Case Study and Genomic Analysis of a Hypervirulent ST25 Klebsiella pneumoniae Strain in a Liver Cirrhosis Patient.

Bloodstream infections (BSIs) caused by Klebsiella pneumoniae (K. pneumoniae) are associated with high morbidity and mortality rates. This study presents a sequence type 25 (ST25) strain of hypermucoid K. pneumoniae A1 isolated from the blood of a patient with liver cirrhosis (LC) who succumbed to severe infections. We performed whole-genome sequencing of K. pneumoniae A1, which revealed virulence factors and antibiotic resistance genes. The strain harbors virulence genes encoding aerobactin, salmochelin, yersiniabactin, enterobactin, and rmpA. Additionally, the strain possessed five drug resistance genes: blaSHV-110, blaSHV-81, fosA6, OqxA, and OqxB. We further constructed a phylogenetic tree using 98 ST25 K. pneumoniae strains downloaded from NCBI together with K. pneumoniae A1. Phylogenetic analysis revealed that our isolated strain was closely related to a highly virulent strain isolated from a neonate in our region, differing by only 123 single nucleotide polymorphisms (SNPs). K. pneumoniae A1 is highly suspected to be Hypervirulent Klebsiella pneumoniae (hvKp). This study provided the first in-depth genomic analysis of ST25 K. pneumoniae in a patient with LC in China, highlighting the urgent need for early identification and diagnosis to combat this emerging threat.

HDAC5 deacetylates c-Myc and facilitates cell cycle progression in hepatocellular carcinoma cells.

Histone deacetylase 5 (HDAC5) is an enzyme that deacetylates lysine residues on the N-terminal of histones and other proteins. It has been reported that HDAC5 deacetylates p53, the critical factor regulating cell cycle, in response to cellular stress, but the transcriptional products haven't been identified. Herein, we used p53 signaling pathway qPCR-chip to determine how HDAC5-mediated deacetylation of p53 affects cell cycle. However, validation using immunoblotting analysis revealed that acetylation of p53 at K120 impacted little to the expression of the genes identified using the qPCR-chip, indicating HDAC5 might deacetylate some other proteins to facilitate cell cycle via transactivating the differentially expressed genes determined by the qPCR-chip. The subsequent assays demonstrated that HDAC5 deacetylated c-Myc at K143 and K157 to facilitate the transactivation of CDK1, CDK4, and CDC25C, promoting cell cycle progression of hepatocellular carcinoma (HCC). This study shows that HDAC5 plays important roles in modulating deacetylation of c-Myc and regulating cell cycle progression, and it proves that LMK-235, the inhibitor targeting HDAC5 potentially serves as a drug for combating HCC via promoting acetylation of c-Myc at K143 and K157.

The validity and reliability of the My Jump 2 app for measuring vertical stiffness in male college players.

Background: Vertical stiffness (Kvert) can be used to evaluate sports performance and injury risk in players. The My Jump 2 smartphone application (App), is increasingly being used by researchers, coaches, and players in the competitive sports field. We aimed to analyze the reliability and concurrent validity of the My Jump 2 app for measuring Kvert in male college players. Methods: Twenty male college players (10 soccer players, 10 basketball players; age, 20.2 ± 1.3 years old; weight, 76.4 ± 6.0 kg; height, 178.3 ± 4.7 cm) volunteered to take part in this study. Three drop jumps were performed by participants from 30 cm to 40 cm on a force platform and retested after three days. All the jumps were recorded by both the Force platform and the My Jump 2 app. Data obtained from the above two devices were compared using the paired t tests, intraclass correlation coefficient (ICC), coefficient of variation (CV), Pearson product moment correlation coefficient (r), Bland-Altman plots, and one-way regression. Results: There was almost perfect agreement between measurement instruments for the Kvert value (ICC > 0.972, 95% CI = 0.954-0.992, P < 0.01). Almost perfect agreement was observed between evaluators (ICC > 0.989, 95% CI = 0.981-0.997, P < 0.05). Also, the My Jump 2 app showed excellent intra-rater reliability in all participants (ICC = 1.000, 95% CI = 1.000-1.000, P < 0.001). The My Jump 2 showed good variability when measuring Kvert at T1 30 cm (CV = 5.4%), T1 40 cm (CV = 6.7%), T2 30 cm (CV = 5.0%), and T2 40 cm (CV = 10.3%). The test-retest reliability of My Jump 2 was moderate to good at 30 cm (ICC = 0.708, 95% CI = 0.509-0.827); however, it was lower to moderate at 40 cm (ICC = 0.445, 95% CI = 0.222-0.625). Very large correlations were observed between the force platform and the My Jump 2 for Kvert (r > 0.9655, P < 0.001). Conclusion: The My Jump 2 smartphone application showed excellent reliability and intra-rater consistency in measuring Kvert in male college players. While demonstrating excellent intra-rater consistency and strong agreement with force platform measurements, it showed slightly lower reliability at higher jump heights. Overall, the My Jump 2 app is a valid tool for evaluating Kvert in college players with careful consideration of its limitations, particularly at higher jump heights.

