Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors.

BACKGROUND: While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship. METHODS: We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together. RESULTS: We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes. CONCLUSION: This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.

Gene variants and clinical characteristics of children with sitosterolemia.

OBJECTIVE: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients. METHODS: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected. RESULTS: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment. CONCLUSION: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids.

Maternal vitamin D status modifies the effects of early life tobacco exposure on child lung function.

BACKGROUND: Prior studies suggest that vitamin D may modify the effects of environmental exposures; however, none have investigated gestational vitamin D and cumulative tobacco smoke exposure (TSE) throughout pregnancy and early life. OBJECTIVES: This study investigated the effects of early life TSE on child lung function and the modulatory effects of gestational vitamin D on this association. METHODS: The VDAART (Vitamin D Antenatal Asthma Reduction Trial) recruited nonsmoking pregnant women and followed the mother-child pairs to age 6 years. TSE was assessed with questionnaires and plasma cotinine measurements in the mothers (10-18 and 32-38 gestational weeks) and children (1, 3, and 6 years). Cumulative TSE was calculated from the repeated cotinine measurements. 25-hydroxyvitamin D (25[OH]D) levels were measured at 10-18 and 32-38 gestational weeks. Lung function was assessed at 6 years with spirometry and impulse oscillometry. RESULTS: Of the 476 mother-child pairs, 205 (43%) had increased cotinine levels at ≥1 time point. Cumulative TSE was associated with decreased FEV1 (ß = -0.043 L, P = .018) and increased respiratory resistance at 5 Hz (R5; ß = 0.060 kPa/L/s, P = .002). This association persisted in subjects with insufficient (<30 ng/mL) 25(OH)D levels throughout pregnancy (ß = 0.077 kPa/L/s, P = .016 for R5) but not among those with sufficient levels throughout pregnancy. CONCLUSIONS: Cumulative TSE from pregnancy to childhood is associated with dose- and duration-dependent decreases in child lung function at 6 years even in the absence of reported maternal smoking. Gestational vitamin D may modulate this effect and have therapeutic potential for minimizing the adverse effect of TSE on lung throughout early life. RANDOMIZED TRIAL: Maternal Vitamin D Supplementation to Prevent Childhood Asthma (VDAART); clinicaltrials.gov identifier: NCT00920621.

Regulatory mechanism of GPER in the invasion and migration of ectopic endometrial stromal cells in endometriosis.

Endometriosis (EMS) is a chronic inflammatory disorder of high incidence that causes serious reproductive consequences. High estrogen production is a consistently observed endocrine feature of EMS. The present study aims to probe the molecular mechanism of G protein-coupled estrogen receptor 1 (GPER) in the invasion and migration of ectopic endometrial stromal cells (Ect-ESCs) and provides a new rationale for EMS treatment. Eutopic and ectopic endometrial tissues were collected from 41 EMS patients, and primary ESCs were separated. GPER, miR-16-5p, and miR-103a-3p levels in cells and tissues were determined by qRT-PCR or Western blot assay. Cell viability, proliferation, invasion, and migration were evaluated by CCK-8, colony formation, and Transwell assays. The upstream miRNAs of GPER were predicted by databases, and dual-luciferase assay was performed to validate the binding of miR-16-5p and miR-103a-3p to GPER 3'UTR. GPER was highly expressed in EMS tissues and Ect-ESCs. Inhibition of GPER mitigated the proliferation, invasion, and migration of Ect-ESCs. GPER was regulated by miR-16-5p and miR-103a-3p. Overexpression of miR-16-5p and miR-103a-3p negatively regulated GPER expression and inhibited the invasion and migration of Ect-ESC. In conclusion, GPER promoted the invasion and migration of Ect-ESCs, which can be reversed by upstream miR-16-5p and miR-103a-3p.

Metabo-Endotypes of Asthma Reveal Differences in Lung Function: Discovery and Validation in Two TOPMed Cohorts.

