Exploration of shared gene signatures and molecular mechanisms between type 2 diabetes and osteoporosis.

Type 2 diabetes mellitus (T2D) and osteoporosis (OP) are systemic metabolic diseases and often coexist. The mechanism underlying this interrelationship remains unclear. We downloaded microarray data for T2D and OP from the Gene Expression Omnibus (GEO) database. Using weighted gene co-expression network analysis (WGCNA), we identified co-expression modules linked to both T2D and OP. To further investigate the functional implications of these associated genes, we evaluated enrichment using ClueGO software. Additionally, we performed a biological process analysis of the genes unique in T2D and OP. We constructed a comprehensive miRNA-mRNA network by incorporating target genes and overlapping genes from the shared pool. Through the implementation of WGCNA, we successfully identified four modules that propose a plausible model that elucidates the disease pathway based on the associated and distinct gene profiles of T2D and OP. The miRNA-mRNA network analysis revealed co-expression of PDIA6 and SLC16A1; their expression was upregulated in patients with T2D and islet ß-cell lines. Remarkably, PDIA6 and SLC16A1 were observed to inhibit the proliferation of pancreatic ß cells and promote apoptosis in vitro, while downregulation of PDIA6 and SLC16A1 expression led to enhanced insulin secretion. This is the first study to reveal the significant roles of PDIA6 and SLC16A1 in the pathogenesis of T2D and OP, thereby identifying additional genes that hold potential as indicators or targets for therapy.

Assessing recent recurrence after hepatectomy for hepatitis B-related hepatocellular carcinoma by a predictive model based on sarcopenia.

BACKGROUND: Sarcopenia may be associated with hepatocellular carcinoma (HCC) following hepatectomy. But traditional single clinical variables are still insufficient to predict recurrence. We still lack effective prediction models for recent recurrence (time to recurrence < 2 years) after hepatectomy for HCC. AIM: To establish an interventable prediction model to estimate recurrence-free survival (RFS) after hepatectomy for HCC based on sarcopenia. METHODS: We retrospectively analyzed 283 hepatitis B-related HCC patients who underwent curative hepatectomy for the first time, and the skeletal muscle index at the third lumbar spine was measured by preoperative computed tomography. 94 of these patients were enrolled for external validation. Cox multivariate analysis was per-formed to identify the risk factors of postoperative recurrence in training cohort. A nomogram model was developed to predict the RFS of HCC patients, and its predictive performance was validated. The predictive efficacy of this model was evaluated using the receiver operating characteristic curve. RESULTS: Multivariate analysis showed that sarcopenia [Hazard ratio(HR) = 1.767, 95%CI: 1.166-2.678, P < 0.05], alpha-fetoprotein ≥ 40 ng/mL (HR = 1.984, 95%CI: 1.307-3.011, P < 0.05), the maximum diameter of tumor > 5 cm (HR = 2.222, 95%CI: 1.285-3.842, P < 0.05), and hepatitis B virus DNA level ≥ 2000 IU/mL (HR = 2.1, 95%CI: 1.407-3.135, P < 0.05) were independent risk factors associated with postoperative recurrence of HCC. Based on the sarcopenia to assess the RFS model of hepatectomy with hepatitis B-related liver cancer disease (SAMD) was established combined with other the above risk factors. The area under the curve of the SAMD model was 0.782 (95%CI: 0.705-0.858) in the training cohort (sensitivity 81%, specificity 63%) and 0.773 (95%CI: 0.707-0.838) in the validation cohort. Besides, a SAMD score ≥ 110 was better to distinguish the high-risk group of postoperative recurrence of HCC. CONCLUSION: Sarcopenia is associated with recent recurrence after hepatectomy for hepatitis B-related HCC. A nutritional status-based prediction model is first established for postoperative recurrence of hepatitis B-related HCC, which is superior to other models and contributes to prognosis prediction.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

BACKGROUND: Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. AIM: To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. METHODS: This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. RESULTS: Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1ß, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. CONCLUSION: SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Coexistence of a novel chromosomal integrative and mobilizable element Tn7548 with two blaKPC-2-carrying plasmids in a multidrug-resistant Aeromonas hydrophila strain K522 from China.