Esculetin Alleviates IL-1ß-Evoked Nucleus Pulposus Cell Death, Extracellular Matrix Remodeling, and Inflammation by Activating Nrf2/HO-1/NF-kb.

Inflammation, extracellular matrix metabolic dysfunction, and oxidative stress are key pathogenic characteristics of intervertebral disk degeneration (IVDD), a major pathogenic cause of low back pain. Esculetin possesses anti-injury, anti-inflammation, and antinociceptive properties. This study aimed to explore its role in IVDD. In this research, esculetin exhibited little cytotoxicity to human nucleus pulposus cells (NPCs). Moreover, esculetin increased cell viability under IL-1ß stimulation but attenuated IL-1ß-induced cell apoptosis and caspase-3 activity. Furthermore, IL-1ß-evoked increases in intracellular reactive oxygen species and malondialdehyde (MDA) levels, and decreases in superoxide dismutase (SOD) activity were reversed after esculetin treatment, indicating the antioxidative stress efficacy of esculetin. Esculetin alleviated the inhibitory effects of IL-1ß on the transcription and protein expression of anabolic biomarkers (collagen II and aggrecan), accompanied by decreases in expression and release of catabolic biomarkers MMP-3 and MMP-13 from NPCs. Moreover, IL-1ß exposure enhanced the expression levels of the inflammatory mediator nitric oxide and inflammatory cytokine IL-6 and TNF-α, which were overturned after esculetin treatment. Additionally, esculetin activated the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) to inhibit the activation of nuclear factor κB (NF-κB) signaling in NPCs. Importantly, suppression of Nrf2 signaling reversed the protective efficacy of esculetin against IL-1ß-mediated oxidative injury, matrix metabolism disruption, and inflammatory response in NPCs. Together, esculetin may alleviate IL-1ß-induced dysfunction in NPCs by regulating the Nrf2/HO-1/NF-kb signaling, indicating its potential as a promising therapeutic agent against IVDD.

Genomic and epidemiological characterization of a blaCTX-M-27-carrying ST34 Salmonella enterica serotype Typhimurium in China.

OBJECTIVES: Consuming contaminated food and water is a leading cause of food poisoning, with Salmonella being one of the primary culprits. The aim of this study is to elucidate the genomic characteristics of a blaCTX-M-27-carrying S. enterica strain recovered from a patient with diarrhoea in China. METHODS: Antimicrobial susceptibility of S. enterica strain 123 was determined by microdilution broth assay. Whole-genome sequencing was performed using both long-read MinION and short-read Illumina platforms to fully characterize the genetic structure of the blaCTX-M-27-carrying plasmid of the S. enterica 123. In silico multilocus sequence typing (MLST), antimicrobial resistance genes and genomic epidemiological analysis of 69 Salmonella strains carrying the blaCTX-M-27 gene stored in NCBI GenBank were further analysed by BacWGSTdb 2.0 server. RESULTS: The isolate was resistant to ampicillin, ampicillin/sulbactam, ceftazidime, ceftriaxone, cefepime, aztreonam, azithromycin, but still susceptible to ciprofloxacin, levofloxacin, imipenem, amikacin, trimethoprim-sulfamethoxazole and gentamicin. The complete genome sequence of Salmonella 123 is made up of one chromosome and three plasmids, which could be assigned as sequence type (ST)34. The blaCTX-M-27 gene was found in the 65 644 bp IncFII-type plasmid with IS26 and IS5 exist upstream of blaCTX-M-27 gene, and IS26 and IS1B are located downstream as a truncated fragment. The closest relative of Salmonella 123 was Salmonella strain La89, another ST34 strain recovered in 2011, which differed by only 52 SNPs. CONCLUSION: This study reports the complete genome of a blaCTX-M-27-carrying S. enterica that can be used for gaining insights into the antimicrobial resistance mechanisms and dissemination patterns of the emerging pandemic lineage ST34.

