as the optimal diagnostic lncRNAs, of which PVT1 was significantly correlated with the survival rate of ccRCC. GO analysis of cell components showed that DEmRNAs co-expressed with 4 DElncRNAs were mainly distributed in the extracellular area and the plasma membrane, involved in the transport of metal ions, the transport of proteins across membranes, and the binding of immunoglobulins. Immune infiltration analysis showed that MDSC was the most correlated immune cells with PVT1 and key mRNA SIGLEC8. Validation analysis showed that GABRD, SIGLEC8 and CDKN2A were significantly overexpressed, while ESRRB, ELF5 and UMOD were significantly down-regulated, which was consistent with the expression in our analysis. Furthermore, 84 potential drugs were screened by 6 key mRNAs, of which ABEMACICLIB and RIBOCICLIB were selected for molecular docking with CDKN2A, with stable binding affinity. Conclusion: In summary, 4 key lncRNAs and key mRNAs of ccRCC were identified by integrative bioinformatics analysis. Potential drugs were screened for the treatment of ccRCC, providing a new perspective for disease diagnosis and treatment.

Integrating SWATH-MS proteomics and transcriptome analysis to preliminarily identify three DEGs as biomarkers for proliferative diabetic retinopathy.

PURPOSE: We intended to preliminarily find differentially expressed proteins that play crucial roles in proliferative diabetic retinopathy (PDR), and lay the foundation for subsequent further research on the mechanism. EXPERIMENTAL DESIGN: Here, we developed a new strategy integrated the sequential windowed acquisition of all theoretical fragment ion (SWATH) mass spectra (MS) with multi-dataset joint analysis to screen for the PDR plasma biomarker. The annotation of the given gene list was performed with ClueGO function analysis. Additionally, the protein-protein interaction relationship was also revealed by the STRING database. RESULTS: In SWATH-MS assays, we identified 23 upregulated and 13 downregulated proteins in PDR plasma. In the mRNA database analysis, 375 genes were identified as differentially expressed genes in GSE102485. Only three genes (FCGR3A, DPEP2, and ADGRF5) were characterized as upregulated in both the dataset and the SWATH-MS list. The area under the ROC curve (AUC) of FCGR3A, DPEP2, and ADGRF5 in distinguishing PDR from others was 0.739, 0.770, and 0.739. CONCLUSIONS AND CLINICAL RELEVANCE: We provide a novel strategy for biomarker screening and identified plasma FCGR3A, DPEP2, and ADGRF5 as potential biomarkers for patients with PDR. Identifying the key molecules of the disease is essential for the development of new therapeutic molecules and new uses of existing drugs.

Emergence of bla NDM- 1-Carrying Aeromonas caviae K433 Isolated From Patient With Community-Acquired Pneumonia.

To demonstrate the detailed genetic characteristics of a bla NDM-1-carrying multidrug-resistant Aeromonas caviae strain, the complete genome of the A. caviae strain K433 was sequenced by Illumina HiSeq and Oxford nanopore platforms, and mobile genetic elements associated with antibiotic resistance genes were analyzed by a series of bioinformatics methods. A. caviae K433 which was determined to produce class B carbapenemase, was resistant to most antibiotics tested except amikacin. The genome of K433 consisted of a chromosome cK433 (6,482-kb length) and two plasmids: pK433-qnrS (7.212-kb length) and pK433-NDM (200.855-kb length), the last being the first investigated bla NDM-carrying plasmid from Aeromonas spp. By comparison of the backbone and MDR regions from the plasmids studied, they involved a highly homologous sequence structure. This study provides in-depth genetic insights into the plasmids integrated with bla NDM-carrying genetic elements from Aeromonas spp.

Characterization of Clinical and CT Manifestations of Pulmonary Cryptococcosis with Consolidation.

Considering the insufficient understanding of pulmonary cryptococcosis (PC) with consolidation, 22 patients were evaluated based on the chest computed tomography (CT) images and clinical manifestation. The clinical symptoms were mild, mainly manifesting as cough and sputum. Pulmonary lesions mostly involved a single lobe in a single lung with multiple lesions. Specifically, single lung involvement was observed in 17 cases, single lobe in 16 cases and multiple lesions in 14 case. Fifteen cases were mainly distributed in the periphery and 17 cases in the long axis in parallel to the pleura. Nineteen cases had air bronchograms. Eight cases displayed cavitation inside the lesions and 18 cases had surrounding halo signs. Seventeen cases had pleural thickening, of which 10 cases had "pasting wall" signs. The clinical symptoms of PC with consolidation were relatively mild. Comprehensive clinical and imaging performance could improve the diagnosis of the disease.

Chromosomal Integration of Huge and Complex blaNDM-Carrying Genetic Elements in Enterobacteriaceae.

