Colorectal ALOX15 as a host factor determinant of EPA and DHA effects on colorectal carcinogenesis.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 polyunsaturated fatty acids (ω-3 PUFAs) derived from fish oil, are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. However, studies investigating the effects of EPA and DHA on colorectal carcinogenesis (CRC) have yielded conflicting results. The factors that determine these discrepant results remain unknown. Resolvins, oxidative metabolites of EPA and DHA, inhibit key pro-tumorigenic cytokine and chemokine signaling of colorectal cancer (e.g., IL-6, IL-1ß, and CCL2). 15-lipoxygenase-1 (ALOX15), a critical enzyme for resolvin generation is commonly lost during human CRC. Whether ALOX15 expression, as a host factor, modulates the effects of EPA and DHA on CRC remains unknown. Therefore, we evaluated the effects of ALOX15 transgenic expression in colonic epithelial cells on resolvin generation by EPA and DHA and CRC in mouse models representative of human CRC. Our results revealed that 1) EPA and DHA effects on CRC were diverse, ranging from suppressive to promotive, and these effects were occasionally altered by the formulations of EPA and DHA (free fatty acid, ethyl ester, triglyceride); 2) EPA and DHA uniformly suppressed CRC in the presence of intestinal ALOX15 transgenic expression, which induced the production of resolvins, decreased colonic CCL3-5 and CXCL-5 expression and tumor associated macrophages while increasing CD8 T cell abundance in tumor microenvironment; and 3) RvD5, the predominant resolvin produced by ALOX15, inhibited macrophage generation of pro-tumorigenic cytokines. These findings demonstrate the significance of intestinal ALOX15 expression as a host factor in determining the effects of EPA and DHA on CRC. Significance: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. Studies of EPA and DHA effects on colorectal carcinogenesis (CRC) have revealed inconsistencies; factors determining the direction of their impact on CRC have remained unidentified. Our data show that EPA and DHA effects on CRC were divergent and occasionally influenced by their formulations. More importantly, intestinal 15-lipoxgenase-1 (ALOX15) expression modulated EPA and DHA effects on CRC, leading to their consistent suppression of CRC. ALOX15 promoted EPA and DHA oxidative metabolism to generate resolvins, which inhibited key pro-tumorigenic inflammatory cytokines and chemokines, including IL-6. IL-1ß, and CCL2. ALOX15 is therefore an important host factor in determining EPA and DHA effects on CRC.

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors.

Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

Global Trends and Hotspots in Pediatric Anesthetic Neurotoxicity Research: A Bibliometric Analysis From 2000 to 2023.

The impact of general anesthetics on brain function development is one of the top frontier issues of public concern. However, little bibliometric analysis has investigated this territory systematically. Our study aimed to visualize the publications between 2000 and 2023 to inspire the trends and hotspots in anesthetic neurodevelopmental toxicity research. Publications from 2000 to 2023 were collected from the Web of Science Core Collection. CiteSpace was utilized to plot and analyze the network maps of countries, institutions, authors, journals, and keywords associated with these publications. A total of 864 publications, consisting of 786 original articles and 78 reviews, were extracted from 2000 to 2023. The annual publications have increased constantly over the past two decades. The USA and the People's Republic of China were the leading driving forces in this field. Harvard University was the most productive institution. Zhang Y published the most related articles, and Jevtovic-Todorovic V was mostly cited in this field. The most prolific journal was Pediatric Anesthesia, and the most frequently co-cited journal was Anesthesiology. Keywords were divided into nine clusters: "apoptosis", "propofol", "developing brain", "cognitive dysfunction", "neuronal cell degeneration", "brain", "neuroinflammation", "local anesthesia", and "oxygen therapy". The strongest citation bursts in earlier years were "learning disability", "cell death", and "cognitive function". The emerging trends in the coming years were "awake regional anesthesia", "behavioral outcome", and "infancy general anesthesia compared to spinal anesthesia". We conclude that anesthetic-induced neurotoxicity has received growing attention in the past two decades. Our findings evaluated the present status and research trends in this area, which may provide help for exploring further potential prospects on hot topics and frontiers.

