Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

Noninvasive tests maintain high accuracy for advanced fibrosis in chronic hepatitis B patients with different nomenclatures of steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a new nomenclature proposed in 2023. We aimed to compare the diagnostic efficacy of noninvasive tests (NITs) for advanced fibrosis under different nomenclatures in patients with chronic hepatitis B (CHB). A total of 844 patients diagnosed with CHB and concurrent steatotic liver disease (SLD) by liver biopsy were retrospectively enrolled and divided into four groups. The performances of fibrosis-4 (FIB-4), gamma-glutamyl transpeptidase to platelet ratio index (GPRI), aspartate aminotransferase to platelet ratio index (APRI), and liver stiffness measurement (LSM) were compared among the four groups. The four NITs showed similar diagnostic efficacy for nonalcoholic fatty liver disease (NAFLD), MASLD, and metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with CHB with advanced fibrosis. LSM showed the most stable accuracy for NAFLD (AUC = 0.842), MASLD (AUC = 0.846), and MAFLD (AUC = 0.863) compared with other NITs (p < 0.05). Among the four NITs, APRI (AUC = 0.841) and GPRI (AUC = 0.844) performed best in patients with CHB & MetALD (p < 0.05). The cutoff value for GPRI in patients with CHB & MetALD was higher than that in the other three groups, while further comparisons of NITs at different fibrosis stages showed that the median GPRI of CHB & MetALD (1.113) at F3-4 was higher than that in the CHB & MASLD group (0.508) (p < 0.05). Current NITs perform adequately in patients with CHB and SLD; however, alterations in cutoff values for CHB & MetALD need to be noted.

Aerosol liquid water in PM2.5 and its roles in secondary aerosol formation at a regional site of Yangtze River Delta.

Aerosol liquid water content (ALWC) plays an important role in secondary aerosol formation. In this study, a whole year field campaign was conducted at Shanxi in north Zhejiang Province during 2021. ALWC estimated by ISORROPIA-II was then investigated to explore its characteristics and relationship with secondary aerosols. ALWC exhibited a highest value in spring (66.38 µg/m3), followed by winter (45.08 µg/m3), summer (41.64 µg/m3), and autumn (35.01 µg/m3), respectively. It was supposed that the secondary inorganic aerosols (SIA) were facilitated under higher ALWC conditions (RH > 80%), while the secondary organic species tended to form under lower ALWC levels. Higher RH (> 80%) promoted the NO3- formation via gas-particle partitioning, while SO42- was generated at a relative lower RH (> 50%). The ALWC was more sensitive to NO3- (R = 0.94) than SO42- (R = 0.90). Thus, the self-amplifying processes between the ALWC and SIA enhanced the particle mass growth. The sensitivity of ALWC and OX (NO2 + O3) to secondary organic carbon (SOC) varied in different seasons at Shanxi, more sensitive to aqueous-phase reactions (daytime R = 0.84; nighttime R = 0.54) than photochemical oxidation (daytime R = 0.23; nighttime R = 0.41) in wintertime with a high level of OX (daytime: 130-140 µg/m3; nighttime: 100-140 µg/m3). The self-amplifying process of ALWC and SIA and the aqueous-phase formation of SOC will enhance aerosol formation, contributing to air pollution and reduction of visibility.

Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer.

