LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome.

Enzyme-mediated damage repair or mitigation, while common for nucleic acids, is rare for proteins. Examples of protein damage are elimination of phosphorylated Ser/Thr to dehydroalanine/dehydrobutyrine (Dha/Dhb) in pathogenesis and aging. Bacterial LanC enzymes use Dha/Dhb to form carbon-sulfur linkages in antimicrobial peptides, but the functions of eukaryotic LanC-like (LanCL) counterparts are unknown. We show that LanCLs catalyze the addition of glutathione to Dha/Dhb in proteins, driving irreversible C-glutathionylation. Chemo-enzymatic methods were developed to site-selectively incorporate Dha/Dhb at phospho-regulated sites in kinases. In human MAPK-MEK1, such "elimination damage" generated aberrantly activated kinases, which were deactivated by LanCL-mediated C-glutathionylation. Surveys of endogenous proteins bearing damage from elimination (the eliminylome) also suggest it is a source of electrophilic reactivity. LanCLs thus remove these reactive electrophiles and their potentially dysregulatory effects from the proteome. As knockout of LanCL in mice can result in premature death, repair of this kind of protein damage appears important physiologically.

Hyperuricemia as an independent risk factor for metabolic dysfunction-associated fatty liver disease in nonobese patients without type 2 diabetes mellitus.

According to the latest consensus statement, fatty liver complicated by specific metabolic abnormalities can be diagnosed as metabolic dysfunction-associated fatty liver disease (MAFLD) in nonobese patients without type 2 diabetes mellitus (T2DM). However, hyperuricemia (HUA), a manifestation of metabolic disorders, is excluded from diagnostic criteria. This study explored the association between HUA and MAFLD in nonobese patients without T2DM. A total of 28,187 participants were recruited from the Examination Center of the China-Japan Friendship Hospital from 2018 to 2022 and divided into four subgroups: nonobese patients without T2DM, obese patients without T2DM, nonobese patients with T2DM, and obese patients with T2DM. MAFLD was diagnosed by ultrasound combined with laboratory examinations. The association of HUA with MAFLD subgroups was performed by logistical regression analysis. The predictive ability of UA for MAFLD subgroups was assessed by receiver operating characteristics (ROC). HUA was positively associated with MAFLD in nonobese patients without T2DM in both males and females, even after adjusting for sex, BMI, dyslipidemia, and abnormal liver function. The association increased gradually with aging, especially in those over 40 yr old. HUA was an independent risk factor for MAFLD in nonobese patients without T2DM. We suggest that UA abnormalities might be considered in the diagnosis of MAFLD in nonobese patients without T2DM.NEW & NOTEWORTHY HUA is an independent risk factor for MAFLD in nonobese patients without T2DM. The association of HUA with MAFLD in nonobese patients without T2DM increased gradually with aging, especially in those over 40 yr old. In nonobese patients without T2DM, univariate analysis showed that females with HUA had a higher risk of MAFLD than males. However, the difference was narrowed after adjustment for confounders.

A noninvasive model discriminating significant histological changes in treatment-naive chronic hepatitis B patients with normal ALT.

BACKGROUND: Traditionally part of chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) are recommended to antiviral therapy referring to liver biopsy. However, liver biopsy is an invasive method with various potential complications. A noninvasive model was established in the study to evaluate liver histology and to identify the need of antiviral therapy. METHODS: A total of 614 liver biopsied CHB patients with ALT less than upper limit of normal from 2 centers were retrospectively analyzed. They were divided into a training cohort and a validation cohort. A noninvasive model to predict the significant liver histological changes was established and validated. RESULTS: The results of analysis showed that ALT, Age, platelet (PLT) and liver stiffness (LS) were independent risk factors for significant liver injury. The model was established based on the 4 indexes, with the area under the curve of 0.85 and 0.87 in training cohort and validation cohort. Meanwhile, 2 cut-off scores were selected. By applying the low cut-off score (- 0.207), patients without significant liver injury could be identified with high accuracy, with negative predictive value of 72.7% and 73.7% in training and validation cohorts. By applying the high cut-off score (0.537), the presence of significant liver injury could be diagnosed with high accuracy, with positive predictive value of 90.3% and 88.8% in the training and validation cohorts. By applying the model, liver biopsy would have been avoided in 87.6% (538/614) patients, with correct prediction in 87.9% (473/538). CONCLUSION: The novel noninvasive model composed of ALT, Age, PLT, LS can correctly assess liver histology in CHB patient with normal ALT, which helps to determine the need of antiviral therapy without liver biopsy.

