LGP2 Facilitates Bacterial Escape through Binding Peptidoglycan via EEK Motif and Suppressing NOD2-RIP2 Axis in Cyprinidae and Xenocyprididae Families.

RIG-I-like receptors and NOD-like receptors play pivotal roles in recognizing microbe-associated molecular patterns and initiating immune responses. The LGP2 and NOD2 proteins are important members of the RIG-I-like receptor and NOD-like receptor families, recognizing viral RNA and bacterial peptidoglycan (PGN), respectively. However, in some instances bacterial infections can induce LPG2 expression via a mechanism that remains largely unknown. In the current study, we found that LGP2 can compete with NOD2 for PGN binding and inhibit antibacterial immunity by suppressing the NOD2-RIP2 axis. Recombinant CiLGP2 (Ctenopharyngodon idella LGP2) produced using either prokaryotic or eukaryotic expression platform can bind PGN and bacteria in pull-down and ELISA assays. Comparative protein structure models and intermolecular interaction prediction calculations as well as pull-down and colocalization experiments indicated that CiLGP2 binds PGN via its EEK motif with species and structural specificity. EEK deletion abolished PGN binding of CiLGP2, but insertion of the CiLGP2 EEK motif into zebrafish and mouse LGP2 did not confer PGN binding activity. CiLGP2 also facilitates bacterial replication by interacting with CiNOD2 to suppress expression of NOD2-RIP2 pathway genes. Sequence analysis and experimental verification demonstrated that LGP2 having EEK motif that can negatively regulate antibacterial immune function is present in Cyprinidae and Xenocyprididae families. These results show that LGP2 containing EEK motif competes with NOD2 for PGN binding and suppresses antibacterial immunity by inhibiting the NOD2-RIP2 axis, indicating that LGP2 plays a crucial negative role in antibacterial response beyond its classical regulatory function in antiviral immunity.

Eu(III) functionalized ZnMOF based efficient dual-emission sensor integrated with self-calibrating logic gate for intelligent detection of epinephrine.

The rapid detection of epinephrine (EPI) in serum holds immense importance in the early disease diagnosis and regular monitoring. On the basis of the coordination post-synthetic modification (PSM) strategy, a Eu3+ functionalized ZnMOF (Eu3+@ZnMOF) was fabricated by anchoring the Eu3+ ions within the microchannels of ZnMOF as secondary luminescent centers. Benefiting from two independent luminescent centers, the prepared Eu3+@ZnMOF shows great potential as a multi-signal self-calibrating luminescent sensor in visually and efficiently detecting serum EPI levels, with high reliability, fast response time, excellentrecycleability, and low detection limits of 17.8 ng/mL. Additionally, an intelligent sensing system was designed in accurately and reliably detecting serum EPI levels, based on the designed self-calibrating logic gates. Furthermore, the possible sensing mechanisms were elucidated through theoretical calculations as well as spectral overlaps. This work provides an effective and promising strategy for developing MOFs-based self-calibrating intelligent sensing platforms to detect bioactive molecules in bodily fluids.

Gibberellin-Mediated Sensitivity of Rice Roots to Aluminum Stress.

Aluminum toxicity poses a significant constraint on crop production in acidic soils. While phytohormones are recognized for their pivotal role in mediating plant responses to aluminum stress, the specific involvement of gibberellin (GA) in regulating aluminum tolerance remains unexplored. In this study, we demonstrate that external GA exacerbates the inhibitory impact of aluminum stress on root growth of rice seedlings, concurrently promoting reactive oxygen species (ROS) accumulation. Furthermore, rice plants overexpressing the GA synthesis gene SD1 exhibit enhanced sensitivity to aluminum stress. In contrast, the slr1 gain-of-function mutant, characterized by impeded GA signaling, displays enhanced tolerance to aluminum stress, suggesting the negative regulatory role of GA in rice resistance to aluminum-induced toxicity. We also reveal that GA application suppresses the expression of crucial aluminum tolerance genes in rice, including Al resistance transcription factor 1 (ART1), Nramp aluminum transporter 1 (OsNramp4), and Sensitive to Aluminum 1 (SAL1). Conversely, the slr1 mutant exhibits up-regulated expression of these genes compared to the wild type. In summary, our results shed light on the inhibitory effect of GA in rice resistance to aluminum stress, contributing to a theoretical foundation for unraveling the intricate mechanisms of plant hormones in regulating aluminum tolerance.

