Regulation of Biofilm Exopolysaccharide Biosynthesis and Degradation in Pseudomonas aeruginosa.

Microbial communities enmeshed in a matrix of macromolecules, termed as biofilms, are the natural setting of bacteria. Exopolysaccharide is a critical matrix component of biofilms. Here, we focus on biofilm matrix exopolysaccharides in Pseudomonas aeruginosa. This opportunistic pathogen can adapt to a wide range of environments and can form biofilms or aggregates in a variety of surfaces or environments, such as the lungs of people with cystic fibrosis, catheters, wounds, and contact lenses. The ability to synthesize multiple exopolysaccharides is one of the advantages that facilitate bacterial survival in different environments. P. aeruginosa can produce several exopolysaccharides, including alginate, Psl, Pel, and lipopolysaccharide. In this review, we highlight the roles of each exopolysaccharide in P. aeruginosa biofilm development and how bacteria coordinate the biosynthesis of multiple exopolysaccharides and bacterial motility. In addition, we present advances in antibiofilm strategies targeting matrix exopolysaccharides, with a focus on glycoside hydrolases.

Measuring the α-particle charge radius with muonic helium-4 ions.

The energy levels of hydrogen-like atomic systems can be calculated with great precision. Starting from their quantum mechanical solution, they have been refined over the years to include the electron spin, the relativistic and quantum field effects, and tiny energy shifts related to the complex structure of the nucleus. These energy shifts caused by the nuclear structure are vastly magnified in hydrogen-like systems formed by a negative muon and a nucleus, so spectroscopy of these muonic ions can be used to investigate the nuclear structure with high precision. Here we present the measurement of two 2S-2P transitions in the muonic helium-4 ion that yields a precise determination of the root-mean-square charge radius of the α particle of 1.67824(83) femtometres. This determination from atomic spectroscopy is in excellent agreement with the value from electron scattering1, but a factor of 4.8 more precise, providing a benchmark for few-nucleon theories, lattice quantum chromodynamics and electron scattering. This agreement also constrains several beyond-standard-model theories proposed to explain the proton-radius puzzle2-5, in line with recent determinations of the proton charge radius6-9, and establishes spectroscopy of light muonic atoms and ions as a precise tool for studies of nuclear properties.

A bacterial pigment provides cross-species protection from H2O2- and neutrophil-mediated killing.

Bacterial infections are often polymicrobial. Pseudomonas aeruginosa and Staphylococcus aureus cause chronic co-infections, which are more problematic than mono-species infections. Understanding the mechanisms of their interactions is crucial for treating co-infections. Staphyloxanthin (STX), a yellow pigment synthesized by the S. aureus crt operon, promotes S. aureus resistance to oxidative stress and neutrophil-mediated killing. We found that STX production by S. aureus, either as surface-grown macrocolonies or planktonic cultures, was elevated when exposed to the P. aeruginosa exoproduct, 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). This was observed with both mucoid and non-mucoid P. aeruginosa strains. The induction phenotype was found in a majority of P. aeruginosa and S. aureus clinical isolates examined. When subjected to hydrogen peroxide or human neutrophils, P. aeruginosa survival was significantly higher when mixed with wild-type (WT) S. aureus, compared to P. aeruginosa alone or with an S. aureus crt mutant deficient in STX production. In a murine wound model, co-infection with WT S. aureus, but not the STX-deficient mutant, enhanced P. aeruginosa burden and disease compared to mono-infection. In conclusion, we identified a role for P. aeruginosa HQNO mediating polymicrobial interactions with S. aureus by inducing STX production, which consequently promotes resistance to the innate immune effectors H2O2 and neutrophils. These results further our understanding of how different bacterial species cooperatively cause co-infections.

A designed Copper Histidine-brace enzyme for oxidative depolymerization of polysaccharides as a model of lytic polysaccharide monooxygenase.