Rationale: Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a more detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes (i.e., subtypes defined by functional and/or pathobiological mechanisms). Objectives: To validate metabolomic-driven endotypes of asthma and explore their underlying biology. Methods: In the Genetics of Asthma in Costa Rica Study (GACRS), untargeted metabolomic profiling, similarity network fusion, and spectral clustering was used to identify metabo-endotypes of asthma, and differences in asthma-relevant phenotypes across these metabo-endotypes were explored. The metabo-endotypes were recapitulated in the Childhood Asthma Management Program (CAMP), and clinical differences were determined. Metabolomic drivers of metabo-endotype membership were investigated by meta-analyzing findings from GACRS and CAMP. Measurements and Main Results: Five metabo-endotypes were identified in GACRS with significant differences in asthma-relevant phenotypes, including prebronchodilator (p-ANOVA = 8.3 × 10-5) and postbronchodilator (p-ANOVA = 1.8 × 10-5) FEV1/FVC. These differences were validated in the recapitulated metabo-endotypes in CAMP. Cholesterol esters, trigylcerides, and fatty acids were among the most important drivers of metabo-endotype membership. The findings suggest dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. Conclusions: Clinically meaningful endotypes may be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes has the potential to help understand their pathophysiology.

Nucleotide, Phospholipid, and Kynurenine Metabolites Are Robustly Associated with COVID-19 Severity and Time of Plasma Sample Collection in a Prospective Cohort Study.

Understanding the molecular underpinnings of disease severity and progression in human studies is necessary to develop metabolism-related preventative strategies for severe COVID-19. Metabolites and metabolic pathways that predispose individuals to severe disease are not well understood. In this study, we generated comprehensive plasma metabolomic profiles in >550 patients from the Longitudinal EMR and Omics COVID-19 Cohort. Samples were collected before (n = 441), during (n = 86), and after (n = 82) COVID-19 diagnosis, representing 555 distinct patients, most of which had single timepoints. Regression models adjusted for demographics, risk factors, and comorbidities, were used to determine metabolites associated with predisposition to and/or persistent effects of COVID-19 severity, and metabolite changes that were transient/lingering over the disease course. Sphingolipids/phospholipids were negatively associated with severity and exhibited lingering elevations after disease, while modified nucleotides were positively associated with severity and had lingering decreases after disease. Cytidine and uridine metabolites, which were positively and negatively associated with COVID-19 severity, respectively, were acutely elevated, reflecting the particular importance of pyrimidine metabolism in active COVID-19. This is the first large metabolomics study using COVID-19 plasma samples before, during, and/or after disease. Our results lay the groundwork for identifying putative biomarkers and preventive strategies for severe COVID-19.

Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype.

Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated.Objectives: To study the sphingolipid-associated childhood asthma endotype using multiomic data.Methods: We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in de novo sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort.Measurements and Main Results: Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05.Conclusions: This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.

Maternal 17q21 genotype influences prenatal vitamin D effects on offspring asthma/recurrent wheeze.

BACKGROUND: Prenatal vitamin D3 supplementation has been linked to reduced risk of early-life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional single nucleotide polymorphism rs12936231 of the child, which regulates the expression of ORMDL3 (ORM1-like 3) and for which the high-risk CC genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze. METHODS: We determined the rs12936231 genotype of mother-child pairs from two randomised controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010, n=563), to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D3 supplementation versus placebo. RESULTS: Offspring of mothers with the low-risk GG or GC genotype who received high-dose vitamin D3 supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared with the placebo group (hazard ratio (HR) 0.54, 95% CI 0.37-0.77; p<0.001 for VDAART and HR 0.56, 95% CI 0.35-0.92; p=0.021 for COPSAC2010), whereas no difference was observed among the offspring of mothers with the high-risk CC genotype (HR 1.05, 95% CI 0.61-1.84; p=0.853 for VDAART and HR 1.11, 95% CI 0.54-2.28; p=0.785 for COPSAC2010). CONCLUSION: Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.

Fluorometric determination of ziram using CsPbBr3 quantum dots.

A strategy based on CsPbBr3 quantum dots (QDs) is described for the determination of ziram pesticide. A facile and inert gas-free method was used for the synthesis of CsPbBr3 QDs. The obtained CsPbBr3 QDs displayed turn-off fluorescence behavior for ziram. The fluorescence intensity of the CsPbBr3 QDs (Ex/Em = 365/516 nm) was inversely proportional to the concentration of ziram (0.10 to 50.0 ppm) with a detection limit of 0.086 ppm. Notably, satisfactory recoveries (100 ± 0.25 to 107 ± 5.72%) were obtained in spiked fruit samples, which demonstrated that this method is capable of detecting ziram in real samples. In addition, the mechanism for the detection of ziram was investigated in detail. According to the results, this mechanism can be tentatively explained by fluorescence quenching originating from the increased surface defects and the structural changes of the CsPbBr3 QDs. The detection ability of this strategy shows promising applicability in food safety.