Meteorin-like protein overexpression ameliorates fulminant hepatitis in mice by inhibiting chemokine-dependent immune cell infiltration.

Myokines, which are recently identified cytokines secreted by skeletal muscle in response to stimulation, are crucial for the maintenance of liver function. Fulminant hepatitis (FH) is a life-threatening pathological condition with severe hepatic dysfunction. In this study, we investigated the role of meteorin-like (METRNL), a new myokine, in the pathogenesis of FH. We compared serum samples and liver tissues from FH patients and healthy controls and found that hepatic and serum METRNL levels were significantly increased in FH patients, and serum METRNL levels were related to disease severity in FH patients. We then established a concanavalin A-induced FH model in METRNL-overexpressing and control mice. We found that hepatic METRNL levels in FH mice were significantly increased, and METRNL in the liver was mainly derived from macrophages. In the cultured mouse macrophage line (RAW264.7 cells) and mouse primary peritoneal macrophages (PMs), METRNL overexpression significantly inhibited the release of the proinflammatory cytokines TNF and IL-1ß. In METRNL-overexpressing mice, concanavalin A-induced liver injury was significantly ameliorated. Moreover, METRNL overexpression significantly reduced chemokine-dependent inflammatory cell infiltration into the liver. METRNL overexpression also suppressed liver CD4+ T cell differentiation into Th 1 cells and inhibited the secretion of Th 1 cytokines. Taken together, these data suggest that METRNL overexpression effectively ameliorates FH. Therefore, METRNL may serve as a potential biomarker and therapeutic target for FH.

Cold Exposure Regulates Hepatic Glycogen and Lipid Metabolism in Newborn Goats.

Cold exposure influences liver metabolism, thereby affecting energy homeostasis. However, the gene regulatory network of the liver after cold exposure remains poorly understood. In this study, we found that 24 h cold exposure (COLD, 6 °C) increased plasma glucose (GLU) levels, while reducing plasma non-esterified fatty acid (NEFA) and triglyceride (TG) levels compared to the room temperature (RT, 25 °C) group. Cold exposure increased hepatic glycogen content and decreased hepatic lipid content in the livers of newborn goats. We conducted RNA-seq analysis on the livers of newborn goats in both the RT and cold exposure groups. A total of 1600 genes were identified as differentially expressed genes (DEGs), of which 555 genes were up-regulated and 1045 genes were down-regulated in the cold exposure group compared with the RT group. Cold exposure increased the expression of genes involved in glycolysis, glycogen synthesis, and fatty acid degradation pathways. These results can provide a reference for hepatic lipid and glycogen metabolism in newborn goats after cold exposure.

Occurrence, spatial distribution and ecological risks of antibiotics in soil in urban agglomeration.

Antibiotics in soil environment are regarded as emerging pollutants and have introduced increasing risks to soil ecosystem and human health in rapid urbanization areas. Identifying the occurrence and spatial variability of antibiotics in soils is an urgent issue in sustaining soil security. In this study, antibiotics in soils were investigated and analyzed in Beijing-Tianjin-Hebei urban agglomeration. The occurrence, spatial distribution, and related affecting factors of antibiotics in soils were identified and ecological risks of antibiotics in soil environment were assessed. Results showed that (1) The mean concentration of soil antibiotics in Beijing-Tianjin-Hebei urban agglomeration was 21.79 µg/kg. Land use substantially affected the occurrence and concentration of antibiotics in soils. Concentrations of antibiotics in cropland and orchard soils were 2-3 times higher than the other land use types. (2) The concentrations of antibiotics in soils in Beijing-Tianjin-Hebei urban agglomeration presented a spatial pattern of high values in southeast, and low values in northwest. Spatial variability of antibiotics in soils was closely related to the application of organic fertilizer and wastewater irrigation as well as topographical features. Furthermore, soil properties and land management policy had substantial influences on soil antibiotics, and soil heavy metals may aggravate the accumulation of antibiotics in soils. (3) Ecological risks assessment of antibiotics in soils demonstrated that erythromycin (ERY), sulfamethoxazole (SMX), and doxycycline (DOX) may introduce high risks to soil ecosystem health, and more attention should be paid to the areas with intensive human activities that had potential high risk to soil ecosystem health. This study suggests that scientific land and soil management should be considered to prevent soil antibiotic pollution and sustain soil security in urban agglomeration.