OBJECTIVES: Herein, we detected one multidrug-resistant Aeromonas hydrophila strain K522 co-carrying two blaKPC-2 genes together with a novel chromosomal integrative and mobilizable element (IME) Tn7548 from China. To reveal the genetic characteristics of the novel reservoir of blaKPC-2 and IME in Aeromonas, a detailed genomic characterization of K522 was performed, and a phylogenetic analysis of Tn7412-related IMEs was carried out. METHODS: Carbapenemases were detected by using the immunocolloidal gold technique and antimicrobial susceptibility was tested by using VITEK 2. The whole-genome sequences of K522 were analysed using phylogenetics, detailed dissection, and comparison. RESULTS: Strain K522 carried a Tn7412-related chromosomal IME Tn7548 and three resistance plasmids pK522-A-KPC, pK522-B-KPC, and pK522-MOX. A phylogenetic tree of 82 Tn7412-related IMEs was constructed, and five families of IMEs were divided. These IMEs shared four key backbone genes: int, repC, and hipAB, and carried various profiles of antimicrobial resistance genes (ARGs). pK522-A-KPC and pK522-B-KPC carried blaKPC-2 and belonged to IncG and unclassified type plasmid, respectively. The blaKPC-2 regions of these two plasmids were the truncated version derived from Tn6296, resulting in the carbapenem resistance of K522. CONCLUSION: We first reported A. hydrophila harbouring a novel Tn7412-related IME Tn7548 together with two blaKPC-2 carrying plasmids and a MDR plasmid. Three of these four mobile genetic elements (MGEs) discovered in A. hydrophila K522 were novel. The emergence of novel MGEs carrying ARGs indicated the rapid evolution of the resistance gene vectors in A. hydrophila under selection pressure and would contribute to the further dissemination of various ARGs in Aeromonas.

Rapid, visual, label-based biosensor platform for identification of hepatitis C virus in clinical applications.

OBJECTIVES: In the current study, for the first time, we reported a novel HCV molecular diagnostic approach termed reverse transcription loop-mediated isothermal amplification integrated with a gold nanoparticles-based lateral flow biosensor (RT-LAMP-AuNPs-LFB), which we developed for rapid, sensitive, specific, simple, and visual identification of HCV. METHODS: A set of LAMP primer was designed according to 5'untranslated region (5'UTR) gene from the major HCV genotypes 1b, 2a, 3b, 6a, and 3a, which are prevalent in China. The HCV-RT-LAMP-AuNPs-LFB assay conditions, including HCV-RT-LAMP reaction temperature and time were optimized. The sensitivity, specificity, and selectivity of our assay were evaluated in the current study. The feasibility of HCV-RT-LAMP-AuNPs-LFB was confirmed through clinical serum samples from patients with suspected HCV infections. RESULTS: An unique set of HCV-RT-LAMP primers were successfully designed targeting on the 5'UTR gene. The optimal detection process, including crude nucleic acid extraction (approximately 5 min), RT-LAMP reaction (67℃, 30 min), and visual interpretation of AuNPs-LFB results (~ 2 min), could be performed within 40 min without specific instruments. The limit of detection was determined to be 20 copies per test. The HCV-RT-LAMP-AuNPs-LFB assay exhibited high specificity and anti-interference. CONCLUSIONS: These preliminary results confirmed that the HCV-RT-LAMP-AuNPs-LFB assay is a sensitive, specific, rapid, visual, and cost-saving assay for identification of HCV. This diagnostic approach has great potential value for point-of-care (POC) diagnostic of HCV, especially in resource-challenged regions.

Establishment of a prognostic model for hospitalized cirrhotic patients with infection based on lumbar muscle mass.

Background: Sarcopenia frequently complicates cirrhosis and leads to substantial mortality. Infection is a complication of cirrhosis that results in high mortality. Both sarcopenia and infection are accompanied by systemic inflammation and adversely affect the prognosis of cirrhosis. This article was designed to decipher the association of sarcopenia with infection occurrence, and to ascertain the risk factors for the 90-day death rate in hospitalized cirrhotic patients with infection. Methods: A total of 808 cirrhotic patients (373 with infection and 435 without) who had undergone abdominal CT from 2017 to 2021 were recruited for this retrospective single-center research. The skeletal muscle index was assessed at the level of the third lumbar vertebra (L3 SMI). The optimal cutoff value of the CAIL3 model (CTP score, AKI, INR, and L3 SMI) for the prediction of the 90-day death rate was authenticated with receiver operating characteristic (ROC) analysis. Results: L3 SMI was considered to be the independent risk factor for infection in cirrhotic patients and 90-day death rate in these patients with infection (HR 2.840 95% CI 2.076-3.886, p < 0.001 for infection and HR 2.097 95% CI 1.142-3.850, p = 0.017 for 90-day death rate, respectively). CAIL3 had an area under the ROC curve of 0.840, and a cutoff value of 0.21 for predicting the poor outcome (sensitivity 77.22% and specificity 76.53%, respectively). Conclusion: L3 SMI is an essential factor associated with infection and 90-day death rate in cirrhotic patients. CAIL3 may be a novel model for the prediction of the 90-day death risk in cirrhotic patients with infections.