Circulating SHBG (Sex Hormone-Binding Globulin) and Risk of Ischemic Stroke: Findings From the WHI.

Background and Purpose- Circulating levels of SHBG (sex hormone-binding globulin) have been inversely linked to obesity, diabetes mellitus, and other cardiometabolic disorders. It remains uncertain whether low SHBG is prospectively predictive of stroke risk, particularly in women. We investigated whether SHBG is associated with risk of incident ischemic stroke (IS) among women in the WHI (Women's Health Initiative). Methods- From an observational cohort of 161 808 postmenopausal women enrolled in the WHI at 40 sites across the United States from 1993 to 1998, we identified 13 192 participants free of prevalent stroke at baseline who were included in an ancillary study that measured serum SHBG. We used Cox proportional hazards regression, stratified by SHBG measurement assay, to assess IS risk across quintiles of SHBG (Q1-Q5), adjusting first for demographic variables (model 1), additionally for body mass index, hypertension, alcohol use, and smoking status (model 2), and for physical activity and reproductive risk factors (model 3). In sensitivity analyses, potential mediators (diabetes mellitus status, levels of estradiol, testosterone, and CRP [C-reactive protein]) were included. Results- Of 13 192 participants (mean age, 62.5 years; 67.4% non-Hispanic white, 18.5% black, 7.6% Hispanic, and 5.0% Asian), after following for an average of 11.6 years, 768 IS events were adjudicated. Compared with the highest quintile of SHBG levels (referent), women in the lowest SHBG quintile had a higher risk of IS in all 3 multivariable models (model 1: hazard ratio, 1.88 [95% CI, 1.47-2.41]; model 2: hazard ratio, 1.69 [95% CI, 1.30-2.20]; model 3: hazard ratio, 1.61 [95% CI, 1.19-2.19]; trend tests P<0.05 for all models). Including potential mediators such as diabetes mellitus, estradiol, and testosterone in the models attenuated but did not eliminate significant inverse associations between SHBG and IS. Conclusions- In this prospective cohort of postmenopausal women, there was a statistically significant inverse association between serum SHBG levels and IS risk, which supports the notion that SHBG could be used as a risk stratification tool for predicting IS in women.

Metabolomic signatures of lead exposure in the VA Normative Aging Study.

BACKGROUND: Lead (Pb) is widespread and exposure to this non-essential heavy metal can cause multiple negative health effects; however the mechanisms underlying these effects remain incompletely understood. OBJECTIVES: To identify plasma metabolomic signatures of Pb exposure, as measured in blood and toenails. METHODS: In a subset of men from the VA Normative Aging Study, mass-spectrometry based plasma metabolomic profiling was performed. Pb levels were measured in blood samples and toenail clippings collected concurrently. Multivariable linear regression models, smoothing splines and Pathway analyses were employed to identify metabolites associated with Pb exposure. RESULTS: In 399 men, 858 metabolites were measured and passed QC, of which 154 (17.9%) were significantly associated with blood Pb (p < 0.05). Eleven of these passed stringent correction for multiple testing, including pro-hydroxy-pro (ß(95%CI): 1.52 (0.93,2.12), p = 7.18x10-7), N-acetylglycine (ß(95%CI): 1.44 (0.85,2.02), p = 1.12x10-6), tartarate (ß(95%CI): 0.68 (0.35,1.00), p = 4.84x10-5), vanillylmandelate (ß(95%CI): 1.05 (0.47,1.63), p = 4.44x10-7), and lysine (ß(95%CI): 1.88 (-2.8,-0.95), p = 9.10x10-5). A subset of 48 men had a second blood sample collected a mean of 6.1 years after their first. Three of the top eleven metabolites were also significant in this second blood sample. Furthermore, we identified 70 plasma metabolites associated with Pb as measured in toenails. Twenty-three plasma metabolites were significantly associated with both blood and toenail measures, while others appeared to be specific to the biosample in which Pb was measured. For example, benzanoate metabolism appeared to be of importance with the longer-term exposure assessed by toenails. DISCUSSION: Pb exposure is responsible for 0.6% of the global burden of disease and metabolomics is particularly well-suited to explore its pathogenic mechanisms. In this study, we identified metabolites and metabolomic pathways associated with Pb exposure that suggest that Pb exposure acts through oxidative stress and immune dysfunction. These findings help us to better understand the biology of this important public health burden.