The "Histidine-brace" (His-brace) copper-binding site, composed of Cu(His)2 with a backbone amine, is found in metalloproteins with diverse functions. A primary example is lytic polysaccharide monooxygenase (LPMO), a class of enzymes that catalyze the oxidative depolymerization of polysaccharides, providing not only an energy source for native microorganisms but also a route to more effective industrial biomass conversion. Despite its importance, how the Cu His-brace site performs this unique and challenging oxidative depolymerization reaction remains to be understood. To answer this question, we have designed a biosynthetic model of LPMO by incorporating the Cu His-brace motif into azurin, an electron transfer protein. Spectroscopic studies, including ultraviolet-visible (UV-Vis) absorption and electron paramagnetic resonance, confirm copper binding at the designed His-brace site. Moreover, the designed protein is catalytically active towards both cellulose and starch, the native substrates of LPMO, generating degraded oligosaccharides with multiturnovers by C1 oxidation. It also performs oxidative cleavage of the model substrate 4-nitrophenyl-D-glucopyranoside, achieving a turnover number ~9% of that of a native LPMO assayed under identical conditions. This work presents a rationally designed artificial metalloenzyme that acts as a structural and functional mimic of LPMO, which provides a promising system for understanding the role of the Cu His-brace site in LPMO activity and potential application in polysaccharide degradation.

Identifying new cancer genes based on the integration of annotated gene sets via hypergraph neural networks.

MOTIVATION: Identifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer genes have been shown to cluster in hallmark signaling pathways and biological processes. The knowledge of annotated gene sets is critical for discovering cancer genes but remains to be fully exploited. RESULTS: Here, we present the DIsease-Specific Hypergraph neural network (DISHyper), a hypergraph-based computational method that integrates the knowledge from multiple types of annotated gene sets to predict cancer genes. First, our benchmark results demonstrate that DISHyper outperforms the existing state-of-the-art methods and highlight the advantages of employing hypergraphs for representing annotated gene sets. Second, we validate the accuracy of DISHyper-predicted cancer genes using functional validation results and multiple independent functional genomics data. Third, our model predicts 44 novel cancer genes, and subsequent analysis shows their significant associations with multiple types of cancers. Overall, our study provides a new perspective for discovering cancer genes and reveals previously undiscovered cancer genes. AVAILABILITY AND IMPLEMENTATION: DISHyper is freely available for download at https://github.com/genemine/DISHyper.

Rescue of cardiac dysfunction during chemotherapy in acute myeloid leukaemia by blocking IL-1α.

BACKGROUND AND AIMS: Patients with acute myeloid leukaemia (AML) suffer from severe myocardial injury during daunorubicin (DNR)-based chemotherapy and are at high risk of cardiac mortality. The crosstalk between tumour cells and cardiomyocytes might play an important role in chemotherapy-related cardiotoxicity, but this has yet to be demonstrated. This study aimed to identify its underlying mechanism and explore potential therapeutic targets. METHODS: Cardiac tissues were harvested from an AML patient after DNR-based chemotherapy and were subjected to single-nucleus RNA sequencing. Cardiac metabolism and function were evaluated in AML mice after DNR treatment by using positron emission tomography, magnetic resonance imaging, and stable-isotope tracing metabolomics. Plasma cytokines were screened in AML mice after DNR treatment. Genetically modified mice and cell lines were used to validate the central role of the identified cytokine and explore its downstream effectors. RESULTS: In the AML patient, disruption of cardiac metabolic homeostasis was associated with heart dysfunction after DNR-based chemotherapy. In AML mice, cardiac fatty acid utilization was attenuated, resulting in cardiac dysfunction after DNR treatment, but these phenotypes were not observed in similarly treated tumour-free mice. Furthermore, tumour cell-derived interleukin (IL)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1α neutralizing antibody could improve cardiac functions in AML mice after DNR treatment. CONCLUSIONS: This study revealed that crosstalk between tumour cells and cardiomyocytes during chemotherapy could disturb cardiac energy metabolism and impair heart function. IL-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients.

Selective C-H Bond Activation in Propane with Molecular Oxygen over Cu(I)-ZSM-5 at Ambient Conditions.

Selective activation of C-H bonds in light alkanes under mild conditions is challenging but holds the promise of efficient upgrading of abundant hydrocarbons. In this work, we report the conversion of propane to propylene with ∼95% selectivity on Cu(I)-ZSM-5 with O2 at room temperature and pressure. The intraporous Cu(I) species was oxidized to Cu(II) during the reaction but could be regenerated with H2 at 220 °C. Diffuse reflectance ultraviolet spectroscopy indicated the presence of both Cu+-O2 and Cu2(µ-O2)2+ species in the zeolite pores during the reaction, and electron paramagnetic resonance results showed that propane activation occurred via a radical-mediated pathway distinct from that with H2O2 as the oxidant. Correlation between spectroscopic and reactivity results on Cu(I)-ZSM-5 with different Cu loadings suggests that the isolated intraporous Cu(I) species is the main active species in propane activation.