Recently, chimeric antigen receptor T cell (CAR-T) therapy has received increasing attention as an adoptive cellular immunotherapy that targets tumors. However, numerous challenges remain for the effective use of CAR-T to treat solid tumors, including ovarian cancer, which is an aggressive and metastatic cancer with a poor therapeutic response. We screened for an effective anti-MSLN single-chain Fv antibody with comparable binding activity and non-off-target properties using human phage display library. A second-generation of anti-MSLN CAR was designed and generated. We demonstrated the efficacy of our anti-MSLN CAR-T cells for ovarian cancer treatment in an in vitro experiment to kill ovarian tumor cell lines. The anti-MSLN CAR-T cells impeded MSLN-positive tumor growth concomitant with a significant increase in cytokine levels compared with the control. Then, we demonstrated the efficacy of anti-MSLN CAR-T cells in an in vivo experiment against ovarian cancer cell-derived xenografts. Furthermore, we herein report three cases with ovarian cancer who were treated with autologous anti-MSLN CAR-T cells and evaluate the safety and effectiveness of adoptive cell therapy. In this investigator-initiated clinical trials, no patients experienced cytokine release syndrome or neurological symptoms over 2 grads. Disease stabilized in two patients, with progression-free survival times of 5.8 and 4.6 months. Transient CAR expression was detected in patient blood after infusion each time. The tumor partially subsided, and the patient's condition was relieved. In conclusion, this work proves the efficacy of the anti-MSLN CAR-T treatment strategy in ovarian cancer and provides preliminary data for the development of further clinical trials.

Associations between abdominal obesity indices and pathological features of non-alcoholic fatty liver disease: Chinese visceral adiposity index.

BACKGROUND AND AIM: Many abdominal obesity indices such as waist circumference (WC), lipid accumulation product (LAP), visceral obesity index (VAI), and Chinese VAI (CVAI) have been considered to be associated with the risk of non-alcoholic fatty liver disease (NAFLD), but the association between abdominal obesity indices and the pathological features of NAFLD is uncertain. This study aims to explore the associations between these indices and the pathological features of NAFLD. METHODS: A total of 147 patients with biopsy-confirmed NAFLD were enrolled in the final analysis. General information, biochemical tests, and pathological information of patients were collected. VAI, LAP, and CVAI were calculated. Spearman's correlation analysis and logistics regression analysis were applied to assess the relationship between abdominal obesity indices and the pathological features of NAFLD. Receiver operating characteristic curve analyses were used to assess the value of abdominal obesity indices in predicting liver fibrosis and non-alcoholic steatohepatitis. RESULTS: Non-alcoholic fatty liver disease activity score (NAS) ≥ 5 significantly correlated with WC, LAP, VAI, and CVAI both in univariate and multivariate analyses (P < 0.05). Fibrosis was significantly and positively correlated with WC, LAP, and CVAI (P < 0.05). After adjustment for potential confounders, fibrosis remained associated with CVAI (P < 0.05). CONCLUSION: CVAI is significantly associated with the pathological features of NAFLD, and CVAI shows the most superior efficacy in diagnosing fibrosis among these indices.

MicroRNA-494-3p Exacerbates Renal Epithelial Cell Dysfunction by Targeting SOCS6 under High Glucose Treatment.

BACKGROUND: Diabetic nephropathy is a common complication of the kidneys induced by diabetes and is the main cause of end-stage renal disease. MicroRNA-494-3p was reported to be upregulated in renal tissues collected from db/db mice, but its specific role in diabetic nephropathy was still unclear. This study aimed to explore the effect of miR-494-3p on renal fibrosis using an in vitro cell model of diabetic nephropathy. METHODS: After human renal tubular epithelial cells (HK-2) were treated with high glucose (HG), the viability and apoptosis of cells were examined by CCK-8 assays and flow cytometry analyses. Additionally, protein levels of fibronectin, collagen I, collagen III, collagen IV, and epithelial-mesenchymal transition (EMT) markers in HG-induced HK-2 cells were quantified by Western blotting. miR-494-3p expression in HK-2 cells was detected by reverse-transcription quantitative polymerase chain reaction. The binding relation between miR-494-3p and the messenger RNA suppressor of cytokine signaling 6 (SOCS6) was detected by luciferase reporter assays. RESULTS: HG reduced cell viability and enhanced cell apoptosis in a time- or concentration-dependent manner. Additionally, HG induced collagen accumulation and triggered the EMT process. miR-494-3p was upregulated in HG-treated HK-2 cells. miR-494-3p inhibition alleviated HG-induced cell dysfunction. Mechanistically, miR-494-3p bound with SOCS6 and negatively regulated SOCS6 expression. Moreover, silencing SOCS6 rescued the suppressive effect of miR-499-5p inhibition on HG-induced cell dysfunction. CONCLUSION: miR-494-3p aggravates renal fibrosis, EMT process, and cell apoptosis by targeting SOCS6, suggesting that the miR-494-3p/SOCS6 axis may become a potential strategy for the treatment of diabetic nephropathy.