A dual-mode fluorometric/colorimetric sensor for Cu2+ detection based on hybridized carbon dots and gold-silver core-shell nanoparticles.

A fluorometric and colorimetric dual mode sensing platform based on hybridized carbon dots (Cdots) and gold-silver core-shell nanoparticles (Au@Ag NPs) has been established for the sensitive detection of trace Cu2+ ions in aqueous solution. In this system, the fluorescence of Cdots was quenched by Au@Ag NPs due to the surface plasmon-enhanced energy transfer. Due to the fact that Cu2+ could accelerate the etching process of Au@Ag NPs in the presence of thiosulfate, the fluorescence of Cdots was recovered. The limit of detection (LOD) is 4.81 nM for fluorometric measurements and 3.85 nM for colorimetric measurements. The dynamic range from these two modes is 0.005-1 µM. Importantly, Cu2+ in solution can also be directly visualized by this sensor via evident color change from the solution. Therefore, this dual mode nanosensor has potential applications for the efficient detection of Cu2+ ions in aqueous samples with great selectivity and high sensitivity.

Tomato yellow leaf curl virus: Characteristics, influence, and regulation mechanism.

Tomato yellow leaf curl virus (TYLCV), a DNA virus belonging to the genus Begomovirus, significantly impedes the growth and development of numerous host plants, including tomatoes and peppers. Due to its rapid mutation rate and frequent recombination events, achieving complete control of TYLCV proves exceptionally challenging. Consequently, identifying resistance mechanisms become crucial for safeguarding host plants from TYLCV-induced damage. This review article delves into the global distribution, dispersal patterns, and defining characteristics of TYLCV. Moreover, the intricate interplay between TYLCV and various influencing factors, such as insect vectors, susceptible host plants, and abiotic stresses, plays a pivotal role in plant-TYLCV interactions. The review offers an updated perspective on recent investigations focused on plant response mechanisms to TYLCV infection, including the intricate relationship between TYLCV, whiteflies, and regulatory factors. This comprehensive analysis aims to establish a foundation for future research endeavors exploring the molecular mechanisms underlying TYLCV infection and the development of plant resistance through breeding programs.

Differentiation of confluent hepatic fibrosis and infiltrative hepatocellular carcinoma on MR imaging.

BACKGROUND: To identify reliable magnetic resonance imaging (MRI) features that can differentiate confluent fibrosis (CF) from infiltrative hepatocellular carcinoma (HCC). METHODS: A retrospective analysis was conducted on Twenty CF patients and 28 infiltrative HCC patients who underwent upper abdomen MRI scans. The imaging features of lesions were analyzed, and the apparent diffusion coefficient (ADC) of lesions were measured. Accuracy, sensitivity and specificity for the diagnosis of CF were calculated for each category individually and combined. RESULTS: Compared to infiltrative HCC, hepatic capsular retraction at the site of lesion, hepatic volume loss at the site of lesion and "nodular surround sign" were more common in patients with CF (all P < 0.001). Hepatic volume loss at the site of lesion, no or mild enhancement in arterial phase, and hyper-enhancing in delayed phase to the background parenchyma showed superior diagnostic accuracy (83.3%, 85.4%, 97.9%, respectively). When the lesion exhibited hepatic volume loss at the site of lesion or no or mild enhancement in arterial phase or hyper-enhancing in delayed phase, a sensitivity of 100.0% for the diagnosis of CF was achieved. When the lesion was positive for any two of three categories, or positive for all three categories, a specificity of 100.0% was achieved. The ADC values of CF were higher than those of infiltrative HCC (P < 0.001). CONCLUSION: The combination of the hepatic volume loss at the site of lesion, no or mild enhancement in arterial phase, and hyper-enhancing in delayed phase to the background parenchyma can be considered reliable MR features for the diagnosis of CF, as they allow differentiation from infiltrative HCC.

Novel bidentate N-coordinated alkylaluminum complexes: synthesis, characterization, and efficient catalysis for hydrophosphonylation.