The evolution of preexisting primary immune thrombocytopenia after COVID-19 onset: A nationally representative, prospective, multicentre, observational study.

The symptoms in patients with primary immune thrombocytopenia (ITP) after COVID-19 onset remain largely unclear. The aim of this study was to describe the platelet count fluctuations in ITP patients following the diagnosis of COVID-19. A prospective multicentre observational study was conducted from December 15th, 2022, to January 31st, 2023 in 39 general hospitals across China. Patients with preexisting primary ITP who were newly diagnosed with COVID-19 were enrolled. A total of 1216 ITP patients with newly-diagnosed COVID-19 were enrolled. 375 (30.8%) patients experienced ITP exacerbation within eight weeks after the diagnosis of COVID-19, and most exacerbation (266/375, 70.9%) developed in the first two weeks. Immunosuppressive therapy for ITP and severe/critical COVID-19 infection were independent variables associated with ITP exacerbation. Overall the platelet count had a transient increasing trend, and the platelet peak value occurred at two weeks after COVID-19 infection. Then, the platelet count decreased to the baseline level in the following weeks. The platelet count had a transient increasing trend in ITP patients following the diagnosis of COVID-19. ITP exacerbation only occurred in less than one-third of ITP patients. Nonimmunosuppressive therapy may have an advantage to prevent ITP exacerbation during COVID-19.

Allosteric inhibitor of SHP2 enhances macrophage endocytosis and bacteria elimination by increasing caveolae activation and protects against bacterial sepsis.

The uncontrolled bacterial infection-induced cytokine storm and sequential immunosuppression are commonly observed in septic patients, which indicates that the activation of phagocytic cells and the efficient and timely elimination of bacteria are crucial for combating bacterial infections. However, the role of dysregulated immune cells and their disrupted function in sepsis remains unclear. Here, we found that macrophages exhibited the impaired endocytosis capabilities in sepsis by Single-cell RNA sequencing and bulk RNA sequencing. Caveolae protein Caveolin-1 (Cav-1) of macrophages was inactivated by SHP2 rapidly during Escherichia coli (E.coli) infection. Allosteric inhibitor of SHP2 effectively maintains Cav-1 phosphorylation to enhance macrophage to endocytose and eliminate bacteria. Additionally, TLR4 endocytosis of macrophage was also enhanced upon E.coli infection by SHP099, inducing an increased and rapidly resolved inflammatory response. In vivo, pretreatment or posttreatment with inhibitor of SHP2 significantly reduced the bacterial burden in organs and mortality of mice subjected E.coli infection or CLP-induced sepsis. The cotreatment of inhibitor of SHP2 with an antibiotic conferred complete protection against mortality in mice. Our findings suggest that Cav-1-mediated endocytosis and bacterial elimination may play a critical role in the pathogenesis of sepsis, highlighting inhibitor of SHP2 as a potential therapeutic agent for sepsis.

Role of autophagy and mitophagy of group 2 innate lymphoid cells in allergic and local allergic rhinitis.

Background: Roles of ILC2s in allergic rhinitis (AR) and local allergic rhinitis (LAR) are unclear. In this study, we are determined to find the levels of autophagy and mitophagy of ILC2s in allergic nasal inflammation. Methods: ELISA was used to detect type 2 inflammatory cytokines. Hematoxylin and eosin (H&E) staining were used to compare the eosinophil (EOS) infiltration of nasal tissue specimens. Flow cytometry was used to detect the levels of ILC2s and Th2 cells. Immunohistochemistry (IHC) and Western blot (WB) were used to detect the levels of Beclin1, LC3, p62, PINK1, Parkin, FUNDC1, and BNIP3 in nasal mucosa. The levels of autophagy related proteins and mitophagy related proteins of the ILC2s were detected by WB. The number of autophagosomes of ILC2s was observed by transmission electron microscopy. The co-localization levels of GFP-LC3 and Mito tracker in ILC2s were observed by confocal microscopy using immunofluorescence. Results: We found that the level of type 2 inflammation in AR and LAR mice was significantly increased. The levels of autophagy and mitophagy of AR and LAR mice in nasal mucosa and ILC2s were both increased. Conclusions: ILC2s may be associated with the occurrence and development of nasal allergic inflammation. The abnormal increase of autophagy and mitophagy levels in the nose may be associated with the incidence of AR and LAR. Abnormal autophagy and mitophagy levels of ILC2s cells may be one of the causes of allergic nasal inflammation.