Heterovalent Metal Pair Sites on Metal-Organic Framework Ordered Macropores for Multimolecular Co-Activation.

The precise design of catalytic metal centers with multiple chemical states to facilitate sophisticated reactions involving multimolecular activation is highly desirable but challenging. Herein, we report an ordered macroporous catalyst with heterovalent metal pair (HMP) sites comprising CuII-CuI on the basis of a microporous metal-organic framework (MOF) system. This macroporous HMP catalyst with proximity heterovalent dual copper sites, whose distance is controlled to ∼2.6 Å, on macropore surface exhibits a co-activation behavior of ethanol at CuII and alkyne at CuI, and avoids microporous restriction, thereby promoting additive-free alkyne hydroboration reaction. The desired yield enhances dramatically compared with the pristine MOF and ordered macroporous MOF both with solely isovalent CuII-CuII sites. Density functional theory calculations reveal that the Cu-HMP sites can stabilize the Bpin-CuII-CuI-alkyne intermediate and facilitate C-B bond formation, resulting in a smooth alkyne hydroboration process. This work provides new perspectives to design multimolecular activation catalysts for sophisticated matter transformations.

Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer.

BACKGROUND: Osimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the interactions between the tumor and the tumor microenvironment (TME) also account for drug resistance. Therefore, we provide a new sight into post-osimertinib management, focusing on the alteration of TME. METHODS: We conducted a retrospective study on the prognosis of different treatments after osimertinib resistance. Next, we carried out in vivo experiment to validate our findings using a humanized mouse model. Furthermore, we performed single-cell transcriptome sequencing (scRNA-seq) of tumor tissue from the above treatment groups to explore the mechanisms of TME changes. RESULTS: Totally 111 advanced NSCLC patients have been enrolled in the retrospective study. The median PFS was 9.84 months (95% CI 7.0-12.6 months) in the osimertinib plus anti-angiogenesis group, significantly longer than chemotherapy (P = 0.012) and osimertinib (P = 0.003). The median OS was 16.79 months (95% CI 14.97-18.61 months) in the osimertinib plus anti-angiogenesis group, significantly better than chemotherapy (P = 0.026), the chemotherapy plus osimertinib (P = 0.021), and the chemotherapy plus immunotherapy (P = 0.006). The efficacy of osimertinib plus anlotinib in the osimertinib-resistant engraft tumors (R-O+A) group was significantly more potent than the osimertinib (R-O) group (P<0.05) in vitro. The combinational therapy could significantly increase the infiltration of CD4+ T cells (P<0.05), CD25+CD4+ T cells (P<0.001), and PD-1+CD8+ T cells (P<0.05) compared to osimertinib. ScRNA-seq demonstrated that the number of CD8+ T and proliferation T cells increased, and TAM.mo was downregulated in the R-O+A group compared to the R-O group. Subtype study of T cells explained that the changes caused by combination treatment were mainly related to cytotoxic T cells. Subtype study of macrophages showed that proportion and functional changes in IL-1ß.mo and CCL18.mo might be responsible for rescue osimertinib resistance by combination therapy. CONCLUSIONS: In conclusion, osimertinib plus anlotinib could improve the prognosis of patients with a progressed disease on second-line osimertinib treatment, which may ascribe to increased T cell infiltration and TAM remodeling via VEGF-VEGFR blockage.

Cluster-Cluster Co-Nucleation Induced Defective Polyoxometalate-Based Metal-Organic Frameworks for Efficient Tandem Catalysis.

The construction of defective sites is one of the effective strategies to create high-activity Metal-Organic frameworks (MOFs) catalysts. However, traditional synthesis methods usually suffer from cumbersome synthesis steps and disordered defect structures. Herein, a cluster-cluster co-nucleation (CCCN) strategy is presented that involves the in situ introduction of size-matched functional polyoxometalates (H6P2W18O62, {P2W18}) to intervene the nucleation process of cluster-based MOFs (UiO-66), achieving one-step inducement of exposed defective sites without redundant post-processing. POM-induced UiO-66 ({P2W18}-0.1@UiO-66) exhibits a classical reo topology for well-defined cluster defects. Moreover, the defective sites and the interaction between POM and skeletal cluster nodes are directly observed by Integrated Differential Phase Contrast in Scanning Transmission Electron Microscopy (iDPC-STEM). Owing to the molecular-level proximity between defective sites and POM in the same nano-reaction space, {P2W18}-0.1@UiO-66 exhibits efficient tandem catalysis in the preparation of γ-valerolactone (γ-GVL) from laevulinic acid (LA) by the combination of Lewis and Brønsted acids with 11 times higher performance than defective UiO-66 formed by conventional coordination modulation strategy. The CCCN strategy is applicable to different POM and has the potential to be extended to other cluster-based MOFs, which will pave a new way for the construction of functional MOFs with multi-centered synergistic catalysis.