[Distribution characteristics of 46 elements in drinking water in Ankang area in 2020].

OBJECTIVE: To understand the distribution characteristics of 46 elements in drinking water in Ankang area of Shanxi Province. METHODS: A total of 46 elements in drinking water samples collected in Ankang area during dry and wet seasons in 2020 were determined by inductively coupled plasma mass spectrometry(ICP-MS). According to the "drinking water hygiene standards"(GB 5749-2022) and "food safety national standards". the 46 elements were classified As general chemical indexes(Al, Mn, Fe, Cu, Zn), toxicological indexes(Cr, As, Cd, Hg, Pb, Ba, B, Mo, Ni, Sb, Be, Ag, Tl), new reference indexes(U, V), and major elements(K, Ca, N) A, Mg), trace elements(Li, Co, Se, Sr, Sn) and rare earth elements(Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Th) were analyzed and described. RESULTS: The maximum values of Al and Fe in drinking water in Ankang area were 1.21 and 0.98 mg/L, exceeding the limits of 0.2 and 0.3 mg/L. In dry season, the median content of Fe in drinking water of different water sources was higher in groundwater than in surface water. The Al and Fe of surface water were higher than that of groundwater in wet season. The toxicological indexes all met the standard requirements, and there was no significant difference among districts and counties. The median content of Na in drinking water of different water sources was higher in groundwater than in surface water, while Mg, K and Ca were higher in surface water than in groundwater. The maximum value of the newly added reference index U was 0.015 mg/L lower than the limit standard 0.03 mg/L, and the maximum value of V was 0.019 mg/L higher than the limit standard 0.01 mg/L, but the median of both indexes were low. The median content of Li in drinking water of different water sources was that surface water was higher than groundwater, while Se and Sr were higher in groundwater than surface water. The maximum content of Se was 0.016 mg/L in Ziyang County, and Sr content was generally higher. The content of rare earth elements was low, mostly below the detection. CONCLUSION: The drinking water quality in Ankang area is excellent and rich in strontium. However, the general chemical indexes Al, Fe and the newly added appendix index V in some sampling points exceed the limit standard, so supervision and monitoring should be strengthened.

N-myc and STAT interactor correlates with severity and prognosis in acute-on-chronic liver failure of hepatitis B virus.

BACKGROUND AND AIM: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is characterized by acute deterioration of chronic liver disease with excessive inflammation. N-myc and STAT interactor (NMI), an inflammation-mediated protein, involves in various inflammatory-related diseases, but the role of NMI in development and prognosis in HBV-ACLF remains to be elucidated. METHODS: Serum NMI from healthy controls (HCs, n = 20), chronic hepatitis B (CHB, n = 50) patients, and HBV-ACLF patients (n = 50) was determined using ELISA. NMI from peripheral blood mononuclear cells and liver was confirmed using quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. RESULTS: Serum NMI was increased 1.9-fold or 2.2-fold from HBV-ACLF patients compared with that from HCs (P < 0.01) or CHB patients (P < 0.01). Consistently, NMI from peripheral blood mononuclear cells was upregulated significantly from HBV-ACLF patients compared with that from HCs and CHB patients at mRNA and protein levels. Hepatic NMI from HBV-ACLF patients was 2.8-fold higher than that from HCs. Serum NMI was correlated with Model for End-stage Liver Disease, Chronic Liver Failure Consortium ACLF score, and ACLF grades. In contrast, serum NMI was significantly decreased in HBV-ACLF ameliorated patients during follow-up, whereas serum NMI was sustained at high levels in non-ameliorated patients. Elevated serum NMI (≥ 198.5 pg/mL) was correlated with poor survival rate of HBV-ACLF patients. Using receiver operating characteristics curves, it was suggested that serum NMI was a potential biomarker in predicting 3-month mortality of HBV-ACLF patients. CONCLUSIONS: Our study highlights the potential role of NMI in assessing the development and prognosis of HBV-ACLF.

