The two-component system TtrRS boosts Vibrio parahaemolyticus colonization by exploiting sulfur compounds in host gut.

One of the greatest challenges encountered by enteric pathogens is responding to rapid changes of nutrient availability in host. However, the mechanisms by which pathogens sense gastrointestinal signals and exploit available host nutrients for proliferation remain largely unknown. Here, we identified a two-component system in Vibrio parahaemolyticus, TtrRS, which senses environmental tetrathionate and subsequently activates the transcription of the ttrRS-ttrBCA-tsdBA gene cluster to promote V. parahaemolyticus colonization of adult mice. We demonstrated that TsdBA confers the ability of thiosulfate oxidation to produce tetrathionate which is sensed by TtrRS. TtrRS autoregulates and directly activates the transcription of the ttrBCA and tsdBA gene clusters. Activated TtrBCA promotes bacterial growth under micro-aerobic conditions by inducing the reduction of both tetrathionate and thiosulfate. TtrBCA and TsdBA activation by TtrRS is important for V. parahaemolyticus to colonize adult mice. Therefore, TtrRS and their target genes constitute a tetrathionate-responsive genetic circuit to exploit the host available sulfur compounds, which further contributes to the intestinal colonization of V. parahaemolyticus.

Mutations of RAS genes identified in acute myeloid leukemia affect glycerophospholipid metabolism pathway.

Background: Acute myeloid leukemia (AML) is a malignant disease originating from myeloid hematopoietic stem cells. Recent studies have shown that certain gene mutations promote tumor cell survival and affect the prognosis of patients by affecting metabolic mechanisms in tumor cells. RAS gene mutations are prevalent in AML, and the RAS signaling pathway is closely related to many metabolic pathways. However, the effects of different RAS gene mutations on AML cell metabolism are unclear. Objectives: The main purpose of this study was to explore the effect of RAS gene mutation on the metabolic pathway of tumor cells. Methods: In this study, we first used a retrovirus carrying a mutant gene to prepare Ba/F3 cell lines with RAS gene mutations, and then compared full-transcriptome data of Ba/F3 cells before and after RAS gene mutation and found that differentially expressed genes after NRASQ61K and KRASG12V mutation. Results: We found a total of 1899 differentially expressed genes after NRASQ61K and KRASG12V mutation. 1089 of these genes were involved in metabolic processes, of which 167 genes were enriched in metabolism-related pathways. In metabolism-related pathways, differential genes were associated with the lipid metabolism pathway. Moreover, by comparing groups, we found that the expression of the DGKzeta and PLA2G4A genes in the glycerophospholipid metabolism pathway was significantly upregulated. Conclusion: In conclusion, our study revealed that RAS gene mutation is closely related to the glycerophospholipid metabolism pathway in Ba/F3 cells, which may contribute to new precision therapy strategies and the development and application of new therapeutic drugs for AML.

Relationship between the Co-Continuous Morphology of Immiscible Polymer Blends and the Structure of an In Situ Formed Graft Copolymer.

In order to get stable co-continuous morphology in immiscible polymer blends, besides reducing the interfacial tension, the compatibilizer should not only promote the formation of flat interface between different phases, but also not hinder the coalescence of the dispersed phase. Herein, the relationship between the morphology of the compatibilized polystyrene/nylon 6/styrene-maleic anhydride (PS/PA6/SMA) immiscible polymer blends and the structures of the in-situ formed SMA-g-PA6 graft copolymers as well as the processing conditions are studied. Two kinds of SMA are used: SMA28 (28 wt.% MAH) and SMA11 (11 wt.% MAH). After melt blending with PA6, the in-situ formed copolymer SMA28-g-PA6 has on average of four PA6 side chains, while that of SMA11-g-PA6 has only one. Dissipative particle dynamics simulation results indicate that both SMA28-g-PA6 copolymer and PS/PA6/SMA28 blends tend to form co-continuous structure, while those related to SMA11 intend to form sea-island morphologies. These results are correct only at relatively low rotor speed (60 rpm). When the rotor speed is higher (105 rpm), sea-island morphologies are obtained in SMA28 systems, while that for SMA11 ones are co-continuous. This indicates that higher shear stress can elongate the minor phase domains to form flat interfaces, while the SMA28-g-PA6 copolymers can be pulled out from the interface.