CRTAC1 identified as a promising diagnosis and prognostic biomarker in lung adenocarcinoma.

CRTAC1, one of the pyroptosis-related genes, has been identified as a protective factor in certain kinds of cancer, such as gastric adenocarcinoma and bladder cancer. The study aimed to investigate the role of CRTAC1 in lung adenocarcinoma (LUAD). LUAD datasets were obtained from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA), pyroptosis-related genes from GeneCard. Limma package used to find differentially expressed genes (DEGs), least absolute shrinkage and selection operator (LASSO) regression and weighted genes co-expression network analysis (WGCNA) to identify CRTAC1 as hub gene. CRTAC1 expression was confirmed in a real-world cohort using quantitative polymerase chain reaction (qPCR) and Western Blot (WB) analyses. Cellular experiments were conducted to investigate CRTAC1's potential oncogenic mechanisms. CRTAC1 mRNA expression was significantly lower in LUAD tissues (p < 0.05) and showed high accuracy in diagnosing LUAD. Reduced CRTAC1 expression was associated with a poor prognosis. Higher CRTAC1 expression correlated with increased immune cell infiltration. Individuals with high CRTAC1 expression showed increased drug sensitivity. Additionally, qPCR and WB analyses showed that CRTAC1 expression was lower in tumor tissue compared to adjacent normal tissue at both the RNA and protein levels. Upregulation of CRTAC1 significantly inhibited LUAD cell proliferation, invasion, and migration in cellular experiments. CRTAC1 has the potential to serve as a diagnostic and prognostic biomarker in LUAD.

Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis.

INTRODUCTION: Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. METHODS: This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. RESULTS: Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627-1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177-0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD. CONCLUSION: This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.

Effect of pyrite particle size on the denitrification performance of autotrophic or split-mixotrophic bioreactors supported by pyrite/polycaprolactone.

In this study, a pyrite-based autotrophic denitrification (PAD) system, a polycaprolactone (PCL)-supported heterotrophic denitrification (PHD) system, and a pyrite+PCL-based split-mixotrophic denitrification (PPMD) system were constructed. The pyrite particle size was controlled in 1-3, 3-5, or 5-8 mm in both the PAD and PPMD systems to investigate the effect of pyrite particle size on the denitrification performance of autotrophic or split-mixotrophic bioreactors. It was found that the PAD system achieved the best denitrification efficiency with an average removal rate of 98.98% in the treatment of 1- to 3-mm particle size, whereas it was only 19.24% in the treatment of 5- to 8-mm particle size. At different phases of the whole experiment, the nitrate removal rates of both the PHD and PPMD systems remained stable at a high level (>94%). Compared with the PAD or PHD system, the PPMD system reduced the concentrations of sulfate and chemical oxygen demand in the final effluent efficiently. The interconnection network diagram explained the intrinsic metabolic pathways of nitrogen, sulfur, and carbon in the three denitrification systems at different phases. In addition, the microbial community analysis showed that the PPMD system was beneficial for the enrichment of Firmicutes. Finally, the impact mechanism of pyrite particle size on the performance of the PPMD system was proposed. PRACTITIONER POINTS: The reduction of pyrite particle size was beneficial for improving the efficiency of the PAD process. The change in particle size had an effect on NO2 --N accumulation in the PAD system. The accumulation of NH4 +-N in the PPMD system increased with the decrease in particle size. The reduction of pyrite particle size increased the production of SO4 2- in the PAD and PPMD systems. The correlations among the effluent indicators of the PAD and PPMD systems could be well explained.

Engineering Phage Nanocarriers Integrated with Bio-Intelligent Plasmids for Personalized and Tunable Enzyme Delivery to Enhance Chemodynamic Therapy.