Numerical Study on the Coagulation and Breakage of Nanoparticles in the Two-Phase Flow around Cylinders.

The Reynolds averaged N-S equation and dynamic equation for nanoparticles are numerically solved in the two-phase flow around cylinders, and the distributions of the concentration M0 and geometric mean diameter dg of particles are given. Some of the results are validated by comparing with previous results. The effects of particle coagulation and breakage and the initial particle concentration m00 and size d0 on the particle distribution are analyzed. The results show that for the flow around a single cylinder, M0 is reduced along the flow direction. Placing a cylinder in a uniform flow will promote particle breakage. For the flow around multiple cylinders, the values of M0 behind the cylinders oscillate along the spanwise direction, and the wake region in the flow direction is shorter than that for the flow around a single cylinder. For the initial monodisperse particles, the values of dg increase along the flow direction and the effect of particle coagulation is larger than that of particle breakage. The values of dg fluctuate along the spanwise direction; the closer to the cylinders, the more frequent the fluctuations of dg values. For the initial polydisperse particles with d0 = 98 nm and geometric standard deviation σ = 1.65, the variations of dg values along the flow and spanwise directions show the same trend as for the initial monodisperse particles, although the differences are that the values of dg are almost the same for the cases with and without considering particle breakage, while the distribution of dg along the spanwise direction is flatter in the case with initial polydisperse particles.

Heat Transfer and Pressure Drop of Nanofluid with Rod-like Particles in Turbulent Flows through a Curved Pipe.

Pressure drop, heat transfer, and energy performance of ZnO/water nanofluid with rodlike particles flowing through a curved pipe are studied in the range of Reynolds number 5000 ≤ Re ≤ 30,000, particle volume concentration 0.1% ≤ Φ ≤ 5%, Schmidt number 104 ≤ Sc ≤ 3 × 105, particle aspect ratio 2 ≤ λ ≤ 14, and Dean number 5 × 103 ≤ De ≤ 1.5 × 104. The momentum and energy equations of nanofluid, together with the equation of particle number density for particles, are solved numerically. Some results are validated by comparing with the experimental results. The effect of Re, Φ, Sc, λ, and De on the friction factor f and Nusselt number Nu is analyzed. The results showed that the values of f are increased with increases in Φ, Sc, and De, and with decreases in Re and λ. The heat transfer performance is enhanced with increases in Re, Φ, λ, and De, and with decreases in Sc. The ratio of energy PEC for nanofluid to base fluid is increased with increases in Re, Φ, λ, and De, and with decreases in Sc. Finally, the formula of ratio of energy PEC for nanofluid to base fluid as a function of Re, Φ, Sc, λ, and De is derived based on the numerical data.

Transcriptomic profiling provides molecular insights into hydrogen peroxide-induced adventitious rooting in mung bean seedlings.