Sunitinib selectively targets leukemogenic signaling of mutant SHP2 in juvenile myelomonocytic leukemia.

Leukemogenic SHP2 mutations occur in 35% of patients with juvenile myelomonocytic leukemia (JMML), a hematopoietic malignancy with poor response to cytotoxic chemotherapy. Novel therapeutic strategies are urgently needed for patients with JMML. Previously, we established a novel cell model of JMML with HCD-57, a murine erythroleukemia cell line that depends on EPO for survival. SHP2-D61Y or -E76K drove the survival and proliferation of HCD-57 in absence of EPO. In this study, we identified sunitinib as a potent compound to inhibit SHP2-mutant cells by screening a kinase inhibitor library with our model. We used cell viability assay, colony formation assay, flow cytometry, immunoblotting, and a xenograft model to evaluate the effect of sunitinib against SHP2-mutant leukemia cells in vitro and in vivo. The treatment of sunitinib selectively induced apoptosis and cell cycle arrest in mutant SHP2-transformed HCD-57, but not parental cells. It also inhibited cell viability and colony formation of primary JMML cells with mutant SHP2, but not bone marrow mononuclear cells from healthy donors. Immunoblotting showed that the treatment of sunitinib blocked the aberrantly activated signals of mutant SHP2 with deceased phosphorylation levels of SHP2, ERK, and AKT. Furthermore, sunitinib effectively reduced tumor burdens of immune-deficient mice engrafted with mutant-SHP2 transformed HCD-57. Our data demonstrated that sunitinib selectively inhibited SHP2-mutant leukemia cells, which could serve as an effective therapeutic strategy for SHP2-mutant JMML in the future.

Possible mechanism of metabolic and drug resistance with L-asparaginase therapy in childhood leukaemia.

L-asparaginase, which hydrolyzes asparagine into aspartic acid and ammonia, is frequently used to treat acute lymphoblastic leukaemia in children. When combined with other chemotherapy drugs, the event-free survival rate is 90%. Due to immunogenicity and drug resistance, however, not all patients benefit from it, restricting the use of L-asparaginase therapy in other haematological cancers. To solve the problem of immunogenicity, several L-ASNase variants have emerged, such as Erwinia-ASNase and PEG-ASNase. However, even when Erwinia-ASNase is used as a substitute for E. coli-ASNase or PEG-ASNase, allergic reactions occur in 3%-33% of patients. All of these factors contributed to the development of novel L-ASNases. Additionally, L-ASNase resistance mechanisms, such as the methylation status of ASNS promoters and activation of autophagy, have further emphasized the importance of personalized treatment for paediatric haematological neoplasms. In this review, we discussed the metabolic effects of L-ASNase, mechanisms of drug resistance, applications in non-ALL leukaemia, and the development of novel L-ASNase.

Alterations in cellular metabolisms after TKI therapy for Philadelphia chromosome-positive leukemia in children: A review.

Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children than in adults due to different biological and host factors. After the clinical application of tyrosine kinase inhibitor (TKI) blocking BCR/ABL kinase activity, the prognosis of children with CML and Ph+ ALL has improved dramatically. Yet, off-target effects and drug tolerance will occur during the TKI treatments, contributing to treatment failure. In addition, compared to adults, children may need a longer course of TKIs therapy, causing detrimental effects on growth and development. In recent years, accumulating evidence indicates that drug resistance and side effects during TKI treatment may result from the cellular metabolism alterations. In this review, we provide a detailed summary of the current knowledge on alterations in metabolic pathways including glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic processes. In order to obtain better TKI treatment outcomes and avoid side effects, it is essential to understand how the TKIs affect cellular metabolism. Hence, we also discuss the relevance of cellular metabolism in TKIs therapy to provide ideas for better use of TKIs in clinical practice.