Ambient temperature fabrication of a covalent organic framework from 1,3,5-triformylphloroglucinol and 1,4-phenylenediamine as a coating for use in open-tubular capillary electrochromatography of drugs and amino acids.

A covalent organic framework (COF) named TpPa-1 was designed and synthesized at ambient temperature by an ultrasound-assisted method from 1,3,5-triformylphloroglucinol (Tp) and 1,4-phenylenediamine (Pa-1). It was utilized as a stationary phase in open-tubular capillary electrochromatography (OT-CEC). The column was coated with TpPa-1 using a covalent bonding strategy. The coated capillary was characterized by morphology, crystallography, and mesoporous analysis to confirm the successful fabrication. The OT-CEC method was utilized for the analysis of tetracyclines, sulfonamides, cephalosporins and amino acids with high-resolution (Rs > 1.81) and good precision (RSD < 4.9%). It takes about 12 h from COF preparation to OT-CEC separation. Graphical abstract A covalent organic framework (COF) named TpPa-1 was synthesized at ambient temperature by an ultrasound-assisted method from 1,3,5-triformylphloroglucinol (Tp) and 1,4-phenylenediamine (Pa-1). COF-TpPa-1 modified capillary column was utilized for the analysis of tetracyclines, sulfonamides, cephalosporins and amino acids with high-resolution and good precision.

Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways.

Bisphosphonates are a major class of drugs used to treat osteoporosis, Paget's disease, and cancer. They have been proposed to act by inhibiting one or more targets including protein prenylation, the epidermal growth factor receptor, or the adenine nucleotide translocase. Inhibition of the latter is due to formation in cells of analogs of ATP: the isopentenyl ester of ATP (ApppI) or an AppXp-type analog of ATP, such as AMP-clodronate (AppCCl2p). We screened both ApppI as well as AppCCl2p against a panel of 369 kinases finding potent inhibition of some tyrosine kinases by AppCCl2p, attributable to formation of a strong hydrogen bond between tyrosine and the terminal phosphonate. We then synthesized bisphosphonate preprodrugs that are converted in cells to other ATP-analogs, finding low nM kinase inhibitors that inhibited cell signaling pathways. These results help clarify our understanding of the mechanisms of action of bisphosphonates, potentially opening up new routes to the development of bone resorption, anticancer, and anti-inflammatory drug leads.

Antiinfectives targeting enzymes and the proton motive force.

There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 µg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.

A Highly Efficient Single-Chain Metal-Organic Nanoparticle Catalyst for Alkyne-Azide "Click" Reactions in Water and in Cells.

We show that copper-containing metal-organic nanoparticles (MONPs) are readily synthesized via Cu(II)-mediated intramolecular cross-linking of aspartate-containing polyolefins in water. In situ reduction with sodium ascorbate yields Cu(I)-containing MONPs that serve as highly efficient supramolecular catalysts for alkyne-azide "click chemistry" reactions, yielding the desired 1,4-adducts at low parts per million catalyst levels. The nanoparticles have low toxicity and low metal loadings, making them convenient, green catalysts for alkyne-azide "click" reactions in water. The Cu-MONPs enter cells and perform efficient, biocompatible click chemistry, thus acting as intracellular nanoscale molecular synthesizers.

Chemical Exchange Saturation Transfer (CEST) Agents: Quantum Chemistry and MRI.