Predicting disease progression in cirrhotic patients after transjugular intrahepatic portosystemic shunt implantation: A sex-stratified analysis.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) has been extensively used to treat portal hypertension-associated complications, including cirrhosis. The prediction of post-TIPS prognosis is important for cirrhotic patients, as more aggressive liver transplantation is needed when the post-TIPS prognosis is poor. AIM: To construct a nutrition-based model that could predict the disease progression of cirrhotic patients after TIPS implantation in a sex-dependent manner. METHODS: This study retrospectively recruited cirrhotic patients undergoing TIPS implantation for analysis. Muscle quality was assessed by measuring the skeletal muscle index (SMI) by computed tomography. Multivariate Cox proportional hazard models were utilized to determine the association between SMI and disease progression in cirrhotic patients after TIPS implantation. RESULTS: This study eventually included 186 cirrhotic patients receiving TIPS who were followed up for 30.5 ± 18.8 mo. For male patients, the 30-mo survival rate was significantly lower and the probability of progressive events was higher (3.257-fold) in the low-level SMI group than in the high-level SMI group. According to the multivariate Cox analysis of male patients, SMI < 32.8 was an independent risk factor for long-term adverse outcomes after TIPS implantation. A model was constructed, which involved creatinine, plasma ammonia, SMI, and acute-on-chronic liver failure and hepatic encephalopathy occurring within half a year after surgery. This model had an area under the receiver operating characteristic curve of 0.852, sensitivity of 0.926, and specificity of 0.652. According to the results of the DeLong test, this model outperformed other models (Child-Turcotte-Pugh, Model for End-Stage Liver Disease, and Freiburg index of post-TIPS survival) (P < 0.05). CONCLUSION: SMI is strongly associated with poor long-term outcomes in male patients with cirrhosis who underwent TIPS implantation.

Cuproptosis-related lncRNAs as potential biomarkers of AML prognosis and the role of lncRNA HAGLR/miR-326/CDKN2A regulatory axis in AML.

Acute myeloblastic leukemia (AML) is the most prevalent form of AML in adults. Despite the availability of various treatment options, including radiotherapy and chemotherapy, many patients fail to respond to treatment or relapse. Copper is a necessary cofactor for all organisms; however, it turns toxic when concentrations reach a certain threshold maintained by homeostatic systems that have been conserved through evolution. However, the mechanism through which excess copper triggers cell death remains unknown. In this study, data on long non-coding RNAs (lncRNAs) related to cuproptosis were retrieved from publicly available databases. LASSO and univariate and multivariate Cox regression analyses were performed to establish an lncRNA model associated with cuproptosis specific to AML. To investigate the risk model, the Kaplan-Meier curve, principal component analysis, functional enrichment analysis, and nomographs were employed. The underlying clinicopathological characteristics were determined, and drug sensitivity predictions against the model were identified. Six cuproptosis-related lncRNA-based risk models were identified as the independent prognostic factors. By regrouping patients using a model-based method, we were able to more accurately differentiate patients according to their responses to immunotherapy. In addition, prospective compounds targeting AML subtypes have been identified. Using qRT-PCR, we examined the expression levels of six cuproptosis-associated lncRNAs in 30 clinical specimens. The cuproptosis-associated lncRNA risk-scoring model developed herein has implications in monitoring AML prognosis and in the clinical prediction of the response to immunotherapy. Furthermore, we identified and verified the ceRNA of the cuproptosis-related lncRNA HAGLR/miR-326/CDKN2A regulatory axis using bioinformatic tools. HAGLR is highly expressed in AML and AML cell lines. HAGLR inhibition significantly reduced the proliferation of AML cells and promoted apoptosis. Elesclomol promotes the degradation of CDKN2A and inhibits the proliferation of AML cells. Elesclomol combined with si-HAGLR inhibited the AML progression of AML both in vitro and in vivo.