BACKGROUND: Hydrogen peroxide (H2O2) has been known to function as a signalling molecule involved in the modulation of various physiological processes in plants. H2O2 has been shown to act as a promoter during adventitious root formation in hypocotyl cuttings. In this study, RNA-Seq was performed to reveal the molecular mechanisms underlying H2O2-induced adventitious rooting. RESULTS: RNA-Seq data revealed that H2O2 treatment greatly increased the numbers of clean reads and expressed genes and abundance of gene expression relative to the water treatment. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that a profound change in gene function occurred in the 6-h H2O2 treatment and that H2O2 mainly enhanced gene expression levels at the 6-h time point but reduced gene expression levels at the 24-h time point compared with the water treatment. In total, 4579 differentially expressed (2-fold change > 2) unigenes (DEGs), of which 78.3% were up-regulated and 21.7% were down-regulated; 3525 DEGs, of which 64.0% were up-regulated and 36.0% were down-regulated; and 7383 DEGs, of which 40.8% were up-regulated and 59.2% were down-regulated were selected in the 6-h, 24-h, and from 6- to 24-h treatments, respectively. The number of DEGs in the 6-h treatment was 29.9% higher than that in the 24-h treatment. The functions of the most highly regulated genes were associated with stress response, cell redox homeostasis and oxidative stress response, cell wall loosening and modification, metabolic processes, and transcription factors (TFs), as well as plant hormone signalling, including auxin, ethylene, cytokinin, gibberellin, and abscisic acid pathways. Notably, a large number of genes encoding for heat shock proteins (HSPs) and heat shock transcription factors (HSFs) were significantly up-regulated during H2O2 treatments. Furthermore, real-time quantitative PCR (qRT-PCR) results showed that, during H2O2 treatments, the expression levels of ARFs, IAAs, AUXs, NACs, RD22, AHKs, MYBs, PIN1, AUX15A, LBD29, LBD41, ADH1b, and QORL were significantly up-regulated at the 6- and/or 24-h time points. In contrast, PER1 and PER2 were significantly down-regulated by H2O2 treatment. These qRT-PCR results strongly correlated with the RNA-Seq data. CONCLUSIONS: Using RNA-Seq and qRT-PCR techniques, we analysed the global changes in gene expression and functional profiling during H2O2-induced adventitious rooting in mung bean seedlings. These results strengthen the current understanding of H2O2-induced adventitious rooting and the molecular traits of H2O2 priming in plants.

Transcriptomic analysis reveals the gene expression profile that specifically responds to IBA during adventitious rooting in mung bean seedlings.

BACKGROUND: Auxin plays a critical role in inducing adventitious rooting in many plants. Indole-3-butyric acid (IBA) is the most widely employed auxin for adventitious rooting. However, the molecular mechanisms by which auxin regulate the process of adventitious rooting are less well known. RESULTS: The RNA-Seq data analysis indicated that IBA treatment greatly increased the amount of clean reads and the amount of expressed unigenes by 24.29 % and 27.42 % and by 4.3 % and 5.04 % at two time points, respectively, and significantly increased the numbers of unigenes numbered with RPKM = 10-100 and RPKM = 500-1000 by 13.04 % and 3.12 % and by 24.66 % and 108.2 % at two time points, respectively. Gene Ontology (GO) enrichment analysis indicated that the enrichment of down-regulated GOs was 2.87-fold higher than that of up-regulated GOs at stage 1, suggesting that IBA significantly down-regulated gene expression at 6 h. The GO functional category indicated that IBA significantly up- or down-regulated processes associated with auxin signaling, ribosome assembly and protein synthesis, photosynthesis, oxidoreductase activity and extracellular region, secondary cell wall biogenesis, and the cell wall during the development process. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment indicated that ribosome biogenesis, plant hormone signal transduction, pentose and glucuronate interconversions, photosynthesis, phenylpropanoid biosynthesis, sesquiterpenoid and triterpenoid biosynthesis, ribosome, cutin, flavonoid biosynthesis, and phenylalanine metabolism were the pathways most highly regulated by IBA. A total of 6369 differentially expressed (2-fold change > 2) unigenes (DEGs) with 3693 (58 %) that were up-regulated and 2676 (42 %) down-regulated, 5433 unigenes with 2208 (40.6 %) that were up-regulated and 3225 (59.4 %) down-regulated, and 7664 unigenes with 3187 (41.6 %) that were up-regulated and 4477 (58.4 %) down-regulated were detected at stage 1, stage 2, and between stage 1 and stage 2, respectively, suggesting that IBA treatment increased the number of DEGs. A total of 143 DEGs specifically involved in plant hormone signaling and 345 transcription factor (TF) genes were also regulated by IBA. qRT-PCR validation of the 36 genes with known functions indicated a strong correlation with the RNA-Seq data. CONCLUSIONS: The changes in GO functional categories, KEGG pathways, and global DEG profiling during adventitious rooting induced by IBA were analyzed. These results provide valuable information about the molecular traits of IBA regulation of adventitious rooting.