Diamagnetic chemical exchange saturation transfer (CEST) contrast agents offer an alternative to Gd(3+) -based contrast agents for MRI. They are characterized by containing protons that can rapidly exchange with water and it is advantageous to have these protons resonate in a spectral window that is far removed from water. Herein, we report the first results of DFT calculations of the (1) H nuclear magnetic shieldings in 41 CEST agents, finding that the experimental shifts can be well predicted (R(2) =0.882). We tested a subset of compounds with the best MRI properties for toxicity and for activity as uncouplers, then obtained mice kidney CEST MRI images for three of the most promising leads finding 16 (2,4-dihydroxybenzoic acid) to be one of the most promising CEST MRI contrast agents to date. Overall, the results are of interest since they show that (1) H NMR shifts for CEST agents-charged species-can be well predicted, and that several leads have low toxicity and yield good in vivo MR images.

[Active sites of N-acetylhexosamine 1-kinase from Bifidobacterium longum].

OBJECTIVE: To study the active sites of N-acetylhexosamine 1-kinase (NahK) from Bifidobacterium longum JCM12 17. METHODS: We obtained expression strains of 10 single-mutants at 4 sites of NahK by site-directed mutagenesis, and expressed and purified both wild-type (WT) and mutant enzymes. Then, their optimum pH and optimum concentration of Mg²âº were determined by DNS assay and NADH-coupled microplate photometric assay, and their kinetic parameters were measured. RESULTS: Four mutants (D208A, D208N, D208E and I24A) lost most part of the catalytic activity. The optimum pH of mutants H31A, H31V, F247A and I24V switched from pH 7.5 (for WT) to pH 7.0, and the optimum concentration of Mg²âº of mutants H31A and F247A increased to 10 mmol/L from 5 mmol/L (for WT). The kinetic parameters of WT and mutants indicate that mutant F247Y had higher enzymatic activity toward GlcNAc, GalNAc and ATP than WT. CONCLUSION: The key amino acids that affect the catalytic activity of NahK were determined by site-directed mutagenesis, and together with the mutant that has higher catalytic efficiency, this has laid a foundation for further modification and evolution of NahK.

Levels and Health Risk Assessment of Inorganic Arsenic, Methylmercury, and Heavy Metals in Edible Mushrooms Collected from Online Supermarket in China.

Chromium (Cr), total arsenic (As), inorganic arsenic (iAs), cadmium (Cd), mercury (Hg), methylmercury (MeHg), and lead (Pb) were analyzed in in Agaricus blazei, Tricholoma matsutake, Pholiota nameko, agrocybe aegirit, Boletus edulis, Auricularia auricula, and Lentinus edodes collected from online supermarket in China from 2015 to 2017. The order of mean concentrations for the five heavy metals in edible mushrooms was As > Cd > Cr > Pb > Hg. No positive correlation was found between total As and iAs, nor between total Hg and MeHg. The contents of iAs were at a low level except for A. blazei samples. The contents of MeHg were at a low level in all test mushroom samples. And Cr, Cd, and Pb pollution were common problems in the test mushroom samples. The comprehensive factor pollution index was between 0.569 (A. auricula) and 3.056 (B. edulis). The THQ values for the five heavy metals from P. nameko, A. auricula, A. aegirit, and L. edodes samples were less than 1. The hazard index (HI) values of A. blazei, T. matsutake, and B. edulis samples for adults and children were greater than 1, indicating significant health hazard to the adults and children consumers. The cancer risk (CR) values for iAs ranged from 3.82 × 10- 6 (T. matsutake) to 8.61 × 10- 5 (A. blazei), indicating no potential carcinogenic risk to the consumers. The order for carcinogenic risk of each edible mushroom species was A. blazei > L. edodes > P. nameko > A. aegirit > A. auricula > B. edulis > T. matsutake.

Metformin inhibits high glucose-induced apoptosis of renal podocyte through regulating miR-34a/SIRT1 axis.