Coexistence of c-rmpA with p-rmpA and p-rmpA2 rather than excessive siderophores confers higher virulence in K1 Klebsiella pneumoniae.

Pyogenic liver abscess (PLA), which is particularly endemic in East Asia, is a relatively common and fatal infectious disease. Over the last 30-40 years, Klebsiella pneumoniae has replaced Escherichia coli as the dominant and overwhelming pathogen. To investigate the survival advantage of serotype K1 K. pneumoniae, we determined sequence types (STs), serotypes, and 11 virulence genes (allS, entB, irp2, iroN, iucA, fimH, mrkD, p-rmpA2, c-rmpA, p-rmpA, and peg-344). Virulence genes c-rmpA, p-rmpA, and p-rmpA2 in K. pneumoniae NTUH-K2044, which all confer hypercapsule and consequent hypervirulence, were deleted individually, and the consequent effects were evaluated. The lethality of various K1 K. pneumoniae strains was compared by using the Galleria mellonella model. In total, 31 K1 K. pneumoniae strains causing PLA and 30 causing non-PLA were identified. A significantly higher rate of c-rmpA was presented in PLA-derived K. pneumoniae strains than in non-PLA-derived strains. Similar ST23 (which dominates K1 strains) and string test-positive rates were observed in the two groups. Deletion of c-rmpA, p-rmpA, and p-rmpA2 individually did not confer significant effects on morphologies, such as positive string test, hypercapsule, and growth speed. Δc-rmpA presented weaker expressions of p-rmpA/p-rmpA2 than NTUH-K2044 and showed a higher expression of manC than Δp-rmpA and Δp-rmpA2. Three rmpAs conferred more virulence than one or two rmpAs, which presented an equally lethal effect in K1 K. pneumoniae. Klebsiella pneumoniae strains (H19 and H34) with the same genetic backgrounds except for siderophores showed equal virulence, but were less virulent than strain NTUH-K2044. Thus, the coexistence of c-rmpA with p-rmpA and p-rmpA2 enhances the lethality of K1 K. pneumoniae strains and the development of PLA. Excessive siderophores are not vital for the hypervirulence of K1 K. pneumoniae strains, although K1 strains usually harbour them on a molecular basis.

Clinical characteristics, risk factors, and outcomes of patients with polymicrobial Pseudomonas aeruginosa bloodstream infections.

BACKGROUND: Previous studies on polymicrobial Pseudomonas aeruginosa bloodstream infections (Pa-BSIs) are dated, and it is necessary to reanalyze polymicrobial Pa-BSIs. The aim of this study was to investigate clinical characteristics and risk factors for polymicrobial Pa-BSI in comparison with monomicrobial Pa-BSI. METHODS: A double-center retrospective observational study was performed between January 1, 2013 and June 30, 2022, in two tertiary hospitals. All patients with Pa-BSI were enrolled, and their clinical data were collected by reviewing electronic medical records. RESULTS: A total of 278 patients with Pa-BSI were enrolled, including 77 patients (27.7%) with polymicrobial Pa-BSI. Compared with monomicrobial Pa-BSI, the main source of polymicrobial Pa-BSI was pneumonia (49.4% vs 31.3%, p < 0.01), whereas the main source of monomicrobial Pa-BSI was primary BSIs (21.9% vs 2.6%, p = 0.04). In multivariate analysis, a history of cerebrovascular accident (CVA) (adjusted odds ratio [OR], 3.62; 95% CI, 1.46-8.92) was independently associated with polymicrobial Pa-BSI. Primary BSI was associated with monomicrobial Pa-BSI (OR, 0.08; 95% CI, 0.02-0.38). Patients with polymicrobial Pa-BSI had a longer intensive care unit (ICU) length of stay after onset of BSI than those with monomicrobial Pa-BSI (2 [2, 16] vs 13 [3.75, 29], p = 0.02). CONCLUSION: Patients with Pa-BSI and the presence of CVA need to be alert to the possibility of polymicrobial BSI occurrence. Prolonged ICU stay and pneumonia as a source of BSI warrant clinician attention for polymicrobial Pa-BSI, and primary BSIs are likely associated with monomicrobial BSIs.