Fiber degradation potential of natural co-cultures of Neocallimastix frontalis and Methanobrevibacter ruminantium isolated from yaks (Bos grunniens) grazing on the Qinghai Tibetan Plateau.

Several natural anaerobic fungus-methanogen co-cultures have been isolated from rumen and feces source of herbivores with strong fiber degrading ability. In this study, we isolated 7 Neocallimastix with methanogen co-cultures from the rumen of yaks grazing on the Qinghai Tibetan Plateau. Based on morphological characteristics and internal transcribed spacer 1 sequences (ITS1), all the fungi were identified as Neocallimastix frontalis. The co-cultures were confirmed as the one fungus - one methanogen pattern by the PCR-denatured gradient gel electrophoresis (DGGE) assay. All the methanogens were identified as Methanobrevibacter ruminantium by 16s rRNA gene sequencing. We investigated the biodegrading capacity of the co-culture (N. frontalis + M. ruminantium) Yaktz1 on wheat straw, corn stalk and rice straw in a 7 days-incubation. The in vitro dry matter digestibility (IVDMD), acid detergent fiber digestibility (ADFD) and neural detergent fiber digestibility (NDFD) values of the substrates in the co-culture were significantly higher than those in the mono-culture N. frontalis Yaktz1. The co-culture exhibited high polysaccharide hydrolase (xylanase and FPase) and esterase activities. The xylanase in the co-culture reached the highest activity of 12500 mU/ml on wheat straw at the day 3 of the incubation. At the end of the incubation, 3.00 mmol-3.29 mmol/g dry matter of methane were produced by the co-culture. The co-culture also produced high level of acetate (40.00 mM-45.98 mM) as the end-product during the biodegradation. Interestingly, the N. frontalis Yaktz1 mono-culture produced large amount of lactate (8.27 mM-11.60 mM) and ethanol (163.11 mM-242.14 mM), many times more than those recorded in the previously reported anaerobic fungi. Our data suggests that the (N. frontalis + M. ruminantium) Yaktz1 co-culture and the N. frontalis Yaktz1 mono-culture both have great potentials for different industrial use.

[Value of controlled attenuation parameter in diagnosis of fatty liver using FibroScan].

OBJECTIVE: To investigate the value of controlled attenuation parameter (CAP) in the diagnosis of fatty liver using FibroScan in patients with chronic liver disease (CLD). METHODS: A prospective cohort study was performed for the patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD) who underwent liver pathological examination followed by CAP measurement within 1 week in The Second People's Hospital of Tianjin from February 2013 to May 2014. According to related guidelines, hepatocyte steatosis was classified as S0: <5%, S1: 5%-33%, S2: 34%-66%, or S3: ≥67%. The receiver operating characteristic (ROC) curves were plotted with positive results as the diagnostic criteria, and the optimal cut-off values were determined at the maximum Youden index. Single linear regression and multiple stepwise regression were applied to analyze the influencing factors for CAP. RESULTS: A total of 427 patients were enrolled, consisting of 19 patients (4.4%) with NAFLD, 383 (89.7%) with CHB, and 25 (5.9%) with CHC. The optimal cut-off values for CAP in the diagnosis of steatosis ≥5%, ≥34%, and ≥67% were 230 dB/m, 252 dB/m, and 283 dB/m, respectively, and the areas under the ROC curve were 0.803, 0.942, and 0.938, respectively (Z = 14.194, 28.385, and 16.486, respectively, all P < 0.01). CAP differentiated S0 from S1, S1 from S2, S0 from S2, S0 from S3, and S1 from S3 (Z = 10.109, 10.224, 47.81, 29.917, and 10.999, all P < 0.01), but was not able to differentiate S2 from S3 (Z = 0.656, P = 0.5116). The single linear regression and multiple stepwise regression analyses showed that only body mass index (BMI; B = 4.001, P < 0.01) and hepatic steatosis (B = 33.015, P = 0.000) were correlated with CAP. The coincidence rates between CAP and liver pathological diagnosis were 77.4%, 81.0%, and 96.2% for S0, S3, and ≥S2, respectively. CONCLUSION: CAP has a good value in the diagnosis of fatty liver in CLD patients, and can well differentiate between all stages of fatty liver except S2 and S3. CAP is influenced by BMI, but is not found to be associated with liver fibrosis, inflammation, liver stiffness measurement, and etiology.