Five new alkylaluminum complexes with different pyridinyl-substituted imines or cyclohexyl-substituted imines were synthesized and characterized successfully. The aluminum complex [FlCHNCH(CH3)Py]AlMe2(Py = 2-pyridyl) (1) was obtained by reacting 9-[2-pyridyl-CH(CH3)-NCH]Fl (Fl = fluorenyl) (L1) and equimolar AlMe3. The reactions of 9-(2-pyridyl-NCH)Fl (L2) and 9-[2-N(CH3)2-cyclohexyl-NCH]Fl (L3) with equimolar AlMe3 or AlEt3 afforded other alkylaluminum complexes [FlCHNPy]AlMe2(Py = 2-pyridyl) (2), [FlCHNPy]AlEt2 (Py = 2-pyridyl) (3), [FlCHNCyN(CH3)2]AlMe2 (Cy = 2-cyclohexyl) (4) and [FlCHNCyN(CH3)2]AlEt2 (Cy = 2-cyclohexyl) (5). All these complexes (1-5) were characterized using NMR spectroscopy, elemental analysis, and X-ray crystal structure analysis. The catalytic properties of these new alkylaluminum complexes for the hydrophosphonylation of aldimines were examined. Complex 5 showed the best catalytic performance under mild reaction conditions with a low catalyst loading (1 mol%), and 20 different substituents of aldimines were isolated with more than 90% yields.

Metabolite signatures associated with microRNA miR-143-3p serve as drivers of poor lung function trajectories in childhood asthma.

BACKGROUND: Lung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants. METHODS: We utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and SNPs in their target genes. Statistical significance was determined using an false discovery rate-adjusted Q-value. FINDINGS: The top metabolite principal component, PCLF, was significantly associated with better LFTs after multiple-testing correction (Q-value = 0.03). PCLF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PCLF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PCLF was also significantly associated with microRNA miR-143-3p, and SNPs in three miR-143-3p target genes; CCZ1 (P-value = 2.6 × 10-5), SLC8A1 (P-value = 3.9 × 10-5); and TENM4 (P-value = 4.9 × 10-5). INTERPRETATION: This study reveals associations between metabolites, miR-143-3p and LFTs in children with asthma, offering insights into asthma physiology and possible interventions to enhance lung function and long-term health. FUNDING: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).

Magnetic resonance imaging features of bile duct adenoma.

Objectives: To evaluate the magnetic resonance imaging (MRI) features of bile duct adenoma. Methods: The data of 28 patients [with 32 pathologically confirmed bile duct adenomas, including 15 with malignant change (malignant group) and 17 without malignant change (benign adenoma group)] were retrospectively reviewed. Abdominal MRI was performed for all patients; in addition, dynamic enhanced MRI was performed for 18 lesions. The MRI features, including lesion location, maximum size, morphology, signal characteristics, enhancement type, and appearance of the bile duct, were assessed by two abdominal radiologists. Apparent diffusion coefficient (ADC) values were measured and compared. Results: Of the 32 bile duct adenomas, 22 (68.75%) involved the common bile duct (CBD). While 14/32 (43.75%) lesions presented as focal eccentric-type masses, 9/32 (28.13%) presented as plaque-like masses, 4/32 (12.50%) as bile duct casting masses, and 5/32 (15.62%) as infiltrative masses. A frond-like superficial appearance was seen in 8/32 (25%) lesions. Infiltrative masses were significantly more common in the malignant group than in the benign adenoma group (P = 0.015). While 23/32 (71.88%) lesions were isointense on T1-weighted imaging (T1WI), 24/32 (75%) were hyperintense on T2-weighted imaging (T2WI). Bile duct dilatation was present upstream of the lesion in all cases. Bile duct dilatation at the lesion was seen in 24/32 (75%) cases and downstream of the lesion in 6/32 (18.75%) cases. Of the 18 lesions that underwent dynamic enhanced MRI, 14 (77.78%) showed moderate enhancement and 13 (72.22%) showed persistent enhancement. On diffusion-weighted imaging (DWI), 27/32 (84.37%) lesions showed hyperintensity. Mean ADC value was comparable between the malignant group and the benign adenoma group (P = 0.156). Conclusions: Bile duct adenoma primarily presents as intraductal growth in the CBD, usually with bile duct dilatation at the lesion site or upstream to it. Most lesions are isointense on T1WI, are hyperintense on T2WI and DWI, and show moderate enhancement. A superficial frond-like appearance of the lesion and bile duct dilatation at the lesion or downstream to it might be characteristics of bile duct adenoma. An infiltrative appearance might indicate malignant transformation.

Plasma concentrations of per- and polyfluoroalkyl substances are associated with perturbations in lipid and amino acid metabolism.