Molecular classification of small cell lung cancer subtypes: Characteristics, prognostic factors, and clinical translation.

ABSTRACT: Small cell lung cancer (SCLC) is a highly malignant tumor with a very poor prognosis; therefore, more effective treatments are urgently needed for patients afflicted with the disease. In recent years, emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology, metastasis, immune microenvironment, and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes. Additionally, advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease. Herein, we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.

USP10 promotes migration and cisplatin resistance in esophageal squamous cell carcinoma cells.

Cisplatin-based chemotherapy is the main treatment option for advanced or metastatic esophageal squamous cell carcinoma (ESCC). However, most ESCC patients develop drug resistance within 2 years after receiving cisplatin chemotherapy. Ubiquitin-specific protease 10 (USP10) is abnormally expressed in a variety of cancers, but the mechanistic roles of USP10 in ESCC are still obscure. Here, the effects of USP10 on the migration and cisplatin resistance of ESCC in vivo and in vitro and the underlying mechanisms have been investigated by bioinformatics analysis, RT-PCR, western blotting, immunoprecipitation, immunohistochemistry, cell migration and MTS cell proliferation assays, deubiquitination assay, and mouse tail vein injection model. USP10 was significantly up-regulated in ESCC tissues compared with adjacent normal tissues in both public databases and clinical samples and was closely associated with overall survival. Subsequent results revealed that USP10 contributed to the migration and cisplatin resistance of ESCC cells, while knocking down USP10 in cisplatin-resistant cells exhibited opposite effects in vitro and in vivo. Further Co-IP experiments showed that integrin ß1 and YAP might be targets for USP10 deubiquitination. Moreover, deficiency of USP10 significantly inhibited the migrative and chemo-resistant abilities of ESCC cells, which could be majorly reversed by integrin ß1 or YAP reconstitution. Altogether, USP10 was required for migration and cisplatin resistance in ESCC through deubiquinating and stabilizing integrin ß1/YAP, highlighting that inhibition of USP10 may be a potential therapeutic strategy for ESCC.

Phillyrin ameliorates influenza a virus-induced pulmonary inflammation by antagonizing CXCR2 and inhibiting NLRP3 inflammasome activation.

Influenza is an acute viral respiratory illness with high morbidity rates worldwide. Excessive pulmonary inflammation is the main characteristic of lethal influenza A virus (IAV) infections. Therapeutic options for managing influenza are limited to vaccines and some antiviral medications. Phillyrin is one of the major bioactive components of the Chinese herbal medicine Forsythia suspensa, which has the functions of sterilization, heat clearing and detoxification. In this work, the effect and mechanism of phillyrin on H1N1 influenza (PR8)-induced pneumonia were investigated. We reported that phillyrin (15 mg/kg) treatment after viral challenge significantly improved the weight loss, ameliorated pulmonary inflammation and inhibited the accumulation of multiple cytokines and chemokines in bronchoalveolar lavage fluid on 7 days post infection (dpi). In vitro, phillyrin suppressed influenza viral replication (Matrixprotein and nucleoprotein messenger RNA level) and reduced influenza virus-induced cytopathic effect (CPE). Furthermore,chemokine receptor CXCR2 was confirmed to be markedly inhibited by phillyrin. Surface plasmon resonance results reveal that phillyrin exhibits binding affinity to CXCR2, having a binding affinity constant (KD) value of 1.858e-5 M, suggesting that CXCR2 is a potential therapeutic target for phillyrin. Moreover, phillyrin inhibited the mRNA and protein expression levels of Caspase1, ASC and NLRP3 in the lungs of mice with H1N1-induced pneumonia.This study reveals that phillyrin ameliorates IAV-induced pulmonary inflammation by antagonizing CXCR2 and inhibiting NLRP3 inflammasome activation partly.