Controlled attenuation parameter for noninvasive assessment of hepatic steatosis using Fibroscan®: validation in chronic hepatitis B.

BACKGROUND AND AIM: The controlled attenuation parameter (CAP) using transient elastography (TE) was validated in chronic hepatitis C to evaluate hepatic steatosis; however, limited data are available on chronic hepatitis B (CHB). Therefore, we assessed the accuracy and the efficacy of CAP for the detection of steatosis in CHB. METHODS: Consecutive CHB patients underwent liver biopsy and liver stiffness measurements (LSM) with simultaneous CAP determination using the M probe of the TE. The area under the receiver operating characteristics curve (AUROC) was used to evaluate the performance of CAP in diagnosing steatosis compared with biopsy. RESULTS: A total of 340 patients were included: 60 % were male, the median age was 37 years; the body mass index (BMI) was ≥ 28 kg/m(2) for 14 % of the subjects; and the distribution of the steatosis grade was S0 58.2 %, S1 34.2 %, S2 5.0 % and S3 2.6 %. The median (range) of CAP was 218 (100-400) dB/m, and CAP correlated with the BMI (ρ = 3.622) and steatosis grade (ρ = 29.203) according to a multivariate analysis (both P < 0.001). CAP could detect the different grades of steatosis: ≥ S1 with AUROC of 0.81 at a cutoff of 224 dB/m, ≥ S2 with AUROC of 0.90 at a cutoff of 236 dB/m and ≥ S3 with AUROC of 0.97 at a cutoff of 285 dB/m. Furthermore, the LSM and fibrosis and activity grades on biopsy did not influence the CAP performance. CONCLUSIONS: CAP presented excellent diagnostic performance for severe steatosis with high sensitivity and specificity in Chinese patients with CHB.

The Diagnostic Value of Liver Biopsy for Unexplained Liver Dysfunction: A Retrospective Study.

Objective: To analyse clinical manifestations of unexplained abnormal liver function and perform hepatobiliary histopathology procedures on patients to evaluate the value of liver biopsy in diagnosing the aetiology of unexplained abnormal liver function. Methods: A convenience sampling method was used to retrospectively collect the data of patients who were diagnosed with unexplained abnormal liver function and who received liver biopsy in the Pathology Department of Tianjin Second People's Hospital, China, between March 2022 and July 2023 to analyse liver pathology and clinical manifestations. Results: A total of 1302 patients were included in this study, which mainly included 11 diseases: autoimmune liver disease (74 cases, 5.68%), drug-induced liver injury (DILI) (204 cases, 15.67%), cancer (237 cases, 18.20%), non-alcoholic fatty liver disease (104 cases, 7.99%), non-alcoholic steatohepatitis (74 cases, 5.68%), viral hepatitis (490 cases, 37.63%), other types of hepatitis (30 cases, 2.30%), cholestatic liver disease (17 cases, 1.31%), alcoholic liver disease (15 cases, 1.15%), hepatic cyst (5 cases, 0.38%) and Gilbert syndrome (4 cases, 0.31%). The success rate of liver biopsy sampling was 100%, and (1.52 ± 0.130) tissue strips were sampled. The average operating time was 11.52 minutes. The percutaneous liver biopsy did not significantly increase short-term liver function index values (serum γ-glutamyl transpeptidase, total bilirubin, alanine transaminase, aspartate aminotransferase, alkaline phosphatase). Ninety-two patients had a small amount of liver subcapsular fluid, but there was no progress after medical treatment. Conclusion: Ultrasound-guided percutaneous liver biopsy has value in the diagnosis of unexplained abnormal liver function. Viral hepatitis, cancer and DILI are the most common causes of unexplained abnormal liver function. Liver biopsy does not aggravate the organic and functional impairment of the liver.