Age-Related Effect of Uric Acid on Contrast-Induced Acute Kidney Injury of Patients Undergoing Coronary Angiography.

Background: The association between uric acid (UA) and contrast-induced acute kidney injury (CI-AKI) following coronary angiography (CAG) has been established. However, whether the association would vary with age remained undetermined. Methods: We performed the retrospective analysis based on the Cardio-renal Improvement II study, (ClinicalTrials.gov NCT05050877), which enrolled consecutive patients undergoing coronary angiography in 5 teaching hospitals in China from 2007 to 2020. The primary outcome was CI-AKI defined as the rise of serum creatinine (SCr) ≥ 0.5 mg/dL or 25% compared with the baseline value within 48 hours following CAG. The effect of age on the association between uric acid and CI-AKI was assessed by the logistic regression model. Results: A total of 36,550 patients (mean age 63.08±5.6-year-old, 41.7% men) were included in the study. After adjusting for the confounders, the risk of CI-AKI between each quartile of uric acid was insignificant in the young group. In patients of the middle group, lower UA was associated with a lower risk of CI-AKI while higher UA was associated with a higher risk (Q1 OR: 0.853, 95% CI: 0.734-0.993; Q4 OR: 1.797, 95% CI: 1.547-2.09). In patients of the elder group, lower and higher UA were both associated with a higher risk of CI-AKI (Q1 OR: 1.247, 95% CI: 1.003-1.553; Q4 OR: 1.688, 95% CI: 1.344-2.124). The restricted cubic spline indicated a non-linear association between UA and CI-AKI in middle and elder age groups but a linear association in the young age group. Conclusion: The association between uric acid and CI-AKI vary in patients of different age. Patients with elder age should maintain a middle level of uric acid while patients with middle age should consider a lower level of uric acid to reduce the risk of CI-AKI. The level of UA was an insignificant risk factor for CI-AKI in young patients.

Clostridium ramosum Bacteremia in an Immunocompetent Patient with SARS-CoV-2 Infection: A Case Report.

We report a case of Clostridium ramosum bacteremia in a 73-year-old patient with SARS-CoV-2 infection and right lower abdominal tenderness in China. The microbiological features and genomic epidemiological characteristics of C. ramosum worldwide were investigated to identify the possible sources of infection. Whole-genome sequencing of C. ramosum WD-I2 was performed using an Illumina NovaSeq 6000 platform. Phylogenetic analysis of C. ramosum WD-I2 and other publicly available C. ramosum isolates was performed and visualized using the interactive Tree of Life (iTOL) web server. The resistome of C. ramosum WD-I2 consists of two antimicrobial resistance genes (tetM and ermB), which explains the antimicrobial resistance trait to tetracycline and macrolides. Phylogenetic analysis showed that the strain closest to our isolated strain WD-I2 was SUG1069, recovered from a pig feces sample from Canada, which differed by 589 SNPs. To our knowledge, this is the first report of C. ramosum bacteremia in China. Our findings highlight the potential risk of invasive C. ramosum infections during the COVID-19 pandemic.

Bacteremia Caused by a Serotype Ob5 Vibrio cholerae Strain in a Cirrhotic Patient in China.