Size Dependent Phase Transformation of Liquid Gallium.

As the most popular liquid metal (LM), gallium (Ga) and its alloys are emerging as functional materials due to their unique combination of fluidic and metallic properties near room temperature. As an important branch of utilizing LMs, micro- and submicron-particles of Ga-based LM are widely employed in wearable electronics, catalysis, energy, and biomedicine. Meanwhile, the phase transition is crucial not only for the applications based on this reversible transformation process, but also for the solidification temperature at which fluid properties are lost. While Ga has several solid phases and exhibits unusual size-dependent phase behavior. This complex process makes the phase transition and undercooling of Ga uncontrollable, which considerably affects the application performance. In this work, extensive (nano-)calorimetry experiments are performed to investigate the polymorph selection mechanism during liquid Ga crystallization. It is surprisingly found that the crystallization temperature and crystallization pathway to either α -Ga or ß -Ga can be effectively engineered by thermal treatment and droplet size. The polymorph selection process is suggested to be highly relevant to the capability of forming covalent bonds in the equilibrium supercooled liquid. The observation of two different crystallization pathways depending on the annealing temperature may indicate that there exist two different liquid phases in Ga.

Effects of trimetazidine on cardiac function in adult cyanotic congenital heart disease patients: Protocol for a 3-month multicenter, randomized, double-blind controlled trial.

BACKGROUND: Nearly 20% Patients with cyanotic congenital heart disease (CCHD) are not able to receive surgery. These patients experience a decline in cardiac function as they age, which has been demonstrated to be associated with changes in energy metabolism in cardiomyocytes. Trimetazidine (TMZ), a metabolic regulator, is supposed to alleviate such maladaptation and reserve cardiac function in CCHD patients. METHODS: This is a randomized, double-blind, placebo-controlled clinical trial. Eighty adult CCHD patients will be recruited and randomized to the TMZ (20 mg TMZ 3 times a day for 3 months) or placebo group (placebo 3 times a day for 3 months). The primary outcome is the difference in cardiac ejection fractions (EF) measured by cardiac magnetic resonance (MRI) between baseline and after 3 months of TMZ treatment. The secondary outcomes include TMZ serum concentration, rate of cardiac events, NYHA grading, fingertip SpO2, NT-proBNP levels, 6-minute walking test (6MWT), KCCQ-CSS questionnaire score, echocardiography, ECG, routine blood examination, liver and kidney function test, blood pressure and heart rate. DISCUSSION: This trial is designed to explore whether the application of TMZ in adult CCHD patients can improve cardiac function, reduce cardiac events, and improve exercise performance and quality of life. The results will provide targeted drug therapy for CCHD patients with hypoxia and support the application of TMZ in children with CCHD.

The Impact of Delayed Transition From Noninvasive to Invasive Mechanical Ventilation on Hospital Mortality in Immunocompromised Patients With Sepsis.

OBJECTIVE: To determine whether mortality differed between initial invasive mechanical ventilation (IMV) or noninvasive ventilation (NIV) followed by delayed IMV in immunocompromised patients with sepsis. DESIGN: Retrospective analysis using the National Data Center for Medical Service claims data in China from 2017 to 2019. SETTING: A total of 3530 hospitals across China. PATIENTS: A total of 36,187 adult immunocompromised patients with sepsis requiring ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was hospital mortality. Patients were categorized into NIV initiation or IMV initiation groups based on first ventilation. NIV patients were further divided by time to IMV transition: no transition, immediate (≤ 1 d), early (2-3 d), delayed (4-7 d), or late (≥ 8 d). Mortality was compared between groups using weighted Cox models. Over the median 9-day follow-up, mortality was similar for initial NIV versus IMV (adjusted hazard ratio [HR] 1.006; 95% CI, 0.959-1.055). However, among NIV patients, a longer time to IMV transition is associated with stepwise increases in mortality, from immediate transition (HR 1.65) to late transition (HR 2.51), compared with initial IMV. This dose-response relationship persisted across subgroups and sensitivity analyses. CONCLUSIONS: Prolonged NIV trial before delayed IMV transition is associated with higher mortality in immunocompromised sepsis patients ultimately intubated.