Customizable and number-tunable enzyme delivery nanocarriers will be useful in tumor therapy. Herein, a phage vehicle, T4-Lox-DNA-Fe (TLDF), which adeptly modulates enzyme numbers using phage display technology to remodel the tumor microenvironment (TME) is presented. Regarding the demand for lactic acid in tumors, each phage is engineered to display 720 lactate oxidase (Lox), contributing to the depletion of lactic acid to restructure the tumor's energy metabolism. The phage vehicle incorporated dextran iron (Fe) with Fenton reaction capabilities. H2O2 is generated through the Lox catalytic reaction, amplifying the H2O2 supply for dextran iron-based chemodynamic therapy (CDT). Drawing inspiration from the erythropoietin (EPO) biosynthetic process, an EPO enhancer is constructed to impart the EPO-Keap1 plasmid (DNA) with tumor hypoxia-activated functionality, disrupting the redox homeostasis of the TME. Lox consumes local oxygen, and positive feedback between the Lox and the plasmid promotes the expression of kelch ECH Associated Protein 1 (Keap1). Consequently, the downregulation of the antioxidant transcription factor Nrf2, in synergy with CDT, amplifies the oxidative killing effect, leading to tumor suppression of up to 78%. This study seamlessly integrates adaptable T4 phage vehicles with bio-intelligent plasmids, presenting a promising approach for tumor therapy.

Integrative single-cell analysis of LUAD: elucidating immune cell dynamics and prognostic modeling based on exhausted CD8+ T cells.

Background: The tumor microenvironment (TME) plays a pivotal role in the progression and metastasis of lung adenocarcinoma (LUAD). However, the detailed characteristics of LUAD and its associated microenvironment are yet to be extensively explored. This study aims to delineate a comprehensive profile of the immune cells within the LUAD microenvironment, including CD8+ T cells, CD4+ T cells, and myeloid cells. Subsequently, based on marker genes of exhausted CD8+ T cells, we aim to establish a prognostic model for LUAD. Method: Utilizing the Seurat and Scanpy packages, we successfully constructed an immune microenvironment atlas for LUAD. The Monocle3 and PAGA algorithms were employed for pseudotime analysis, pySCENIC for transcription factor analysis, and CellChat for analyzing intercellular communication. Following this, a prognostic model for LUAD was developed, based on the marker genes of exhausted CD8+ T cells, enabling effective risk stratification in LUAD patients. Our study included a thorough analysis to identify differences in TME, mutation landscape, and enrichment across varying risk groups. Moreover, by integrating risk scores with clinical features, we developed a new nomogram. The expression of model genes was validated via RT-PCR, and a series of cellular experiments were conducted, elucidating the potential oncogenic mechanisms of GALNT2. Results: Our study developed a single-cell atlas for LUAD from scRNA-seq data of 19 patients, examining crucial immune cells in LUAD's microenvironment. We underscored pDCs' role in antigen processing and established a Cox regression model based on CD8_Tex-LAYN genes for risk assessment. Additionally, we contrasted prognosis and tumor environments across risk groups, constructed a new nomogram integrating clinical features, validated the expression of model genes via RT-PCR, and confirmed GALNT2's function in LUAD through cellular experiments, thereby enhancing our understanding and approach to LUAD treatment. Conclusion: The creation of a LUAD single-cell atlas in our study offered new insights into its tumor microenvironment and immune cell interactions, highlighting the importance of key genes associated with exhausted CD8+ T cells. These discoveries have enabled the development of an effective prognostic model for LUAD and identified GALNT2 as a potential therapeutic target, significantly contributing to the improvement of LUAD diagnosis and treatment strategies.

Monochasma Savatieri Aqueous Extract inhibits Human Breast Cancer Cell Line Migration and Adhesion Without Generating Toxicity.

BACKGROUND: Monochasma savatieri, is a rare and endangered plant used to treat cancer in Chinese traditional medicine. OBJECTIVE: To evaluate the anti-cancer activity of M. savatieri aqueous extract by determining its cytotoxicity, anti-migratory, and anti-adhesion effects on breast cancer cells. METHODS: Cell viability, migration, adhesion, circularity, and cell cycle were evaluated by crystal violet (CV) staining, wound-healing, and transwell assays and flow cytometry in MCF7 and MDA-MB-231 cells. Caveolin-1, snail, vimentin and activated Erk and Akt expression were determined by western blot in MDA-MB-231 cells. Immunofluorescent assays confirmed caveolin-1 expression in MDA-MB-231 cells. RESULTS: Survival and cell cycle of MCF7 and MDA-MB-231 cells were not modified by doses up to 500 µg/mL of the extract. The extract inhibited cell migration and adhesion of MDA-MB-231 cells. When cells were exposed to the extract, there was a slight decrease in protein expression of factors related to epithelial-to-mesenchymal transition (snail and vimentin) and a strong decrease in the expression of the oncogenic membrane protein caveolin- 1. Furthermore, the levels of phosphorylated Erk and Akt were also decreased. The content of acteoside, a phenylpropanoid glycoside with reported anti-cancer activity present in M. savatieri, was almost 5 times as much as isoacteoside. CONCLUSION: M. savatieri possesses anti-cancer activity without exerting cytotoxicity on breast cancer cells. The extract exhibited anti-migratory and anti-adhesion effects on breast cancer cells by regulating Erk and Akt signaling pathways and the expression of caveolin-1. In addition, acteoside present in M. savatieri could be responsible for the observed effects.