The increasing incidence of non-O1/non-O139 Vibrio cholerae (NOVC) has been observed worldwide. However, septicemia caused by NOVC remains a rare condition that has received limited attention. Currently, there are no established treatment guidelines for bloodstream infections caused by NOVC, and the understanding of this condition mainly relies on individual case reports. Although NOVC bacteremia can be fatal in a small percentage of cases, knowledge about its microbiological features remains limited. Here, we present a case of V. cholerae septicemia caused by NOVC in a 46-year-old man with chronic viral hepatitis and liver cirrhosis. The isolated strain, named V. cholerae VCH20210731 and classified as a new sequence type (ST), ST1553, was found to be susceptible to most of the antimicrobial agents tested. O-antigen serotyping of V. cholerae VCH20210731 revealed that it belonged to serotype Ob5. Interestingly, the ctxAB genes, which are typically associated with V. cholerae, were absent in VCH20210731. However, the strain possessed 25 other potential virulence genes, such as hlyA, luxS, hap, and rtxA. The resistome of V. cholerae VCH20210731 included several genes, including qnrVC4, crp, almG, and parE. Nevertheless, susceptibility testing demonstrated that the isolate was susceptible to most of the antimicrobial agents tested. Phylogenetic analysis indicated that the closest strain to VCH20210731 was strain 120 from Russia, differing by 630 single-nucleotide polymorphisms (SNPs). Our findings contribute to the understanding of the genomic epidemiological characteristics and antibiotic resistance mechanisms of this invasive bacterial pathogen. IMPORTANCE This study highlights the discovery of a novel ST1553 V. cholerae strain in China, providing valuable insights into the genomic epidemiology and global transmission dynamics of V. cholerae. It is important to note that clinical presentations of NOVC bacteremia can vary significantly, and the isolates demonstrate genetic diversity. Consequently, health care professionals and public health experts should remain vigilant about the potential for infection with this pathogen, particularly considering the elevated prevalence of liver disease in China.

Adaptive Density Spatial Clustering Method Fusing Chameleon Swarm Algorithm.

The density-based spatial clustering of application with noise (DBSCAN) algorithm is able to cluster arbitrarily structured datasets. However, the clustering result of this algorithm is exceptionally sensitive to the neighborhood radius (Eps) and noise points, and it is hard to obtain the best result quickly and accurately with it. To solve the above problems, we propose an adaptive DBSCAN method based on the chameleon swarm algorithm (CSA-DBSCAN). First, we take the clustering evaluation index of the DBSCNA algorithm as the objective function and use the chameleon swarm algorithm (CSA) to iteratively optimize the evaluation index value of the DBSCAN algorithm to obtain the best Eps value and clustering result. Then, we introduce the theory of deviation in the data point spatial distance of the nearest neighbor search mechanism to assign the identified noise points, which solves the problem of over-identification of the algorithm noise points. Finally, we construct color image superpixel information to improve the CSA-DBSCAN algorithm's performance regarding image segmentation. The simulation results of synthetic datasets, real-world datasets, and color images show that the CSA-DBSCAN algorithm can quickly find accurate clustering results and segment color images effectively. The CSA-DBSCAN algorithm has certain clustering effectiveness and practicality.

TRIM55 inhibits colorectal cancer development via enhancing protein degradation of c-Myc.

BACKGROUND: Colorectal cancer (CRC) is one of the most common and lethal malignancies which including colon and rectum cancer. Tripartite motif containing 55 (TRIM55) is an E3 ubiquitin ligase belonging to the TRIM family. Although the aberrant TRIM55 expression has been implicated in several tumors, its functional role, and molecular mechanisms in CRC remain unknown. METHODS: Immunohistochemical studies, qRT-PCR, and Western blot were performed to analyze the expression of TRIM55 in CRC patients and cell lines. TRIM55 expression and its relevance to clinical traits and prognosis were further explored in the TCGA database, and in our 87 clinical samples. Subsequently, we performed a series of functional assays to explore the effect of TRIM55 on CRC progression. Finally, the molecular mechanism of TRIM55 was investigated by immunoprecipitation and ubiquitination analyses. RESULTS: Here, we demonstrated that TRIM55 was markedly downregulated in CRC cell lines and tumors from CRC patients. Moreover, overexpression of TRIM55 could suppress CRC cell growth in vitro and inhibit CRC xenograft tumor development in vivo. Additionally, TRIM55 overexpression dampened CRC cell migration and invasion. Further bioinformatics analysis indicated that TRIM55 suppressed cyclin D1 and c-Myc expression. Mechanistically, co-immunoprecipitation assay revealed that TRIM55 directly interacted with c-Myc and down-regulated its protein expression level via protein ubiquitination. Intriguingly, c-Myc overexpression partially antagonized the function of TRIM55 overexpression. CONCLUSIONS: Taken together, our findings suggest that TRIM55 inhibits CRC tumor development via, at least in part, enhancing protein degradation of c-Myc. Targeting TRIM55 could provide a new therapeutic approach for CRC patients.