BACKGROUND: Previous studies have reported SIRT1 was inversely modulated by miR-34a, However, mechanism of metformin (MFN)'s renal podocyte protection under high glucose (HG) conditions and the connection between miR-34a and SIRT1 expression in diabetic nephropathy (DN) remain unclear. METHOD: We aimed to further elucidate the role of miR-34a in HG-treated podocytes in DN. A conditionally immortalized human podocyte cell line was cultivated in d-glucose (30 mM). RESULTS: Microarray and RT-qPCR revealed that miR-34a was downregulated in HG-treated podocytes. Additionally, miR-34a levels increased in MFN-treated HG-induced podocytes. CCK-8 assay, colony formation assay, flow cytometry, and Western blot detection showed that HG treatment reduced cell viability and promoted via HG treatment, and MFN treatment reversed this phenotypic change. MiR-34a upregulation caused restored cell viability and suppressed cell apoptosis in HG-treated podocytes, and miR-34a downregulation led to damaged cell survival and induced apoptosis in MFN-administered and HG-treated podocytes. The dual luciferase reporter assay showed that SIRT1 3'-UTR was a direct miR-34a target. Further studies demonstrated an elevation in SIRT1 levels in HG-exposed podocytes, whereas MFN treatment decreased SIRT1 levels. In addition, miR-34a upregulation led to reduced SIRT1 expression, whereas miR-34a inhibition increased SIRT1 levels in cells. MFN-induced miR-34a suppresses podocyte apoptosis under HG conditions by acting on SIRT1. CONCLUSION: This study proposes a promising approach to interpret the mechanisms of action of the MFN-miR-34a axis involved in DN.

The association between indoor air pollution from solid fuels and cognitive impairment: a systematic review and meta-analysis.

This study aimed to comprehensively and methodically evaluate the correlation between cognitive impairment and indoor air pollution from solid fuel used for cooking/heating. PubMed, Web of Science, EMBASE, and Cochrane Library databases were searched up to December January 2023. 13 studies from three countries with a total of 277,001 participants were enrolled. A negative correlation was discovered between solid fuel usage for cooking and total cognitive score (ß=-0.73, 95 % CI: -0.90 to -0.55) and episodic memory score (ß=-0.23, 95 % CI: -0.30 to -0.17). Household solid fuel usage for cooking was considerably associated with a raised risk of cognitive impairment (HR=1.31, 95 % CI: 1.09-1.57) and cognitive decline (HR=1.24, 95 % CI: 1.18-1.30). Compared to continuous solid fuel use for cooking, sustained use of clean fuel and switching from solid fuel to clean fuel were associated with a lower risk of cognitive decline (OR=0.55, 95 % CI: 0.42-0.73; OR=0.81, 95 % CI: 0.71-0.93). A negative association was found between solid fuel usage for heating and total cognitive score (ß=-0.43, 95 % CI: -0.59 to -0.26) and episodic memory score (ß=-0.22, 95 % CI: -0.34 to -0.10). Our research provided evidence that exposure to indoor air pollution from solid fuel is a potential cause of cognitive impairment and cognitive decline. Making the switch from solid fuels to cleaner fuels could be an important step in preventing cognitive impairment in the elderly.

Correlation between the Severity of Metabolic Dysfunction-Associated Fatty Liver Disease and Serum Uric Acid to Serum Creatinine Ratio.

Purpose: As one of the most common chronic liver diseases, metabolic dysfunction-associated fatty liver disease (MAFLD) had different prognoses between mild and moderate-severe levels. Serum uric acid to serum creatinine ratio (sUA/Cr) can reflect the overall metabolic status of the body. To explore a convenient indicator to screen MAFLD and distinguish the severity of the disease, this study analyzed the correlation between sUA/Cr and the severity of MAFLD. Methods: 228 participants were enrolled and divided into 2 groups, including mild MAFLD and non-MAFLD group and moderate-severe MAFLD group, based on liver/spleen computed tomography (CT) ratios. The correlations between sUA/Cr and the severity of MAFLD were analyzed by logistic and linear regression. Receiver operating characteristics (ROCs) analyzed the predictive ability of sUA/Cr for the severity of MAFLD expressed by the area under curve (AUC). Results: The level of sUA/Cr was higher in themoderate-severe MAFLD group than mild MAFLD and non-MAFLD group (6.14 ± 1.55 vs. 5.51 ± 1.19, P = 0.008). After adjustment for confounders, the correlation analysis showed that patients with elevated sUA/Cr had a higher risk of moderate-severe MAFLD (OR: 1.350, P = 0.036). A higher sUA/Cr level was associated with lower liver CT values (ß = -0.133, P = 0.039) and liver/spleen CT ratio (ß = -0.154, P = 0.016). sUA/Cr had the ability to discriminate the severity of MAFLD (AUC: 0.623). Conclusion: sUA/Cr was positively associated with the risk of moderate-severe MAFLD and had the predictive ability to discriminate the moderate-severe MAFLD from mild MAFLD and non-MAFLD. The sUA/Cr level was suggested to be monitored and controlled in the screening and treatment of MAFLD.