Coexistence of blaKPC-2 and blaNDM-1 in one IncHI5 plasmid confers transferable carbapenem resistance from a clinical isolate of Klebsiella michiganensis in China.

OBJECTIVES: This study firstly identified an IncHI5 plasmid pK254-KPC_NDM co-carrying two different class carbapenemase genes blaKPC-2 and blaNDM-1 in Klebsiella michiganensis K254. METHODS: The strain K254 was sequenced by high-throughput genome sequencing. A detailed genomic and phenotypic characterization of pK254-KPC_NDM was performed. RESULTS: pK254-KPC_NDM displayed the conserve IncHI5 backbone and carried a resistant accessory region: Tn1696-related transposon Tn7414 containing blaKPC-2 and blaNDM-1. A sequence comparison was applied to a collection of four Tn1696-related transposons (Tn7414-Tn7417) harbouring carbapenemase genes. For all these four transposons, the blaNDM-1 was carried by Tn125 derivatives within three different mobile genetic elements. Tn7414 further acquired another carbapenemase gene, blaKPC-2, because of the integration of the local blaKPC-2 genetic environment from Tn6296, resulting in the high-level carbapenem resistance of K. michiganensis K254. The conjugal transfer and plasmid stability experiments confirmed that pK254-KPC_NDM could be transferred intercellularly and keep the stable vertical inheritance in different bacteria, which would contribute to the further dissemination of multiple carbapenemase genes and enhance the adaption and survival of K. michiganensis under complex and diverse antimicrobial selection pressures. CONCLUSION: This study was the first to report the K. michiganensis isolate coharbouring blaKPC-2 and blaNDM-1 in the Tn1696-related transposon in IncHI5 plasmid. The emergence of novel transposons simultaneously carrying multiple carbapenemase genes might contribute to the further dissemination of high-level carbapenem resistance in the isolates of the hospital settings and pose new challenges for the treatment of nosocomial infection.

Epidemiology, molecular characterization, and drug resistance of IncHI5 plasmids from Enterobacteriaceae / Epidemiología, caracterización molecular y farmacorresistencia de plásmidos IncHI5 de Enterobacteriaceae

The increasingly frequent occurence of IncHI5 plasmids has attracted worldwide attention. The aim of this study was to perform an in-depth bioinformatics analysis to determine the genetic characteristics and global distribution of all IncHI5 plasmids. The geographic distribution and epidemiology of all IncHI5 plasmids from GenBank were analyzed based on relevant literature reports and background information from the National Center for Biotechnology Information (NCBI). Detailed annotation of antibiotic resistance genes was performed. A total of 65 IncHI5 plasmid genomes were collected in GenBank. All IncHI5 plasmids were carried by Enterobacteriaceae, of which Klebsiella pneumoniae accounted for the largest proportion (50%, 33/65). The host bacterium of IncHI5 plasmids was mainly isolated from Homo Sapiens (81%, 53/65). All strains carrying IncHI5 plasmids were mainly distributed in China (83%, 54/65). Evolutionary analysis can divide IncHI5 plasmids into two groups, namely Groups I/II, of which Group II was more widely distributed worldwide. This study showed that Enterobacteriaceae, especially Klebsiella, was the main host for IncHI5 plasmid. Almost all IncHI5 plasmids carried multiple types of antibiotic resistance genes, related to Tn1696 or Tn6535. The IncHI5 plasmids should be of continuing interest as good repositories for antibiotic resistance genes.(AU)

Genomic analysis of chromosomal cointegrated bla NDM-1-carrying ICE and bla RSA-1-carrying IME from clinical multidrug resistant Aeromonas caviae.

