Non-intrusive reduced-order model for time-dependent stochastic partial differential equations utilizing dynamic mode decomposition and polynomial chaos expansion.

In this study, we present a novel non-intrusive reduced-order model (ROM) for solving time-dependent stochastic partial differential equations (SPDEs). Utilizing proper orthogonal decomposition (POD), we extract spatial modes from high-fidelity solutions. A dynamic mode decomposition (DMD) method is then applied to vertically stacked matrices of projection coefficients for future prediction of coefficient fields. Polynomial chaos expansion (PCE) is employed to construct a mapping from random parameter inputs to the DMD-predicted coefficient field. These lead to the POD-DMD-PCE method. The innovation lies in vertically stacking projection coefficients, ensuring time-dimensional consistency in the coefficient matrix for DMD and facilitating parameter integration for PCE analysis. This method combines the model reduction of POD with the time extrapolation strengths of DMD, effectively recovering field solutions both within and beyond the training time interval. The efficiency and time extrapolation capabilities of the proposed method are validated through various nonlinear SPDEs. These include a reaction-diffusion equation with 19 parameters, a two-dimensional heat equation with two parameters, and a one-dimensional Burgers equation with three parameters.

Erratum: Author correction to 'FGF4 protects the liver from immune-mediated injury by activating CaMKKß-PINK1 signal pathway to inhibit hepatocellular apoptosis' [Acta Pharm Sin B 14 (2024) 1605-1623].

[This corrects the article DOI: 10.1016/j.apsb.2023.12.012.].

FGF4 protects the liver from immune-mediated injury by activating CaMKKß-PINK1 signal pathway to inhibit hepatocellular apoptosis.

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca2+/calmodulin-dependent protein kinasekinase 2 (CaMKKß) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

[Correlations of Birth Defects With Birth Weight and Gestational Age].

Objective To analyze the incidence rate of birth defects in infants born at different gestational ages and birth weights,so as to provide a basis for improving the surveillance system and reducing the incidence of birth defects. Methods Data of all perinatal infants born at and after 28 weeks of gestation and within 7 days after delivery in all the hospitals with the obstetrical department from October 1,2003 to September 30,2015 were collected. Results From 2003 to 2015,1 236 937 perinatal infants were monitored,including 10 619 with birth defects (incidence rate of 8.59‰).Among the infants with birth defects identified by the hospital surveillance system of birth defects in Xi'an during the study period,3 306,3 473,and 224 infants showed the birth weights less than 2 500 g,the gestational age within the range of [28,37] weeks,and the gestation age≥42 weeks,respectively.The low birth weight infants showed higher incidence rate of birth defects than the normal birth weight infants (χ2=37 097.79,P<0.001).The premature infants (gestational age<37 weeks) and postterm infants (gestational age≥42 weeks) showed higher incidence rates of birth defects than infants born at normal gestational age (χ2=24 998.24,P<0.001;χ2=196.40,P<0.001).The top five birth defects of low birth weight infants were congenital hydrocephalus,spina bifida,congenital heart disease,anencephaly,and cleft lip and cleft palate.The outcomes of birth defects in normal weight infants and low weight infants were mainly live births (68.60%) and stillbirths (54.72%),respectively,which showed a significant difference (χ2=647.59,P<0.001).The main outcomes of birth defects in the infants born at normal gestation age,postterm infants,and premature infants were mainly live births (77.38%),live births (83.93%),and stillbirths (57.79%),respectively,which showed significant differences (premature infants vs.infants born at normal gestation age: χ2=2 025.08,P<0.001;premature infants vs. postterm infants:χ2=245.39,P<0.001;infants born at normal gestation age vs.postterm infants:χ2=16.28,P=0.001). Conclusions Premature infants,low birth weight infants,and postterm infants showed significantly higher incidence rate of birth defects than the infants born at normal gestation age.The outcomes of birth defects had significant differences between low birth weight infants and normal birth weight infants,between premature infants and infants born at normal gestation age,between premature infants and postterm infants,and between infants born at normal gestation age and postterm infants.

Engineered FGF19ΔKLB protects against intrahepatic cholestatic liver injury in ANIT-induced and Mdr2-/- mice model.

BACKGROUND: The major safety concern of the clinical application of wild type FGF19 (FGF19WT) emerges given that its extended treatment causes hepatocellular carcinoma. Therefore, we previously generated a safer FGF19 variant - FGF19ΔKLB, which have same effects on glycemic control and bile acid production but much less mitogenic activity. However, it remains unclear as to whether FGF19ΔKLB ameliorates intrahepatic cholestasis. RESULTS: We found that, similar to that of FGF19WT, the chronic administration of FGF19ΔKLB protects mice from cholestatic liver injury in these two models. The therapeutic benefits of FGF19ΔKLB on cholestatic liver damage are attributable, according to the following mechanistic investigation, to the reduction of BA production, liver inflammation, and fibrosis. More importantly, FGF19ΔKLB did not induce any tumorigenesis effects during its prolonged treatment. CONCLUSIONS: Together, our findings raise hope that FGF19ΔKLB may represent a useful therapeutic strategy for the treatment of intrahepatic cholestasis.

[Multiple Correspondence of Abnormal Birth History with Genetic and Environmental Risk Factors].