Clinic-radiomics model using liver magnetic resonance imaging helps predict chronicity of drug-induced liver injury.

BACKGROUND AND AIMS: Some drug-induced liver injury (DILI) cases may become chronic, even after drug withdrawal. Radiomics can predict liver disease progression. We established and validated a predictive model incorporating the clinical characteristics and radiomics features for predicting chronic DILI. METHODS: One hundred sixty-eight DILI patients who underwent liver gadolinium-diethylenetriamine pentaacetate-enhanced magnetic resonance imaging were recruited. The patients were clinically diagnosed using the Roussel Uclaf causality assessment method. Patients who progressed to chronicity or recovery were randomly divided into the training (70%) and validation (30%) cohorts, respectively. Hepatic T1-weighted images were segmented to extract 1672 radiomics features. Least absolute shrinkage and selection operator regression was used for feature selection, and Rad-score was constructed using support vector machines. Multivariable logistic regression analysis was performed to build a clinic-radiomics model incorporating clinical characteristics and Rad-scores. The clinic-radiomics model was evaluated for its discrimination, calibration, and clinical usefulness in the independent validation set. RESULTS: Of 1672 radiomics features, 28 were selected to develop the Rad-score. Cholestatic/mixed patterns and Rad-score were independent risk factors of chronic DILI. The clinic-radiomics model, including the Rad-score and injury patterns, distinguished chronic from recovered DILI patients in the training (area under the receiver operating characteristic curve [AUROC]: 0.89, 95% confidence interval [95% CI]: 0.87-0.92) and validation (AUROC: 0.88, 95% CI: 0.83-0.91) cohorts with good calibration and great clinical utility. CONCLUSION: The clinic-radiomics model yielded sufficient accuracy for predicting chronic DILI, providing a practical and non-invasive tool for managing DILI patients.

Estimating Potential Outcome Distributions with Collaborating Causal Networks.

Traditional causal inference approaches leverage observational study data to estimate the difference in observed (factual) and unobserved (counterfactual) outcomes for a potential treatment, known as the Conditional Average Treatment Effect (CATE). However, CATE corresponds to the comparison on the first moment alone, and as such may be insufficient in reflecting the full picture of treatment effects. As an alternative, estimating the full potential outcome distributions could provide greater insights. However, existing methods for estimating treatment effect potential outcome distributions often impose restrictive or overly-simplistic assumptions about these distributions. Here, we propose Collaborating Causal Networks (CCN), a novel methodology which goes beyond the estimation of CATE alone by learning the full potential outcome distributions. Estimation of outcome distributions via the CCN framework does not require restrictive assumptions of the underlying data generating process (e.g. Gaussian errors). Additionally, our proposed method facilitates estimation of the utility of each possible treatment and permits individual-specific variation through utility functions (e.g. risk tolerance variability). CCN not only extends outcome estimation beyond traditional risk difference, but also enables a more comprehensive decision making process through definition of flexible comparisons. Under assumptions commonly made in the causal inference literature, we show that CCN learns distributions that asymptotically capture the correct potential outcome distributions. Furthermore, we propose an adjustment approach that is empirically effective in alleviating sample imbalance between treatment groups in observational studies. Finally, we evaluate the performance of CCN in multiple experiments on both synthetic and semi-synthetic data. We demonstrate that CCN learns improved distribution estimates compared to existing Bayesian and deep generative methods as well as improved decisions with respects to a variety of utility functions.