Y-mediated optimization of 3DG-PbO2 anode for electrochemical degradation of PFOS.

In our previous study, the three-dimensional graphene-modified PbO2 (3DG-PbO2) anode was prepared for the effective degradation of perfluorooctanesulfonat (PFOS) by the electrochemical oxidation process. However, the mineralization efficiency of PFOS at the 3DG-PbO2 anode still needs to be further improved due to the recalcitrance of PFOS. Thus, in this study, the yttrium (Y) was doped into the 3DG-PbO2 film to further improve the electrochemical activity of the PbO2 anode. To optimize the doping amount of Y, three Y and 3DG codoped PbO2 anodes were fabricated with different Y3+ concentrations of 5, 15, and 30 mM in the electroplating solution, which were named Y/3DG-PbO2-5, Y/3DG-PbO2-15 and Y/3DG-PbO2-30, respectively. The results of morphological, structural, and electrochemical characterization revealed that doping Y into the 3DG-PbO2 anode further refined the ß-PbO2 crystals, increased the oxygen evolution overpotential and active sites, and reduced the electron transfer resistance, resulting in a superior electrocatalytic activity. Among all the prepared anodes, the Y/3DG-PbO2-15 anode exhibited the best activity for electrochemical oxidation of PFOS. After 120 min of electrolysis, the TOC removal efficiency was 80.89% with Y/3DG-PbO2-15 anode, greatly higher than 69.13% with 3DG-PbO2 anode. In addition, the effect of operating parameters on PFOS removal was analyzed by response surface, and the obtained optimum values of current density, initial PFOS concentration, pH, and Na2SO4 concentration were 50 mA/cm2, 12.21 mg/L, 5.39, and 0.01 M, respectively. Under the optimal conditions, the PFOS removal efficiency reached up to 97.16% after 40 min of electrolysis. The results of the present study confirmed that the Y/3DG-PbO2 was a promising anode for electrocatalytic oxidation of persistent organic pollutants.

Characteristics and therapeutic approaches for patients diagnosed with T-ALL/LBL exhibiting t(8;14)(q24;q11)/TCRA/D:MYC translocation.

T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients with t(8;14)(q24;q11)/TCRA/D::MYC translocation represent a rare subgroup, with an aggressive course. In our retrospective analysis of 14 patients, all were identified during refractory or relapsed stages (5 primary tumor, 9 relapse). Notably, extramedullary invasion was detected in most patients. Four exhibited STIL::TAL1 translocation, and six demonstrated CDKN2A/B gene loss. The therapeutic outcomes were notably poor for all seven patients who received only chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT); all eventually succumbed to the disease with a median OS of 3 months. In the application of CD7 CAR-T therapy in six patients, five achieved CR. Of the four patients who underwent HSCT following CAR-T therapy, all have remained disease-free. The prognosis for T-ALL/LBL patients with t(8;14) translocation remains bleak, but interventions involving CD7 CAR-T may offer a potential pathway to CR. HSCT following CAR-T could be a viable strategy for long-term survival.

Heterometallic ZnHoMOF as a Dual-Responsive Luminescence Sensor for Efficient Detection of Hippuric Acid Biomarker and Nitrofuran Antibiotics.

Developing efficient and sensitive MOF-based luminescence sensors for bioactive molecule detection is of great significance and remains a challenge. Benefiting from favorable chemical and thermal stability, as well as excellent luminescence performance, a porous Zn(II)Ho(III) heterometallic-organic framework (ZnHoMOF) was selected here as a bifunctional luminescence sensor for the early diagnosis of a toluene exposure biomarker of hippuric acid (HA) through "turn-on" luminescence enhancing response and the daily monitoring of NFT/NFZ antibiotics through "turn-off" quenching effects in aqueous media with high sensitivity, acceptable selectivity, good anti-interference, exceptional recyclability performance, and low detection limits (LODs) of 0.7 ppm for HA, 0.04 ppm for NFT, and 0.05 ppm for NFZ. Moreover, the developed sensor was employed to quantify HA in diluted urine samples and NFT/NFZ in natural river water with satisfactory results. In addition, the sensing mechanisms of ZnHoMOF as a dual-response chemosensor in efficient detection of HA and NFT/NFZ antibiotics were conducted from the view of photo-induced electron transfer (PET), as well as inner filter effects (IFEs), with the help of time-dependent density functional theory (TD-DFT) and spectral overlap experiments.