Exposure to per- and polyfluoroalkyl substances (PFAS) through the environment can lead to harmful health outcomes and the development of disease. However, little is known about how PFAS impact underlying biology that contributes to these adverse health effects. The metabolome represents the end product of cellular processes and has been used previously to understand physiological changes that lead to disease. In this study, we investigated whether exposure to PFAS was associated with the global, untargeted metabolome. In a cohort of 459 pregnant mothers and 401 children, we quantified plasma concentrations of six individual PFAS- PFOA, PFOS, PFHXS, PFDEA, and PFNA- and performed plasma metabolomic profiling by UPLC-MS. In adjusted linear regression analysis, we found associations between plasma PFAS and perturbations in lipid and amino acid metabolites in both mothers and children. In mothers, metabolites of 19 lipid pathways and 8 amino acid pathways were significantly associated with PFAS exposure at an FDR<0.05 threshold; in children, metabolites of 28 lipid pathways and 10 amino acid pathways exhibited significant associations at FDR<0.05 with PFAS exposure. Our investigation found that metabolites of the Sphingomyelin, Lysophospholipid, Long Chain Polyunsaturated Fatty Acid (n3 and n6), Fatty Acid- Dicarboxylate, and Urea Cycle showed the most significant associations with PFAS, suggesting these may be particular pathways of interest in the physiological response to PFAS. To our knowledge, this is the first study to characterize associations between the global metabolome and PFAS across multiple periods in the life course to understand impacts on underlying biology, and the findings presented here are relevant in understanding how PFAS disrupt normal biological function and may ultimately give rise to harmful health effects.

The value of prospective metabolomic susceptibility endotypes: broad applicability for infectious diseases.

BACKGROUND: As new infectious diseases (ID) emerge and others continue to mutate, there remains an imminent threat, especially for vulnerable individuals. Yet no generalizable framework exists to identify the at-risk group prior to infection. Metabolomics has the advantage of capturing the existing physiologic state, unobserved via current clinical measures. Furthermore, metabolomics profiling during acute disease can be influenced by confounding factors such as indications, medical treatments, and lifestyles. METHODS: We employed metabolomic profiling to cluster infection-free individuals and assessed their relationship with COVID severity and influenza incidence/recurrence. FINDINGS: We identified a metabolomic susceptibility endotype that was strongly associated with both severe COVID (ORICUadmission = 6.7, p-value = 1.2 × 10-08, ORmortality = 4.7, p-value = 1.6 × 10-04) and influenza (ORincidence = 2.9; p-values = 2.2 × 10-4, ßrecurrence = 1.03; p-value = 5.1 × 10-3). We observed similar severity associations when recapitulating this susceptibility endotype using metabolomics from individuals during and after acute COVID infection. We demonstrate the value of using metabolomic endotyping to identify a metabolically susceptible group for two-and potentially more-IDs that are driven by increases in specific amino acids, including microbial-related metabolites such as tryptophan, bile acids, histidine, polyamine, phenylalanine, and tyrosine metabolism, as well as carbohydrates involved in glycolysis. INTERPRETATIONS: These metabolites may be identified prior to infection to enable protective measures for these individuals. FUNDING: The Longitudinal EMR and Omics COVID-19 Cohort (LEOCC) and metabolomic profiling were supported by the National Heart, Lung, and Blood Institute and the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health.

Circ-CREBBP inhibits sperm apoptosis via the PI3K-Akt signaling pathway by sponging miR-10384 and miR-143-3p.

Male reproductive diseases are becoming increasingly prominent, and sperm quality is an important indicator to reflect these diseases. Seminal plasma extracellular vesicles (SPEVs) are involved in sperm motility. However, their effects on sperm remain unclear. Here, we identified 222 differentially expressed circRNAs in SPEVs between boars with high or low sperm motility. We found that circ-CREBBP promoted sperm motility and inhibited sperm apoptosis by sponging miR-10384 and miR-143-3p. In addition, miR-10384 and miR-143-3p can regulate the expression of MCL1, CREB1 and CREBBP. Furthermore, we demonstrated that MCL1 interacted directly with BAX and that CREBBP interacted with CREB1 in sperm. We showed that inhibition of circ-CREBBP can reduce the expression of MCL1, CREB1 and CREBBP and increase the expression of BAX and CASP3, thus promoting sperm apoptosis. Our results suggest that circ-CREBBP may be a promising biomarker and therapeutic target for male reproductive diseases.