IsoFrog: a reversible jump Markov Chain Monte Carlo feature selection-based method for predicting isoform functions.

MOTIVATION: A single gene may yield several isoforms with different functions through alternative splicing. Continuous efforts are devoted to developing machine-learning methods to predict isoform functions. However, existing methods do not consider the relevance of each feature to specific functions and ignore the noise caused by the irrelevant features. In this case, we hypothesize that constructing a feature selection framework to extract the function-relevant features might help improve the model accuracy in isoform function prediction. RESULTS: In this article, we present a feature selection-based approach named IsoFrog to predict isoform functions. First, IsoFrog adopts a reversible jump Markov Chain Monte Carlo (RJMCMC)-based feature selection framework to assess the feature importance to gene functions. Second, a sequential feature selection procedure is applied to select a subset of function-relevant features. This strategy screens the relevant features for the specific function while eliminating irrelevant ones, improving the effectiveness of the input features. Then, the selected features are input into our proposed method modified domain-invariant partial least squares, which prioritizes the most likely positive isoform for each positive MIG and utilizes diPLS for isoform function prediction. Tested on three datasets, our method achieves superior performance over six state-of-the-art methods, and the RJMCMC-based feature selection framework outperforms three classic feature selection methods. We expect this proposed methodology will promote the identification of isoform functions and further inspire the development of new methods. AVAILABILITY AND IMPLEMENTATION: IsoFrog is freely available at https://github.com/genemine/IsoFrog.

Current status and future directions in pediatric ventricular assist device.

A ventricular assist device (VAD) is a form of mechanical circulatory support that uses a mechanical pump to partially or fully take over the function of a failed heart. In recent decades, the VAD has become a crucial option in the treatment of end-stage heart failure in adult patients. However, due to the lack of suitable devices and more complicated patient profiles, this therapeutic approach is still not widely used for pediatric populations. This article reviews the clinically available devices, adverse events, and future directions of design and implementation in pediatric VADs.

Wolfberry enhanced the abundance of Akkermansia muciniphila by YAP1 in mice with acetaminophen-induced liver injury.

Drug-induced liver injury (DILI) by acetaminophen (APAP) was one of the most challenging liver diseases. Wolfberry (Lycium barbarum L.), a traditional Chinese medicinal material and food supplement, has a potential effect on increasing the abundance of Akkermansia muciniphila (A. muciniphila) in mice colons. However, the effect and mechanism of wolfberry remain unclear in APAP-induced DILI. In this study, wolfberry promoted the proliferation of activated-A. muciniphila in vitro and in vivo. For the first time, we detected that the activated-A. muciniphila but not the killed-A. muciniphila increased the expression level of Yes-associated protein 1 (YAP1) in the liver and alleviated liver injury in APAP-induced DILI mice. Mechanically, A. muciniphila improved the intestinal mucosal barrier and reduced lipopolysaccharide (LPS) content in the liver, leading to the increased expression level of YAP1. Furthermore, wolfberry increased the A. muciniphila abundance in the colon and YAP1 expression in the liver from APAP-induced DILI mice, which promoted the recovery of APAP-induced liver injury. Meanwhile, wolfberry combination with A. muciniphila synergistically increased AKK abundance and YAP1 expression in the liver. Our research provides an innovative strategy to improve DILI.

Influence of Steric Effects on the Emission Behavior of Pyrene-Based Blue Luminogens.