Quantitation of phenylalanine and tyrosine from dried Blood/Plasma spots with impregnated stable isotope internal standards (SIIS) by FIA-SRM.

BACKGROUND: Dried Blood Spot (DBS) analysis has been used for identification and quantification of diseases and disorders in large populations. Simply collecting blood or plasma samples on cotton paper, followed with an organic solvent extraction, many small molecules can be detected and quantified. In a typical procedure of DBS analysis in newborn screening, stable isotope internal standards (SIIS) are added to extraction solvent as a reference. However, this way of employing SIIS does not reflect extraction efficiency, or protein binding issues, nor does it reflect potential degradation that could occur. In addition, punched-out discs from larger DBS are known to have imprecision typically ≥ 15%. METHODS: We developed and tested an approach, internal quantitative DBS (iqDBS), which delivers an exact volume of whole blood or plasma to a paper disc that is impregnated with a dried concentration of SIIS for quantitation. Amino acids were derivatized to make butyl esters and measured using Flow Injection Analysis with Selected Reaction Monitoring (FIA-SRM). RESULTS: We demonstrated with phenylalanine and tyrosine improved sensitivity and accuracy by applying iqDBS. CONCLUSIONS: We established a new method for quantitative analysis of small molecules from dried blood spots that incorporates stable isotope internal standard at the time of blood collection.

A life-threatening bleeding prediction model for immune thrombocytopenia based on personalized machine learning: a nationwide prospective cohort study.

Rare but critical bleeding events in primary immune thrombocytopenia (ITP) present life-threatening complications in patients with ITP, which severely affect their prognosis, quality of life, and treatment decisions. Although several studies have investigated the risk factors related to critical bleeding in ITP, large sample size data, consistent definitions, large-scale multicenter findings, and prediction models for critical bleeding events in patients with ITP are unavailable. For the first time, in this study, we applied the newly proposed critical ITP bleeding criteria by the International Society on Thrombosis and Hemostasis for large sample size data and developed the first machine learning (ML)-based online application for predict critical ITP bleeding. In this research, we developed and externally tested an ML-based model for determining the risk of critical bleeding events in patients with ITP using large multicenter data across China. Retrospective data from 8 medical centers across the country were obtained for model development and prospectively tested in 39 medical centers across the country over a year. This system exhibited good predictive capabilities for training, validation, and test datasets. This convenient web-based tool based on a novel algorithm can rapidly identify the bleeding risk profile of patients with ITP and facilitate clinical decision-making and reduce the occurrence of adversities.

Romiplostim in primary immune thrombocytopenia that is persistent or chronic: phase III multicenter, randomized, placebo-controlled clinical trial in China.

Background: Multiple trials have confirmed that romiplostim could increase platelet count in individuals with primary immune thrombocytopenia (ITP), but no related study has assessed Chinese patients. Objectives: To assess the effectiveness of romiplostim as a second-line treatment of persistent or chronic ITP in Chinese adults. Methods: This phase III multicenter, randomized, placebo-controlled, double-blind, then open-label clinical trial (NCT02868099, CTR20150395) was conducted at 28 investigational sites in China. The patients were randomly assigned (3:1) to romiplostim (starting and maximum doses of 1 and 10 µg/kg, respectively) or placebo for 9 weeks (double-blind period), followed by the open-label period (both groups administered romiplostim) to week 22. The primary endpoint was the time (in weeks) during which platelet counts were ≥50 × 109/L in the double-blind period. Results: In this study, 202 patients (romiplostim, n = 151; placebo, n = 51) started the treatment. The median (range) numbers of weeks with platelet response after 6 weeks of treatment were 2 (0-6) and 0 (0-2) in patients administered romiplostim and placebo, respectively (P < .001). During the double-blind period, the proportions of patients with treatment-emergent adverse events were comparable between the romiplostim and placebo groups (82.8% vs 82.4%). The treatment-emergent adverse event with ≥10% difference in incidence between these 2 groups was injection site bleeding (1.3% vs 11.8%). Conclusion: Romiplostim significantly increased the time with maintained platelet response in patients with persistent or chronic ITP in comparison with placebo. No new safety signal was observed. Trial registration: ClinicalTrials.gov, NCT02868099. www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml, CTR20150395.