In this study, a detailed genetic dissection of the huge and complex blaNDM-carrying genetic elements and their related mobile genetic elements was performed in Enterobacteriaceae. An extensive comparison was applied to 12 chromosomal genetic elements, including six sequenced in this study and the other six from GenBank. These 12 genetic elements were divided into five groups: a novel IME Tn6588; two related IMEs Tn6523 (SGI1) and Tn6589; four related ICEs Tn6512 (R391), Tn6575 (ICEPvuChnBC22), Tn6576, and Tn6577; Tn7 and its derivatives Tn6726 and 40.7-kb Tn7-related element; and two related IMEs Tn6591 (GIsul2) and Tn6590. At least 51 resistance genes, involved in resistance to 18 different categories of antibiotics and heavy metals, were found in these 12 genetic elements. Notably, Tn6576 carried another ICE Tn6582. In particular, the six blaNDM-carrying genetic elements Tn6588, Tn6589, Tn6575, Tn6576, Tn6726, and 40.7-kb Tn7-related element contained large accessory multidrug resistance (MDR) regions, each of which had a very complex mosaic structure that comprised intact or residual mobile genetic elements including insertion sequences, unit or composite transposons, integrons, and putative resistance units. Core blaNDM genetic environments manifested as four different Tn125 derivatives and, notably, two or more copies of relevant Tn125 derivatives were found in each of Tn6576, Tn6588, Tn6589, and 40.7-kb Tn7-related element. The huge and complex blaNDM-carrying genetic elements were assembled from complex transposition and homolog recombination. Firstly identified were eight novel mobile elements, including three ICEs Tn6576, Tn6577, and Tn6582, two IMEs, Tn6588 and Tn6589, two composite transposons Tn6580a and Tn6580b, and one integron In1718.

Screening key lncRNAs for human rectal adenocarcinoma based on lncRNA-mRNA functional synergistic network.

BACKGROUND: Rectal adenocarcinoma (READ) is one of the deadliest malignancies, and the molecular mechanisms underlying the initiation and development of READ remain largely unknown. In this study, we aimed to find key long noncoding RNAs (lncRNAs) and mRNAs in READ by RNA sequencing. METHODS: RNA sequencing was performed to identify differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) between READ and normal tissue. READ-specific protein-protein interaction (PPI), DElncRNA-DEmRNA coexpression, and DElncRNA-nearby DEmRNA interaction networks were constructed. DEmRNAs and DEmRNAs coexpressed with DElncRNAs were functionally annotated. RESULTS: A total of 2113 DEmRNAs and 150 DElncRNAs between READ and normal tissue were identified. The PPI network identified several hub proteins, including CDK1, AURKB, CDC6, FOXQ1, NUF2, and TOP2A. The DElncRNA-DEmRNA coexpression and DElncRNA-nearby DEmRNA interaction networks identified some hub lncRNAs, including CCAT1, LOC105374879, GAS5, and B3GALT5-AS1. The colorectal cancer pathway, the intestinal immune network for IgA production and the p53 signaling pathway were three pathways significantly enriched in DEmRNAs and DEmRNAs coexpressed with DElncRNAs. MSH6 coexpressed with two DElncRNAs (LOC105374879 and CASC15) and BCL2 coexpressed with B3GALT5-AS1 were significantly enriched in the colorectal cancer signaling pathway. TNFRSF17 coexpressed with B3GALT5-AS1 was enriched in the intestinal immune network for IgA production. CCNB2 coexpressed with LOC105374879 was enriched in the p53 signaling pathway. CONCLUSION: A total of four DEmRNAs (MSH6, BCL2, TNFRSF17, and CCNB2) and three DElncRNAs (LOC105374879, CASC15, and B3GALT5-AS1) may be involved in the pathogenesis of READ; this data may contribute to understanding the mechanisms of READ and the development of therapeutic strategies for READ.

Resveratrol alleviates ischemia/reperfusion injury of diabetic myocardium via inducing autophagy.

The rising incidence and complications of diabetes constitutes a major public health issue. The mortality rate of diabetes-induced myocardial ischemia/reperfusion (I/R) injury is significantly elevated. Resveratrol (RSV) is a naturally occurring polyphenol considered to be a potent cardioprotective compound. The aim of the present study was to explore the function and molecular mechanism of RSV on diabetes-induced myocardial I/R injury. Left anterior descending coronary artery ligation was performed to stimulate myocardial I/R injury in streptozotocin-induced diabetic rats. Heart electrical activity was monitored through an electrocardiogram to confirm successful models. The myocardial infarct volume was detected via 2,3,5-triphenyltetrazolium chloride staining. Western blotting was employed to examine the levels of autophagy markers. It was found that the injection of RSV mitigated the ischemia- or I/R injury-induced myocardial damage on hemodynamic function and infarct size, but the autophagy inhibitor 3-methyladenine significantly blocked the function of RSV. Furthermore, the application of RSV significantly enhanced the expression of Beclin-1 and LC-3II but inhibited the serum levels of tumor necrosis factor-α and interleukin-6. These findings revealed an alleviating effect of RSV on diabetes-induced myocardial I/R injury and provided new evidence for the successful application of RSV on the diabetic myocardium.

Evolutionary Diversity of Prophage DNA in Klebsiella pneumoniae Chromosomes.

Mobile gene elements play an important role in the continuous evolution of the prophage DNA of bacteria, promoting the emergence of new gene structures. This study explored the evolution of four strains of Klebsiella pneumoniae harboring prophages, 19051, 721005, 911021, and 675920, and 16 genomes of K. pneumoniae from GenBank. The results revealed a wide range of genetic variation in the prophage DNA inserted into the sap sites of K. pneumoniae chromosomes. From analysis and comparison of the sequences of the 20 prophage DNAs determined from the four strains and the 16 GenBank genomes of K. pneumoniae using high-throughput sequencing and antimicrobial susceptibility tests, we identified a novel transposon, Tn6556. We also identified at least nine large genetic structures with massive genetic acquisitions or losses and five hotspot sites showing a tendency to undergo insertion of gene elements such as IS1T, IS1R, IS26, ISKpn26, ISKpn28, Tn6556, MDR, and In27-related regions as variable regions; however, the only highly conserved core genes were int and umuCD among the 20 prophage DNAs. These findings provide important insights into the evolutionary diversity of bacteriophage DNA contained in K. pneumoniae.