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

Particle Distribution and Heat Transfer of SiO2/Water Nanofluid in the Turbulent Tube Flow.

In order to clarify the effect of particle coagulation on the heat transfer properties, the governing equations of nanofluid together with the equation for nanoparticles in the SiO2/water nanofluid flowing through a turbulent tube are solved numerically in the range of Reynolds number 3000 ≤ Re ≤ 16,000 and particle volume fraction 0.005 ≤ φ ≤ 0.04. Some results are validated by comparing with the experimental results. The effect of particle convection, diffusion, and coagulation on the pressure drop ∆P, particle distribution, and heat transfer of nanofluid are analyzed. The main innovation is that it gives the effect of particle coagulation on the pressure drop, particle distribution, and heat transfer. The results showed that ∆P increases with the increase in Re and φ. When inlet velocity is small, the increase in ∆P caused by adding particles is relatively large, and ∆P increases most obviously compared with the case of pure water when the inlet velocity is 0.589 m/s and φ is 0.004. Particle number concentration M0 decreases along the flow direction, and M0 near the wall is decreased to the original 2% and decreased by about 90% in the central area. M0 increases with increasing Re but with decreasing φ, and basically presents a uniform distribution in the core area of the tube. The geometric mean diameter of particle GMD increases with increasing φ, but with decreasing Re. GMD is the minimum in the inlet area, and gradually increases along the flow direction. The geometric standard deviation of particle diameter GSD increases sharply at the inlet and decreases in the inlet area, remains almost unchanged in the whole tube, and finally decreases rapidly again at the outlet. The effects of Re and φ on the variation in GSD along the flow direction are insignificant. The values of convective heat transfer coefficient h and Nusselt number Nu are larger for nanofluids than that for pure water. h and Nu increase with the increase in Re and φ. Interestingly, the variation in φ from 0.005 to 0.04 has little effect on h and Nu.

Hepatic steatosis leads to overestimation of liver stiffness measurement in both chronic hepatitis B and metabolic-associated fatty liver disease patients.

BACKGROUND: The impact of hepatic steatosis on liver stiffness measurement (LSM) in both chronic hepatitis B(CHB) and metabolic-associated fatty liver disease (MAFLD) remains controversial. AIMS: To determine whether LSM is affected by hepatic steatosis in CHB-MAFLD. METHODS: Hepatic steatosis and liver fibrosis were assessed by histological and noninvasively methods. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance of LSM. RESULTS: The prevalence of MAFLD in CHB patients (n = 436)was 47.5% (n = 207). For patients with low amounts of fibrosis (F0-1 and F0-2), the median LSM was 8.8 kPa and 9.2 kPa in patients with moderate- severe steatosis,which was significantly higher than that in patients with none-mild steatosis (P < 0.05) . The positive predictive value(PPV) was lower for LSM identifying significant fibrosis (F ≥ 2) as well as severe fibrosis (F ≥ 3) in group which controlled attenuation parameter(CAP) ≥ 268 dB/m than its counterpart(68.2% vs 84.6% and 24.3% vs 45.0%). The AUROC of LSM detected F ≥ 2 was 0.833 at a cutoff of 8.8 kPa and 0.873 at a cutoff of 7.0 kPa in patients with CAP ≥ 268 and CAP < 268, respectively. CONCLUSIONS: The presence of moderate-severe steatosis, detected by histology or CAP, should be taken into account to avoid overestimation of LSM.

A Novel Noninvasive Diagnostic Model of HBV-Related Inflammation in Chronic Hepatitis B Virus Infection Patients With Concurrent Nonalcoholic Fatty Liver Disease.