Dosage effect of micron zero-valent iron during thermophilic anaerobic digestion of waste activated sludge: Performance and functional community.

This work examined the performance and microbial traits in a thermophilic anaerobic digestion (TAD) of waste activated sludge that was impacted by micron zero valent iron (mZVI). Results showed that methane production was promoted by 0.8, 11.9, and 12.0 times, respectively, when mZVI was at dosages of 25, 100, and 250 mg/g total solid (TS). Also, the consumption of volatile fatty acids was increased by mZVI at higher dosages (100 and 250 mg/g TS). Furthermore, 16S rRNA sequencing demonstrated that microbial community stabilized after day 18 regardless of the dosage of mZVI, and that different dosages of mZVI induced different shifts in the functional community of the archaea rather than the bacteria involved in TAD. As a result, mZVI at 100 mg/g TS could increase the relative abundance of archaeal genera Methanothermobacter the most, increasing by 22.8% at the end of TAD compared to CK. Besides, redundancy analysis revealed that the physicochemical properties explained 79.65% and 89.10% of the variations of bacterial and archaeal abundance, respectively. Also, the findings of the correlation analysis revealed that total dissolved iron, ferrous iron, pH, and ammonium nitrogen, may be the key divers of altering functional communities, particularly archaea. Moreover, mZVI at 100 and 250 mg/g TS boosted the metabolic pathways of environmental information processing (ABC transporters) in bacteria and carbon metabolism and methane metabolism for archaea, as well as relative abundances of enzymes and their activities involved in various methanogenic pathways. This study provides new perspectives on the application of mZVI in solid wastes treatments.

Global research trends on B7-H3 for cancer immunotherapy: A bibliometric analysis (2012-2022).

Immunotherapy has revolutionized cancer treatment. B7-H3 is a promising target for cancer immunotherapy (CI). The present study aimed to utilize bibliometric methods to assess the current research status and explore future trends in the use of B7-H3 for CI. We collected publications related to B7-H3/CI from the Clarivate Web of Science Core Collection database. VOSviewer, Microsoft Excel, the bibliometrix R package, and an online platform were used to conduct qualitative and visualized analyses of the literature. A total of 555 papers were analyzed, revealing a significant increase in annual publications since 2018. The most productive countries were China and the USA, and the leading institutions were Soochow University and Sichuan University. Zang and Ferrone were the most popular authors. Among the journals, Frontiers in Immunology had the highest number of papers, whereas Clinical Cancer Research was the most influential. Historical citation analysis reveals the development of B7-H3/CI. Top-cited papers and keyword analyses were performed to highlight current hotspots in the domain. Using cluster analysis, we classified all keywords into four clusters: "immunotherapy," "co-stimulatory molecule," "B7 family," and "PD-L1." Finally, Trends analysis suggested that future research might focus on "chimeric antigen receptor," "pathways," and "targeting B7-H3." This is the first bibliometric crosstalk analysis between B7-H3 and CI. Our study illustrates that the topic of B7-H3/CI is very popular and has great clinical implications and that the number of correlative publications will continue to increase. B7-H3-based CI may lead to new research trends.

Diagnostic and Prognostic Value of Aspartate Transaminase-to-platelet Ratio Index, Gamma-glutamyl Transpeptidase-to-platelet Ratio, and Fibrosis-4 for Compensated Hepatitis B-related Liver Cirrhosis.