Pyrene-based derivatives have been widely deployed in organic luminescent materials because of their bright fluorescence, high charge carrier mobility, and facile modification. Nevertheless, the fluorescence output of conventional pyrenes is prone to quenching upon aggregation due to extensive intermolecular π-π stacking interactions. To address this issue, a set of new Y-shaped pyrene-containing luminogens are synthesized from a new bromopyrene chemical precursor, 2-hydroxyl-7-tert-butyl-1,3-bromopyrene, where the bromo and hydroxyl groups at the pyrene core can be readily modified to obtain the target products and provide great flexibility in tuning the photophysical performances. When the hydroxy group at the 2-position of pyrene was replaced by a benzyl group, the steric hindrance of the benzyl group not only efficiently inhibits the detrimental intermolecular π-π stacking interactions but also rigidifies the molecular conformation, resulting in a narrow-band blue emission. Moreover, the TPE-containing compounds 2c and 3c possessed characteristic aggregation-induced emission (AIE) properties with fluorescence quantum yields of up to 66% and 38% in the solid state, respectively. Thus, this article has methodically investigated the factors influencing the optical behavior, such as intermolecular interactions, and the steric effects of the substituent group, thereby opening up the potential to develop narrow-band pyrene-based blue emitters for OLED device applications.

Pyrene-Based Deep-Blue Fluorophores with Narrow-Band Emission.

High-efficiency narrow-band luminescent materials have attracted intense interest, resulting in their great colorimetric purity. This has led to a variety of high-tech applications in high-definition displays, spectral analysis, and biomedicine. In this study, a rigid pyrene core was employed as the molecular backbone, and four narrow-band pyrene-based blue emitters were synthesized using various synthetic methods (such as Lewis-acid catalyzed cyclization domino reactions, Pd-catalyzed coupling reactions like Suzuki-Miyaura and Sonogashira). Due to the steric effect of the hydroxy group at the 2-position, the target compounds exhibit deep blue emission (<429 nm, CIEy < 0.08) with full width at half-maximum (FWHM) less than 33 nm both in solution and when solidified. The experimental and theoretical results indicated that the substituents at the 1- and 3-positions afford a large dihedral angle with the pyrene core, and the molecular motion is almost fixed by multiple intra- and intermolecular hydrogen bonding interactions in the crystallized state, leading to a suppression of the vibrational relaxation of the molecular structure. Moreover, we observed that the suppression of the vibrational relaxation in the molecular structures and the construction of rigid conjugated structures can help develop narrow-band organic light-emitting materials.

Pharmacokinetics of PEGasparaginase in Infants with Acute Lymphoblastic Leukemia.

BACKGROUND: PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population. METHODS: Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM). RESULTS: 68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m2 were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction. CONCLUSION: The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1-18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m2 for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.

Metabolites mediate the causal associations between gut microbiota and NAFLD: a Mendelian randomization study.

BACKGROUND: Although gut microbiota and serum metabolite composition have been observed to be altered in patients with non-alcoholic fatty liver disease (NAFLD), previous observational studies have demonstrated inconsistent results. As this may be influenced by factors such as confounders and reverse causality, we used Mendelian randomization to clarify the causal effect of gut microbiota and blood metabolites on NAFLD. METHODS: In this research, we performed a two-step Mendelian randomization analysis by utilizing genome-wide association study (GWAS) data obtained from MiBioGen and UK Biobank. To mitigate potential errors, we employed False Discovery Rate (FDR) correction and linkage unbalanced regression (LDSC) analysis. Sensitivity analyses including cML-MA and bidirectional Mendelian randomization were performed to ensure the robustness of the results. RESULTS: In this study, a total of nine gut microbiota and seven metabolites were found to be significantly associated with NAFLD. MR analysis of the above findings revealed a causal relationship between Ruminococcus2 and cysteine-glutathione disulfide (OR = 1.17, 95%CI = 1.006-1.369, P = 0.041), as well as 3-indoleglyoxylic acid (OR = 1.18, 95%CI = 1.011-1.370, P = 0.036). For each incremental standard deviation in Ruminococcus2 abundance, there was a corresponding 26% reduction in NAFLD risk (OR = 0.74, 95%CI = 0.61-0.89, P = 0.0012), accompanied by a 17% increase in cysteine-glutathione disulfide levels (OR = 1.17, 95%CI = 1.01-1.37, P = 0.041) and an 18% increase in 3-indoleglyoxylic acid levels (OR = 1.18, 95%CI = 0.81-1.00, P = 0.036). The proportion mediated by cysteine-glutathione disulfide is 11.2%, while the proportion mediated by 3-indoleglyoxylic acid is 7.5%. CONCLUSION: Our study suggests that increased abundance of specific gut microbiota may reduce the risk of developing NAFLD, and this relationship could potentially be mediated through blood metabolites.