Introduction: The objective of this study is to thoroughly analyze the detailed genomic characteristics of clinical strain 211703 of Aeromonas caviae, which co-carrying bla RSA-1 and bla NDM-1 genes. 211703 was isolated from the patient's cerebrospinal fluid drainage sample in a Chinese tertiary hospital. Methods: Carbapenemase NDM was detected by the immunocolloidal gold technique. The MIC values were determined by VITEK2. The whole genome sequence of 211703 was analyzed using phylogenetics, genomic comparison, and extensive dissection. Results: This study revealed that 211703 only contained a single 4.78 Mb chromosome (61.8% GC content), and no plasmids were discovered in 211703. 15 different types of resistant genes were detected in the genome of 211703, including bla RSA-1 harbored on integrative and mobilizable element (IME) Tn7413a, and bla NDM-1 harbored on integrative and conjugative element (ICE). The ICE and IME were all carried on the chromosome of 211703 (c211703). Detailed comparison of related IMEs/ICEs showed that they shared similar conserved backbone regions, respectively. Comprehensive annotation revealed that bla RSA-1 was carried by the gene cassette of a novel integron In2148 on Tn7413a, and bla NDM-1 was captured by an insertion sequence ISCR14-like on the ICE of 211703. We speculated that mobile genetic elements (MGEs) such as ICE and IME facilitated the spread of resistance genes such as bla RSA-1 and bla NDM-1. Discussion: In conclusion, this study provides an overall understanding of the genomic characterization of clinically isolated A. caviae 211703, and an in-depth discussion of multiple acquisition methods of drug resistance genes in Aeromonas. To the best of our knowledge, this is the first report of A. caviae carrying bla RSA-1 even both bla RSA-1 and bla NDM-1, and this is the first bacterium carrying bla RSA-1 isolated from the clinical setting.

The Systemic Immune Inflammation Index (SII) Combined with the Creatinine-to-Cystatin C Ratio (Cre/CysC) Predicts Sarcopenia in Patients with Liver Cirrhosis Complicated with Primary Hepatocellular Carcinoma.

BACKGROUND: Sarcopenia is a risk factor for poor cancer prognosis. Early identification and timely intervention of sarcopenia can improve patient prognosis. METHODS: A total of 91 patients with liver cirrhosis complicated with primary hepatocellular carcinoma were retrospectively analyzed. Based on the results of multivariable logistic regression analysis, a nomogram was developed. Moreover, 50 patients were enrolled for external validation. The predictive efficacy of the nomogram was evaluated using the receiver operating characteristic curve (ROC). RESULTS: According to the logistic regression analysis results, age, body mass index (BMI), creatinine-to-cystatin C ratio (Cre/CysC), and systemic immune inflammation index (SII) were independent risk factors of sarcopenia in patients with cirrhosis complicated with primary hepatocellular carcinoma (HCC) (all p < 0.05). The ABCS nomogram model was established, and the area under the ROC curve (AUC) was 0.896 (84.7% sensitivity, 81.2% specificity). The calibration curve of the nomogram was close to the ideal diagonal line. The predictive efficacy of the nomogram was verified through the external validation. CONCLUSION: The ABCS model based on SII and Cre/CysC can be used to identify high-risk sarcopenia in patients with cirrhosis complicated with HCC in the early stage.

Visual and rapid identification of Chlamydia trachomatis and Neisseria gonorrhoeae using multiplex loop-mediated isothermal amplification and a gold nanoparticle-based lateral flow biosensor.

Sexually transmitted chlamydia and gonorrhea infections caused by the bacteria Chlamydia trachomatis and Neisseria gonorrhoeae remain a major public health concern worldwide, particularly in less developed nations. It is crucial to use a point of care (POC) diagnostic method that is quick, specific, sensitive, and user-friendly to treat and control these infections effectively. Here, a novel molecular diagnostic assay, combining multiplex loop-mediated isothermal amplification (mLAMP) with a visual gold nanoparticles-based lateral flow biosensor (AuNPs-LFB) was devised and used for highly specific, sensitive, rapid, visual, and easy identification of C. trachomatis and N. gonorrhoeae. Two unique independent primer pairs were successful designed against the ompA and orf1 genes of C. trachomatis and N. gonorrhoeae, respectively. The optimal mLAMP-AuNPs-LFB reaction conditions were determined to be 67°C for 35 min. The detection procedure, involving crude genomic DNA extraction (~5 min), LAMP amplification (35 min), and visual results interpretation (<2 min), can be completed within 45 min. Our assay has a detection limit of 50 copies per test, and we did not observe any cross-reactivity with any other bacteria in our testing. Hence, our mLAMP-AuNPs-LFB assay can potentially be used for POC testing to detect C. trachomatis and N. gonorrhoeae in clinical settings, particularly in underdeveloped regions.

Epidemiology, molecular characterization, and drug resistance of IncHI5 plasmids from Enterobacteriaceae.