Evaluating the prognostic value of CD56 in pediatric acute myeloid leukemia.

BACKGROUND: Many cytogenetic changes and gene mutations are associated with acute myeloid leukemia (AML) survival outcomes. CD56 is related to poor prognosis when expressed in adult AML patients. However, the prognostic value of CD56 in children with AML has rarely been reported. In this research, we aimed to evaluate the prognostic value of CD56 in childhood AML. METHODS: The present retrospective study included 145 newly diagnosed pediatric patients with de novo AML (excluding AML-M3) in two hospitals between January 2015 and April 2021. RESULTS: The total median (range) age was 75 (8-176) months, and the median follow-up time was 35 months. No significant difference in the 3-year overall survival rate was noted between the CD56-positive and CD56-negative groups (67.0% vs. 79.3%, P = 0.157) who received chemotherapy. However, among high-risk patients, the CD56-positive group had a worse overall survival rate and event-free survival rate (P < 0.05). Furthermore, among high-risk patients, the CD56-positive group had higher relapse and mortality rates than the CD56-negative group (P < 0.05). CONCLUSIONS: CD56 represents a potential factor of poor prognosis in specific groups of children with AML and should be considered in the risk stratification of the disease. Given the independent prognostic value of CD56 expression, we should consider integrating this marker with some immunophenotypic or cytogenetic abnormalities for comprehensive analysis.

Network Pharmacology-Based Analysis on the Potential Biological Mechanisms of Yinzhihuang Oral Liquid in Treating Neonatal Hyperbilirubinemia.

Objective: Neonatal hyperbilirubinemia is caused by the excessive production of bilirubin and decreased excretion ability in the neonatal period. It leads to a concentration of blood bilirubin that exceeds a certain threshold. Yinzhihuang oral liquid (YZH) is a traditional Chinese medicine mixture used in the treatment of neonatal hyperbilirubinemia in China. This article systematically explores the pharmacological mechanisms by which YZH acts in the treatment of neonatal hyperbilirubinemia through network pharmacology at the molecular level. Methods: We adopted the method of network pharmacology, which includes active component prescreening, target gene prediction, gene enrichment analysis, and network analysis. Results: According to the network pharmacological analysis, 8 genes (STAT3, AKT1, MAPK14, JUN, TP53, MAPK3, ESR1, and RELA) may be targets of YZH in the treatment of neonatal hyperbilirubinemia. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that YZH may regulate antioxidation, modulate lipid metabolism, and have anti-infective properties. Conclusion: In this study, the pharmacological action and molecular mechanisms of YZH were predicted as a whole. It was found that YZH is a promising drug for treating oxidative stress due to bilirubin, as it reduces immunosuppression and helps to eliminate virus infection.

Effectiveness of Sodium Bicarbonate Infusion on Mortality in Critically Ill Children With Metabolic Acidosis.

Objective: Metabolic acidosis often occurs in the paediatric intensive care unit (PICU). Although sodium bicarbonate (SB) has been widely used in paediatrics, data on the effect of SB on children with metabolic acidosis in the PICU are scarce. Methods: Patients with metabolic acidosis who were treated with SB within 48 h of PICU admission were screened. Multivariate logistic regression, subgroup analysis, and propensity score matching (PSM) were used to investigate the relationships between SB infusion and clinical outcomes. Results: A total of 1,595 patients with metabolic acidosis were enrolled in this study. In the multivariate logistic regression model, SB infusion was not correlated with in-hospital mortality (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.47-1.63, p = 0.668), but was significantly correlated with hypernatraemia (OR 1.98, 95% CI 1.14-3.46, p = 0.016), hypokalaemia (OR 2.01, 95% CI 1.36-2.96, p < 0.001), and hypocalcaemia (OR 4.29, 95% CI 2.92-6.31, p < 0.001). In the pH value, lactate level, acute kidney injury level, age grouping, and anion gap level subgroups, the ORs for SB and in-hospital mortality were not statistically significant. After PSM, the results remained unchanged. Conclusion: SB infusion does not reduce the in-hospital mortality of severely ill children with metabolic acidosis and increases the risk of hypernatraemia, hypokalaemia, and hypocalcaemia. More effort should be focused on eliminating the causes of metabolic acidosis rather than SB infusion.