The aim of this study was to investigate a serodiagnostic model as a substitute for liver stiffness measurement (LSM) for diagnosing compensated liver cirrhosis (LC). This retrospective study included 150 patients with compensated hepatitis B-related LC and 153 with chronic Hepatitis B virus (HBV) infection. It was conducted from May 2017 to June 2022 at Qinghai University Affiliated Hospital, China. The values of LSM, aspartate transaminase-to-platelet ratio index (APRI), gamma-glutamyl transpeptidase-to-platelet ratio (GPR), and fibrosis-4 (FIB-4) were evaluated in all admitted patients. The diagnostic value of APRI, GPR, FIB-4, and LSM was assessed using the receiver operating characteristic (ROC) curve. FIB-4 score (AUC=0.842; specificity=77.8%; sensitivity=80.7%; cut-off=2.824) was the best substitute for LSM from the three serum scoring models. The Cox regression model indicated that a FIB-4 score ≥2.824 was an independent predictor of prognosis for compensated hepatitis B-related LC (HR=1.15, 95%CI: 1.07-1.23, p<0.001). This study's findings suggested that FIB-4 could be the best substitute for LSM and may help to assess LC prognosis. Key Words: APRI, GPR, FIB-4, LSM, Diagnosis, Liver cirrhosis.

Stringent Response Factor DksA Contributes to Fatty Acid Degradation Function to Influence Cell Membrane Stability and Polymyxin B Resistance of Yersinia enterocolitica.

DksA is a proteobacterial regulator that binds directly to the secondary channel of RNA polymerase with (p)ppGpp and is responsible for various bacterial physiological activities. While (p)ppGpp is known to be involved in the regulation and response of fatty acid metabolism pathways in many foodborne pathogens, the role of DksA in this process has yet to be clarified. This study aimed to characterize the function of DksA on fatty acid metabolism and cell membrane structure in Yersinia enterocolitica. Therefore, comparison analysis of gene expression, growth conditions, and membrane permeabilization among the wide-type (WT), DksA-deficient mutant (YEND), and the complemented strain was carried out. It confirmed that deletion of DksA led to a more than four-fold decrease in the expression of fatty acid degradation genes, including fadADEIJ. Additionally, YEND exhibited a smaller growth gap compared to the WT strain at low temperatures, indicating that DksA is not required for the growth of Y. enterocolitica in cold environments. Given that polymyxin B is a cationic antimicrobial peptide that targets the cell membrane, the roles of DksA under polymyxin B exposure were also characterized. It was found that DksA positively regulates the integrity of the inner and outer membranes of Y. enterocolitica under polymyxin B, preventing the leakage of intracellular nucleic acids and proteins and ultimately reducing the sensitivity of Y. enterocolitica to polymyxin B. Taken together, this study provides insights into the functions of DksA and paves the way for novel fungicide development.

Association Between Visceral Fat Area and Cancer Prognosis: A Population-Based Multicenter Prospective Study.

BACKGROUND: Diverse indicators have been used to represent adipose tissue, while the relationship between body adipose mass and the prognosis of patients with cancer remains controversial. OBJECTIVE: This study aimed to explore the indicators of optimal body composition that represent body fat mass to predict risk of cancer-related mortality. METHODS: We conducted a population-based multicenter prospective cohort study of patients with initial cancer between February 2012 and September 2020. Clinical information, body composition indicators, hematologic test results, and follow-up data were collected. Body composition indicators were analyzed using principal component analysis to select the most representative indicators, and the cutoff value was set according to the optimal stratification method. The hazard ratio (HR) for mortality was calculated using Cox proportional hazards regression models. RESULTS: Among 14,018 patients with complete body composition data, visceral fat area (VFA) is a more optimal indicator for body fat content (principal component index: 0.961) than body mass index (principal component index: 0.850). The cutoff points for VFA in terms of time to mortality were 66 cm2 and 102 cm2 for gastric/esophageal cancer and other cancers, respectively. Among the 2788 patients treated systemically, multivariate analyses demonstrated that a lower VFA was associated with a higher risk of death in patients with cancer of diverse types (HR: 1.33; 95% CI: 1.08, 1.64; P = 0.007), especially gastric cancer (HR: 2.13; 95% CI: 1.3, 3.49; P = 0.003), colorectal cancer HR: 1.81; 95% CI: 1.06, 3.08; P = 0.030) and nonsmall-cell lung cancer (HR: 1.27; 95% CI: 1.01, 1.59; P = 0.040). CONCLUSION: VFA is an independent prognostic indicator of muscle mass in patients with diverse types of cancer, particularly gastric, colorectal, and nonsmall-cell lung cancers. TRIAL REGISTRATION NUMBER: ChiCTR1800020329.