Prediction of High-Risk Gastrointestinal Stromal Tumor Recurrence Based on Delta-CT Radiomics Modeling: A 3-Year Follow-up Study After Surgery.

Background: Medium- to high-risk classification-gastrointestinal stromal tumors (MH-GIST) have a high recurrence rate and are difficult to treat. This study aims to predict the recurrence of MH-GIST within 3 years after surgery based on clinical data and preoperative Delta-CT Radiomics modeling. Methods: A retrospective analysis was conducted on clinical imaging data of 242 cases confirmed to have MH-GIST after surgery, including 92 cases of recurrence and 150 cases of normal. The training set and test set were established using a 7:3 ratio and time cutoff point. In the training set, multiple prediction models were established based on clinical data of MH-GIST and the changes in radiomics texture of enhanced computed tomography (CT) at different time periods (Delta-CT radiomics). The area under curve (AUC) values of each model were compared using the Delong test, and the clinical net benefit of the model was tested using decision curve analysis (DCA). Then, the model was externally validated in the test set, and a novel nomogram predicting the recurrence of MH-GIST was finally created. Results: Univariate analysis confirmed that tumor volume, tumor location, neutrophil-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), diabetes, spicy hot pot, CT enhancement mode, and Radscore 1/2 were predictive factors for MH-GIST recurrence (P < .05). The combined model based on these above factors had significantly higher predictive performance (AUC = 0.895, 95% confidence interval [CI] = [0.839-0.937]) than the clinical data model (AUC = 0.735, 95% CI = [0.6 62-0.800]) and radiomics model (AUC = 0.842, 95% CI = [0.779-0.894]). Decision curve analysis also confirmed the higher clinical net benefit of the combined model, and the same results were validated in the test set. The novel nomogram developed based on the combined model helps predict the recurrence of MH-GIST. Conclusions: The nomogram of clinical and Delta-CT radiomics has important clinical value in predicting the recurrence of MH-GIST, providing reliable data reference for its diagnosis, treatment, and clinical decision-making.

Assessment of nomogram model for the prediction of esophageal variceal hemorrhage in hepatitis B-induced hepatic cirrhosis.

BACKGROUND: Esophageal variceal (EV) hemorrhage is a life-threatening consequence of portal hypertension in hepatitis B virus (HBV) -induced cirrhotic patients. Screening upper endoscopy and endoscopic variceal ligation to find EVs for treatment have complications, contraindications, and high costs. We sought to identify the nomogram models (NMs) as alternative predictions for the risk of EV hemorrhage. METHODS: In this case-control study, we retrospectively analyzed 241 HBV-induced liver cirrhotic patients treated for EVs at the Second People's Hospital of Fuyang City, China from January 2021 to April 2023. We applied univariate analysis and multivariate logistic regression to assess the accuracy of various NMs in EV hemorrhage. The area under the curve (AUC) and calibration curves of the receiver's operating characteristics were used to evaluate the predictive accuracy of the nomogram. Decision curve analysis (DCA) was used to determine the clinically relevant of nomograms. RESULTS: In the prediction group, multivariate logistic regression analysis identified platelet distribution and spleen length as independent risk factors for EVs. We applied NMs as the independent risk factors to predict EVs risk. The NMs fit well with the calibration curve and have good discrimination ability. The AUC and DCA demonstrated that NMs with a good net benefit. The above results were validated in the validation cohort. CONCLUSION: Our non-invasive NMs based on the platelet distribution width and spleen length may be used to predict EV hemorrhage in HBV-induced cirrhotic patients. NMs can help clinicians to increase diagnostic performance leading to improved treatment measures.

miR-26b-5p Affects the Progression of Acute Myeloid Leukemia by Regulating the USP48-Mediated Wnt/ß-Catenin Pathway.