E2F1 promotes cell cycle progression by stabilizing spindle fiber in colorectal cancer cells.

BACKGROUND: E2F1 is a transcription factor that regulates cell cycle progression. It is highly expressed in most cancer cells and activates transcription of cell cycle-related kinases. Stathmin1 and transforming acidic coiled-coil-containing protein 3 (TACC3) are factors that enhance the stability of spindle fiber. METHODS: The E2F1-mediated transcription of transforming acidic coiled-coil-containing protein 3 (TACC3) and stathmin1 was examined using the Cancer Genome Atlas (TCGA) analysis, quantitative polymerase chain reaction (qPCR), immunoblotting, chromatin immunoprecipitation (ChIP), and luciferase reporter. Protein-protein interaction was studied using co-IP. The spindle structure was shown by immunofluorescence. Phenotype experiments were performed through MTS assay, flow cytometry, and tumor xenografts. Clinical colorectal cancer (CRC) specimens were analyzed based on immunohistochemistry. RESULTS: The present study showed that E2F1 expression correlates positively with the expression levels of stathmin1 and TACC3 in colorectal cancer (CRC) tissues, and that E2F1 transactivates stathmin1 and TACC3 in CRC cells. Furthermore, protein kinase A (PKA)-mediated phosphorylation of stathmin1 at Ser16 is essential to the phosphorylation of TACC3 at Ser558, facilitating the assembly of TACC3/clathrin/α-tubulin complexes during spindle formation. Overexpression of Ser16-mutated stathmin1, as well as knockdown of stathmin1 or TACC3, lead to ectopic spindle poles including disorganized and multipolar spindles. Overexpression of wild-type but not Ser16-mutated stathmin1 promotes cell proliferation in vitro and tumor growth in vivo. Consistently, a high level of E2F1, stathmin1, or TACC3 not only associates with tumor size, lymph node metastasis, TNM stage, and distant metastasis, but predicts poor survival in CRC patients. CONCLUSIONS: E2F1 drives the cell cycle of CRC by promoting spindle assembly, in which E2F1-induced stathmin1 and TACC3 enhance the stability of spindle fiber.

Emergence of a Multidrug-Resistant Escherichia coli Co-Carrying a New mcr-1.33 Variant and bla NDM-5 Genes Recovered from a Urinary Tract Infection.