The increasingly frequent occurence of IncHI5 plasmids has attracted worldwide attention. The aim of this study was to perform an in-depth bioinformatics analysis to determine the genetic characteristics and global distribution of all IncHI5 plasmids. The geographic distribution and epidemiology of all IncHI5 plasmids from GenBank were analyzed based on relevant literature reports and background information from the National Center for Biotechnology Information (NCBI). Detailed annotation of antibiotic resistance genes was performed. A total of 65 IncHI5 plasmid genomes were collected in GenBank. All IncHI5 plasmids were carried by Enterobacteriaceae, of which Klebsiella pneumoniae accounted for the largest proportion (50%, 33/65). The host bacterium of IncHI5 plasmids was mainly isolated from Homo Sapiens (81%, 53/65). All strains carrying IncHI5 plasmids were mainly distributed in China (83%, 54/65). Evolutionary analysis can divide IncHI5 plasmids into two groups, namely Groups I/II, of which Group II was more widely distributed worldwide. This study showed that Enterobacteriaceae, especially Klebsiella, was the main host for IncHI5 plasmid. Almost all IncHI5 plasmids carried multiple types of antibiotic resistance genes, related to Tn1696 or Tn6535. The IncHI5 plasmids should be of continuing interest as good repositories for antibiotic resistance genes.

Effects of short-term waterfall forest aerosol air exposure on rat lung proteomics.

Background: Chronic exposure to airborne microparticles has been shown to increase the incidence of several chronic diseases. Previous studies have found that waterfall forest aerosols contribute to a diminished immune stress response in patients with asthma. However, the specific effects of short-term waterfall forest aerosol exposure on lung proteins have not been fully elucidated. Methods: This study used liquid chromatography-tandem mass spectrometry (LC-MS) to analyze changes in protein expression in the lungs of rats exposed to short-term waterfall forest aerosol environments. Specific protein markers were identified using bioconductivity analysis screening and validated using immunohistochemistry. Results: Waterfall forest aerosol environment exposure on day 5 downregulated the expression of the classical inflammatory pathway nuclear factor κB (NF-κB) signaling pathway. As the waterfall forest aerosol environment increased due to the duration of exposure, it was involved in oxidative phosphorylation and then hormone signaling in lung cells from the very beginning. In contrast, at day 15 of exposure, there is an effect on the regulation of the immune-related high-affinity IgE receptor pathway. In addition, iron-sulfur Rieske protein (Uqcrfs1), mitochondrial Tu translation elongation factor (Tufm) and ribosomal protein L4 (Rpl4) were identified as possible bioindicators for the evaluation of air quality. Conclusions: These results provide a comprehensive proteomic analysis that supports the positive contribution of a good air quality environment to lung health.

Identification and validation of a T-cell-related MIR600HG/hsa-mir-21-5p competing endogenous RNA network in tuberculosis activation based on integrated bioinformatics approaches.

Background: T cells play critical roles in the progression of tuberculosis (TB); however, knowledge regarding these molecular mechanisms remains inadequate. This study constructed a critical ceRNA network was constructed to identify the potentially important role of TB activation via T-cell regulation. Methods: We performed integrated bioinformatics analysis in a randomly selected training set from the GSE37250 dataset. After estimating the abundance of 18 types of T cells using ImmuCellAI, critical T-cell subsets were determined by their diagnostic accuracy in distinguishing active from latent TB. We then identified the critical genes associated with T-cell subsets in TB activation through co-expression analysis and PPI network prediction. Then, the ceRNA network was constructed based on RNA complementarity detection on the DIANA-LncBase and mirDIP platform. The gene biomarkers included in the ceRNA network were lncRNA, miRNA, and targeting mRNA. We then applied an elastic net regression model to develop a diagnostic classifier to assess the significance of the gene biomarkers in clinical applications. Internal and external validations were performed to assess the repeatability and generalizability. Results: We identified CD4+ T, Tr1, nTreg, iTreg, and Tfh as T cells critical for TB activation. A ceRNA network mediated by the MIR600HG/hsa-mir-21-5p axis was constructed, in which the significant gene cluster regulated the critical T subsets in TB activation. MIR600HG, hsa-mir-21-5p, and five targeting mRNAs (BCL11B, ETS1, EPHA4, KLF12, and KMT2A) were identified as gene biomarkers. The elastic net diagnostic classifier accurately distinguished active TB from latent. The validation analysis confirmed that our findings had high generalizability in different host background cases. Conclusion: The findings of this study provided novel insight into the underlying mechanisms of TB activation and identifying prospective biomarkers for clinical applications.