Acute myeloid leukemia (AML) is a highly heterogeneous disease. Exploring the pathogenesis of AML is still an important topic in the treatment of AML. The expression levels of miR-26b-5p and USP48 were measured by qRT-PCR. The expression levels of related proteins were detected by Western blot. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry, respectively. Coimmunoprecipitation was used to examine the interaction between USP48 and Wnt5a. Bioinformatics analysis showed that high levels of miR-26b-5p and low levels of USP48 were associated with poor prognosis in AML. miR-26b-5p can negatively regulate the expression of USP48. Downregulation of miR-26b-5p inhibited EMT, cell viability and proliferation of AML cells and accelerated apoptosis. Furthermore, the influence of miR-26b-5p inhibition and USP48 knockdown on AML progression could be reversed by a Wnt/ß-catenin signaling pathway inhibitor. This study revealed that miR-26b-5p regulates AML progression, possibly by targeting the USP48-mediated Wnt/ß-catenin molecular axis to affect AML cell biological behavior.

Palladium-Catalyzed Directed Carbon-Carbon Bond Activation of Aryl Nitriles for Cyano Transfer.

Herein, we report the C-H cyanation of indoles via a palladium-catalyzed directed C-CN activation reaction using aryl nitrile as a cyano source. The employment of the phenoxy-oriented group is the key to the cleavage of the C-CN bond. This protocol features a broad substrate scope, good efficiency, and high regioselectivity. Furthermore, the practical application of this protocol was showcased in the late-stage functionalization and synthesis of indole derivatives, which were derived from drugs and natural products, through the process of cyanation.

Photopolymerizable and Antibacterial Hydrogels Loaded with Metabolites from Lacticaseibacillus rhamnosus GG for Infected Wound Healing.

In response to increasing antibiotic resistance and the pressing demand for safer infected wound care, probiotics have emerged as promising bioactive agents. To address the challenges associated with the safe and efficient application of probiotics, this study successfully loaded metabolites from Lacticaseibacillus rhamnosus GG (LGG) into a gelatin cross-linked macromolecular network by an in situ blending and photopolymerization method. The obtained LM-GelMA possesses injectability and autonomous healing capabilities. Importantly, the incorporation of LGG metabolites endows LM-GelMA with excellent antibacterial properties against Staphylococcus aureus and Escherichia coli, while maintaining good biocompatibility. In vivo assessments revealed that LM-GelMA can accelerate wound healing by mitigating infections induced by pathogenic bacteria. This is accompanied by a reduction in the expression of key proinflammatory cytokines such as TNF-α, IL-6, VEGFR2, and TGF-ß, leading to increased re-epithelialization and collagen formation. Moreover, microbiological analysis confirmed that LM-GelMA can modulate the abundance of beneficial wound microbiota at family and genus levels. This study provides a facile strategy and insights into the functional design of hydrogels from the perspective of wound microenvironment regulation.

Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma.

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.

Severe pediatric COVID-19: a review from the clinical and immunopathophysiological perspectives.