Background: Carbapenem-resistant Enterobacterales (CRE) are a significant threat to worldwide public health, resulting in increased morbidity, death, hospitalization time and healthcare expenses. Here, the genomic and phylogenetic characteristics of a multidrug-resistant Escherichia coli isolate carrying both the new mcr-1.33 variant and bla NDM-5 gene obtained from a urinary tract infection in China are investigated. Methods: Antimicrobial susceptibility of E. coli 779 was evaluated by using the broth microdilution method. Short-read Illumina NovaSeq 6000 and long-read Oxford Nanopore MinION platforms were applied to sequence the bacterial whole genomic DNA and then de novo assembled. The genome sequence was annotated using the NCBI Prokaryotic Genome Annotation Pipeline and further subjected to identify the sequence type (ST), capsular type, and antibiotic resistance genes. BacWGSTdb 2.0 was used to perform the core genome multilocus sequence typing (cgMLST) analysis with other closely related E. coli isolates deposited in the public database. Results: E. coli 779 was resistant to aztreonam, levofloxacin, fosfomycin, cefoxitin, cefepime, cefotaxime, imipenem, meropenem, polymyxin, and tigecycline. The complete genome sequence of E. coli 779 is made up of nine contigs totaling 5,667,876 bp, including one chromosome and eight plasmids. The isolate was assigned to ST101, serotype O-:H31, and phylogroup B1. The colistin resistance gene mcr-1.33 (located in a 242,460 bp IncHI2/IncHI2A plasmid) and the ß-lactam resistance gene bla NDM-5 (located in a 46,161 bp IncX3 plasmid) were among the 27 antimicrobial resistance genes discovered. The closest relative of E. coli 779, another ST101 strain (E. coli 443) obtained from a sewage sample in Shandong, China in 2015, differs by only 24 cgMLST alleles. Conclusion: We discovered the first multidrug-resistant ST101 E. coli strain with plasmid-mediated mcr-1.33 variant and bla NDM-5 gene in China. These findings would help us to better understanding the genomic traits, antimicrobial resistance mechanisms and epidemiological aspects of this bacterial pathogen.

MicroRNA-139-5p inhibits inflammatory and oxidative stress responses of Salmonella-infected macrophages through modulating TRAF6.

Evidence indicates that macrophages play an important role in the immune system. Therefore, research involving inflammatory and oxidative stress responses in macrophages is of great significance. Many factors contribute to inflammation and oxidative stress, including Salmonella. We investigated the effect of the miR-139-5p/TRAF6 axis on the inflammatory and oxidative stress responses of Salmonella -infected macrophages. Our findings revealed that miR-139-5p decreased IL-1ß and TNF-α levels to inhibit Salmonella-induced inflammatory responses in the RAW264.7 macrophage cell line. Furthermore, miR-139-5p inhibited Salmonella-induced oxidative stress by strengthening SOD, CAT and GSH-PX activity, as well as lowering the malondialdehyde level in the RAW264.7 macrophages cell line. Subsequently, it was verified that TRAF6 was a downstream target of miR-139-5p in RAW264.7 cells. Rescue assays indicated that the over-expression of miR-139-5p inhibits the effects of TRAF6 on inflammatory and oxidative stress responses including Salmonella infection in RAW264.7 cells. To our knowledge, this study is the first to verify that miR-139-5p inhibits inflammatory and oxidative stress responses of Salmonella-infected macrophages through regulating TRAF6. This discovery may offer new insights on inflammatory and oxidative stress responses in macrophages.

LatinPSO: An algorithm for simultaneously inferring structure and parameters of ordinary differential equations models.

Simultaneously inferring both the structure and parameters of Ordinary Differential Equations (ODEs) for a complex dynamic system is more practical in many systems identification problems, but it remains challenging due to the complexity of the underlying search space. In this research, we propose a novel algorithm based on Particle Swarm Optimization (PSO) and Latin Hypercube Sampling (LHS) to address the above problem. The proposed algorithm is termed LatinPSO, and it can be effectively used for inferring the structure and parameters of ODE models through time course data. To start with, the real Human Immunodeficiency Virus (HIV) model and several synthetic models are used for evaluating the performance of LatinPSO. Experimental results demonstrated that LatinPSO could find satisfactory candidate ODE models with appropriate structure and parameters.

Density propagation based adaptive multi-density clustering algorithm.

The performance of density based clustering algorithms may be greatly influenced by the chosen parameter values, and achieving optimal or near optimal results very much depends on empirical knowledge obtained from previous experiments. To address this limitation, we propose a novel density based clustering algorithm called the Density Propagation based Adaptive Multi-density clustering (DPAM) algorithm. DPAM can adaptively cluster spatial data. In order to avoid manual intervention when choosing parameters of density clustering and still achieve high performance, DPAM performs clustering in three stages: (1) generate the micro-clusters graph, (2) density propagation with redefinition of between-class margin and intra-class cohesion, and (3) calculate regional density. Experimental results demonstrated that DPAM could achieve better performance than several state-of-the-art density clustering algorithms in most of the tested cases, the ability of no parameters needing to be adjusted enables the proposed algorithm to achieve promising performance.