Background and Aims: Patients with chronic hepatitis B virus infection (CBI) with concurrent nonalcoholic fatty liver disease (NAFLD) is becoming increasingly common in clinical practice, and it is quite important to identify the etiology when hepatitis occurs. A noninvasive diagnostic model was constructed to identify patients who need antihepatitis B virus (HBV) therapies [histologic activity index (HAI) ≥ 4] in patients with CBI with concurrent NAFLD by analyzing clinical routine parameters. Approach and Results: In total, 303 out of 502 patients with CBI with concurrent NAFLD proven by liver biopsy from January 2017 to December 2020 in the Tianjin Second People's Hospital were enrolled and they were divided into the HBV-related inflammation (HBV-I) group (HAI ≥ 4,176 cases) and the non-HBV-I group (HAI < 4,127 cases) according to hepatic pathology. The univariate analysis and multivariate logistic regression analysis were performed on the two groups of patients, and then the HBV-I model of patients with CBI with concurrent NAFLD was constructed. The areas under receiver operating characteristic curves (AUROCs) were used to evaluate the parameters of the regression formula. Another 115 patients with CBI with concurrent NAFLD proven by liver biopsy from January 2021 to January 2022 were enrolled as the validation group. There were some statistical differences in demographic data, biochemical indicators, immune function, thyroid function, virology indicator, and blood routine indicators between the two groups (P < 0.05) and liver stiffness measurement (LSM) in the HBV-I group was significantly higher than those in the non-HBV-I group (P < 0.05). While controlled attenuation parameters (CAP) in the HBV-I group were lower than those in the non-HBV-I group (P < 0.05); (2) We developed a novel model by logistic regression analysis: HBV-I = -0.020 × CAP + 0.424 × LSM + 0.376 × lg (HBV DNA) + 0.049 × aspartate aminotransferase (AST) and the accuracy rate was 82.5%. The area under the receiver operating characteristic (AUROC) is 0.907, the cutoff value is 0.671, the sensitivity is 89.30%, the specificity is 77.80%, the positive predictive value is 90.34%, and the negative predictive value is 81.89%; (3) The AUROC of HBV-I in the validation group was 0.871 and the overall accuracy rate is 86.96%. Conclusion: Our novel model HBV-I [combining CAP, LSM, lg (HBV DNA), and AST] shows promising utility for predicting HBV-I in patients with CBI with concurrent NAFLD with high sensitivity, accuracy, and repeatability, which may contribute to clinical application.

Impact of hepatic steatosis on treatment response of autoimmune hepatitis: A retrospective multicentre analysis.

Background: There is a paucity of data on whether steatosis impacts autoimmune hepatitis (AIH) treatment response. We aimed to evaluate the influence of baseline steatosis on the biochemical response, fibrosis progression, and adverse longterm outcomes of AIH. Methods: Steatosis was diagnosed by a controlled attenuation parameter (CAP) ≥ 248 dB / m. Only patients who underwent immunosuppressive therapy with available liver histological material at diagnosis and qualified CAP within seven days of the liver biopsy were included. Univariate and multivariate analyses were subsequently conducted. Results: The multicentre and retrospective cohort enrolled 222 subjects (88.3% female, median age 54 years, median follow-up 48 months) in the final analysis, and 56 (25.2%) patients had hepatic steatosis. Diabetes, hypertension, and significant fibrosis at baseline were more common in the steatosis group than in the no steatosis group. After adjusting for confounding factors, hepatic steatosis was an independent predictor of insufficient biochemical response (OR: 8.07) and identified as an independent predictor of long-term adverse outcomes (HR: 4.07). By subgroup multivariate analysis (different degrees of steatosis, fibrosis, and prednisone dose), hepatic steatosis independently showed a relatively stable correlation with treatment response. Furthermore, in contrast to those without steatosis, a significant increase in liver stiffness (LS) was observed in patients with steatosis (4.1%/year vs. -16%/year, P < 0.001). Conclusions: Concomitant hepatic steatosis was significantly associated with poor response to treatment in AIH patients. Routine CAP measurements are therefore essential to guide the management of AIH.