The Strain Transfer Mechanism of Fiber Bragg Grating Sensor for Extra Large Strain Monitoring.

This research focuses on a desensitization method to develop a wide-range FBG sensor for extra-large strain monitoring, which is an essential requirement in large scale infrastructures or for some special occasions. Under appropriate hypotheses, the strain transfer distribution of wide-range FBG sensor based on the shear-lag theory is conducted to improve the accuracy of extra-large strain measurements. It is also discussed how the elastic modulus of adhesive layer affects the strain transfer rate. Two prototypes in different monitoring ranges are designed and fabricated by two layers of steel pipe encapsulation. The presented theoretical model is verified by experimental results. Moreover, it is demonstrated that experimentation in regards to the calibration of the wide-range FBG sensor, improved the amplification coefficient up to 2.08 times and 3.88 times, respectively. The static errors are both calculated and analyzed in this experiment. The wide-range FBG strain sensor shows favourable linearity and stability, which is an excellent property of sensors for extra-large strain monitoring.

[Effects of Yinzhihuang oral liquid and Lonicera japonica extract on hemolysis and hyperbilirubinemia in rats with glucose-6-phosphate dehydrogenase deficiency].

OBJECTIVE: To investigate the effects of different doses of Yinzhihuang oral liquid and different concentrations of Lonicera japonica extract on hemolysis and hyperbilirubinemia in rats with glucose-6-phosphate dehydrogenase (G6PD) deficiency. METHODS: Male Wistar rats were randomly divided into 10 groups (n=10 each): normal control group (untreated), negative control group (saline-treated), positive control group (primaquine-treated), low-, medium- and high-dose Yinzhihuang oral liquid groups (13.4, 26.8, and 53.6 mL/kg, respectively), and low-, medium-, high-, and very-high-concentration Lonicera japonica groups (6.7 mL/kg administered, containing 8, 40, 80, and 160 mg/mL Lonicera japonica extract, respectively). A rat model of acetylphenylhydrazine-induced G6PD deficiency was established in all groups except the normal control group, as confirmed by the morphological changes in erythrocytes observed using Wright's stain. After treatment, routine blood and biochemical tests were conducted to measure hemolytic indices, as well as changes in total and indirect bilirubin levels. RESULTS: Rats with G6PD deficiency demonstrated irregular erythrocytes with a lighter-staining center. In the positive control group, the red blood cell count decreased, while the free hemoglobin count and the reticulocyte percentage increased, as compared with before treatment (P<0.05); in all the Yinzhihuang oral liquid groups and Lonicera japonica extract groups, all the above indices except reticulocyte percentage returned to the levels before treatment (P<0.05). Compared with the positive control group, all the Yinzhihuang oral liquid groups had significantly reduced total and indirect bilirubin levels (P<0.05), and all the Lonicera japonica group had significantly reduced indirect bilirubin levels (P<0.05). However, the total bilirubin level was significantly higher in the Lonicera japonica groups than in the Yinzhihuang oral liquid groups (P<0.05). The low-dose Yinzhihuang oral liquid group demonstrated a significantly greater decrease in total bilirubin level than the medium- and high-dose Yinzhihuang oral liquid group (P<0.05). CONCLUSIONS: Administration of high-dose Yinzhihuang oral liquid and different concentrations of Lonicera Japonica extract do not cause hemolysis in rats with G6PD deficiency. Yinzhihuang oral liquid is more effective in treating hyperbilirubinemia than Lonicera Japonica extract. However, the efficacy of Yinzhihuang oral liquid may not be dose-dependent.