BACKGROUND: Coronavirus disease 2019 (COVID-19) tends to have mild presentations in children. However, severe and critical cases do arise in the pediatric population with debilitating systemic impacts and can be fatal at times, meriting further attention from clinicians. Meanwhile, the intricate interactions between the pathogen virulence factors and host defense mechanisms are believed to play indispensable roles in severe COVID-19 pathophysiology but remain incompletely understood. DATA SOURCES: A comprehensive literature review was conducted for pertinent publications by reviewers independently using the PubMed, Embase, and Wanfang databases. Searched keywords included "COVID-19 in children", "severe pediatric COVID-19", and "critical illness in children with COVID-19". RESULTS: Risks of developing severe COVID-19 in children escalate with increasing numbers of co-morbidities and an unvaccinated status. Acute respiratory distress stress and necrotizing pneumonia are prominent pulmonary manifestations, while various forms of cardiovascular and neurological involvement may also be seen. Multiple immunological processes are implicated in the host response to COVID-19 including the type I interferon and inflammasome pathways, whose dysregulation in severe and critical diseases translates into adverse clinical manifestations. Multisystem inflammatory syndrome in children (MIS-C), a potentially life-threatening immune-mediated condition chronologically associated with COVID-19 exposure, denotes another scientific and clinical conundrum that exemplifies the complexity of pediatric immunity. Despite the considerable dissimilarities between the pediatric and adult immune systems, clinical trials dedicated to children are lacking and current management recommendations are largely adapted from adult guidelines. CONCLUSIONS: Severe pediatric COVID-19 can affect multiple organ systems. The dysregulated immune pathways in severe COVID-19 shape the disease course, epitomize the vast functional diversity of the pediatric immune system and highlight the immunophenotypical differences between children and adults. Consequently, further research may be warranted to adequately address them in pediatric-specific clinical practice guidelines.

An IROA Workflow for correction and normalization of ion suppression in mass spectrometry-based metabolomic profiling data.

Ion suppression is a major problem in mass spectrometry (MS)-based metabolomics; it can dramatically decrease measurement accuracy, precision, and signal-to-noise sensitivity. Here we report a new method, the IROA TruQuant Workflow, that uses a stable isotope-labeled internal standard (IROA-IS) plus novel companion algorithms to 1) measure and correct for ion suppression, and 2) perform Dual MSTUS normalization of MS metabolomic data. We have evaluated the method across ion chromatography (IC), hydrophilic interaction liquid chromatography (HILIC), and reverse phase liquid chromatography (RPLC)-MS systems in both positive and negative ionization modes, with clean and unclean ion sources, and across different biological matrices. Across the broad range of conditions tested, all detected metabolites exhibited ion suppression ranging from 1% to 90+% and coefficient of variations ranging from 1% to 20%, but the Workflow and companion algorithms were highly effective at nulling out that suppression and error. Overall, the Workflow corrects ion suppression across diverse analytical conditions and produces robust normalization of non-targeted metabolomic data.

Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.

Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.

Identification and Validation of Lipid Metabolism Gene FASN-Associated miRNA in Wilms Tumor.

miRNA has been a research hotspot in recent years and its scope of action is very wide, involving the regulation of cell proliferation, differentiation, apoptosis, and other biological behaviors. This study intends to explore the role of miRNA in the lipid metabolism and development of Wilms tumor (WT) by detecting and analyzing the differences in the expression profiles of miRNAs between the tumor and adjacent normal tissue. Gene detection was performed in tumor tissues and adjacent normal tissues of three cases of WT to screen differentially expressed miRNAs (DEMs). According to our previous research, FASN, which participates in the lipid metabolism pathway, may be a target of WT. The starBase database was used to predict FASN-targeted miRNAs. The above two groups of miRNAs were intersected to obtain FASN-targeted DEMs and then GO Ontology (GO) functional enrichment analysis of FASN-targeted DEMs was performed. Finally, the FASN-targeted DEMs were compared and further verified by qRT‒PCR. Through gene sequencing and differential analysis, 287 DEMs were obtained, including 132 upregulated and 155 downregulated miRNAs. The top ten DEMs were all downregulated. Fourteen miRNAs targeted by the lipid metabolism-related gene FASN were predicted by starBase. After intersection with the DEMs, three miRNAs were finally obtained, namely, miR-107, miR-27a-3p, and miR-335-5p. GO enrichment analysis was mainly concentrated in the Parkin-FBXW7-Cul1 ubiquitin ligase complex and response to prostaglandin E. Further experimental verification showed that miR-27a-3p was significantly correlated with WT (P = 0.0018). Imbalanced expression of miRNAs may be involved in the occurrence and development of WT through lipid metabolism. The expression of miR-27a-3p is related to the malignant degree of WT, and it may become the target of diagnosis, prognosis, and treatment of WT in the later stage.