Mechanism of the Huangguoshu waterfall forest environment's promotive effect on human health in Guizhou, China.

Background: The aim of this study was to investigate the specific mechanisms underlying the human health-promoting effects of the forest environment at Huangguoshu Falls, Guizhou, China. Methods: Ninety-five participants were recruited and an eye tracker was used to record fixation and sweep indices. A questionnaire was also used to evaluate the effects of different subject environments on human emotions, perceived recovery and preferences. Thereafter, 24 participants with chronic fatigue syndrome (CFS) were recruited and the participants' fatigue and stress-related scale indices and inflammatory factor levels were examined. Serum metabolites of the participants under different time waterfall forest interventions were detected by ultra performance liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC-Q/TOF-MS). Results: Eye tracking paradigm analysis showed that the "waterfall" element was the most interesting element for participants and that the "charm" of the waterfall forest environment could be well perceived by participants. Scores on the Fatigue Scale, Anxiety Scale and Depression Scale decreased as the duration of treatment in the waterfall forest environment increased. Levels of inflammatory factors decreased after treatment in the waterfall forest environment. At the same time the level of antioxidants, represented by L-ascorbic acid, increased significantly. Conclusions: The charm of the Huangguoshu waterfall scenery could be perceived by the participants and have a positive modulating effect on mood and cognitive function. In addition, the unique mixture of negative oxygen ions in this environment can increase the content of endogenous antioxidants and balance the metabolism of choline and amino acids.

Emergence of Extensively Drug-Resistant ST170 Citrobacter portucalensis with Plasmids pK218-KPC, pK218-NDM, and pK218-SHV from a Tertiary Hospital, China.

The objective of this study is to characterize the molecular mechanism of a clinical carbapenem-resistant Citrobacter portucalensis strain K218, which coproduces KPC and NDM carbapenemases. K218 was isolated from a patient's blood sample in a Chinese tertiary hospital. Carbapenemases were detected by the immunocolloidal gold technique. The MIC values were determined by VITEK2. Whole-genome sequencing was performed on K218 and sequence data were analyzed using phylogenetics and extensive genomic comparison. This study reveals that K218 contains a single 5.08 Mb chromosome (51.8% GC content) and four plasmids, pK218-KPC (106 Kb), pK218-NDM (111 Kb), pK218-SHV (191 Kb), and pK218-NR (5 Kb). Twenty-nine types of antibiotic resistance genes were carried on K218, including blaKPC-2 harbored on pK218-KPC and blaNDM-1 harbored on pK218-NDM. Detailed comparison of related plasmids of pK218-KPC, pK218-NDM, and pK218-SHV showed that they shared similar conserved backbone regions, respectively. Comprehensive annotation revealed large accessory modules were recombined on the genome of K218. Further analysis speculated that mobile genetic elements bearing abundant resistance genes facilitated the formation of these accessory modules. In conclusion, this study provides an in-depth understanding of the genomic characterization of K218, an extensively drug-resistant C. portucalensis strain coproducing NDM and KPC carbapenemase. To the best of our knowledge, this is the first report of C. portucalensis strain coharboring blaKPC-2 and blaNDM-1 from the clinical setting. IMPORTANCE This is the first report of extensively drug-resistant C. portucalensis harboring both blaKPC-2 and blaNDM-1. This study will not only extend the understanding of the structural dissection of plasmids and chromosomes carried in C. portucalensis, but also expand knowledge of the genetic environment of the blaKPC-2 and blaNDM-1 genes. blaKPC-2 and blaNDM-1 genes have been suggested to facilitate the propagation and persistence of their host bacteria under different antimicrobial selection pressures. Large accessory regions carrying blaKPC-2 and blaNDM-1 genes have become hot spots for transposition and integration, and their structural variation and evolution should receive attention. The multidrug-resistant plasmids pK218-KPC, pK218-NDM, and pK218-SHV with several multidrug resistance regions and the chromosome cK218 with two novel transposons Tn7410 and Tn7411 contribute to the formation of extensively drug-resistant C. portucalensis.