Objective To investigate the multiple correspondence of genetic and environmental risk factors with abnormal birth history and provide a scientific basis for improving the birth defects surveillance system and reducing the incidence of birth defects. Methods Data were collected from all the perinatal infants from 28-week-old fetuses to 7-day-old infants born in all the hospitals with obstetrical department in Xi'an from 2003 to 2015. Results A total of 1 236 937 perinatal infants were surveyed,including 10 619 with birth defects.The average incidence rate of birth defects was 0.86% (0.70%-1.15%).Multiple correspondence analysis showed that the women who had had 1 or 2 children with birth defects were associated with the history of spontaneous abortion,family history of birth defects,and history of exposure to toxic and harmful substances.The women who had had 3 or more children with birth defects showed stronger association with family history of birth defects.The birth defects in women with history of spontaneous abortion (257/10 619) was ranked in the order of congenital heart disease,polydactyly,neural tube defects,congenital hydrocephalus,cleft lip with cleft palate,and simple cleft lip.The birth defects in women who had given birth to children with birth defects (135/10 619) followed the order of cleft lip with cleft palate,anencephaly,hydrocephalus,neural tube defects,cleft lip,and talipes equinovarus. Conclusions Abnormal birth history is associated with family history of birth defects and history of exposure to environmental risk factors.Giving birth to three or more children with birth defects is highly correlated with the family history of birth defects.

An ic-ELISA and immunochromatographic strip assay for the detection of 2,4-dichlorophenoxyacetic acid in bean sprouts and cabbage.

The compound 2,4-dichlorophenoxyacetic acid (2,4-D) is a synthetic plant growth regulator, which is widely used in agricultural production. Consequently, it is necessary to establish a rapid and sensitive detection method to monitor its use and prevent the environmental and human health problems caused by overuse. In this study, a monoclonal antibody (mAb) 2D5 against 2,4-D was prepared, and based on it, an ic-ELISA and an immunochromatographic strip assay (ICA) were developed for rapid detection. The 50% inhibitory concentration (IC 50) of the mAb against 2,4-D was 1.7 ng mL-1 and the mAb showed no cross-reactivity with other plant growth regulators with similar structures to 2,4-D. Under optimum conditions, the ICA showed a visual detection limit (vLOD) of 20 ng mL-1 and a cut-off value of 200 ng mL-1 in bean sprouts, and cabbage samples gave the same results. The quantitative detection showed the linear detection ranges for bean sprouts and cabbage samples were 6.3-73.0 and 5.4-132.6 ng mL-1, respectively. The ICA was successfully applied to detect 2,4-D in bean sprouts and cabbage samples and achieved good recoveries ranging from 94.7% to 104.3% with a coefficient of variation (CV) less than 8.3%. Hence, the ICA provides a sensitive, efficient and reliable detection method, which has broad application prospects in the detection of a large number of samples.

Methanol-Enhanced Liquid Electrode Discharge Microplasma-Induced Vapor Generation of Hg, Cd, and Zn: The Possible Mechanism and Its Application.

Despite increased interest in microplasma-induced vapor generation (µPIVG) over the past several years, applications in real sample analyses remain limited due to their relatively low vapor generation efficiency and ambiguous mechanism. In this work, a novel method using methanol for significantly enhancing the liquid electrode discharge µPIVG efficiency was developed for the simultaneous and sensitive determination of Hg, Cd, and Zn by atomic fluorescence spectrometry (AFS). It is worth noting that the possible enhancement mechanism was investigated via the characterizations of volatile products by AFS, microplasma optical emission spectrometry, online gas chromatography, and gas chromatography-mass spectrometry, which involved the reductive species such as electrons, hydrogen radicals (·H), methyl radicals (·CH3), and other intermediates in the argon plasma adding methanol. Under the optimized conditions, the limits of detection of 0.007, 0.05, and 0.5 µg L-1 were obtained for Hg, Cd, and Zn, respectively, with relative standard deviations of 3.1, 3.7, and 5.2% for these elements, respectively. Vapor generation efficiencies of 90, 83, and 55% were achieved for Hg, Cd, and Zn, respectively, and improved 2.7-, 4.8-, and 7.9-fold, respectively, compared to those obtained in the absence of methanol. The accuracy and practicability of the proposed method were validated by the determination of Hg, Cd, and Zn in a certified reference material (CRM, Lobster hepatopancreas, TORT-3) and crayfish samples collected from three different provinces of China.

Oligoclonal immunoglobulin repertoire in biliary remnants of biliary atresia.

Biliary atresia (BA) is a neonatal cholestatic liver disease that is the leading cause of pediatric liver transplantation, however, the mechanism of disease remains unknown. There are two major forms of BA: isolated BA (iBA) comprises the majority of cases and is thought to result from an aberrant immune response to an environmental trigger, whereas syndromic BA (BASM) has associated malformations and is thought to arise from a congenital insult. To determine whether B cells in BA biliary remnants are antigen driven, we examined the immunoglobulin (Ig) repertoire of diseased tissue from each BA group. Deep sequencing of the Ig chain DNA was performed on iBA and BASM biliary remnants and lymph nodes obtained from the Childhood Liver Disease Research Network (ChiLDReN) repository. Statistical analysis of the Ig repertoire provided measures of Ig clonality and the Ig phenotype. Our data demonstrate that B cells infiltrate diseased iBA and BASM biliary remnant tissue. The Ig repertoires of iBA and BASM disease groups were oligoclonal supporting a role for an antigen-driven immune response in both sub-types. These findings shift the current understanding of BA and suggest a role for antigen stimulation in early iBA and BASM disease pathogenesis.

Prediction of metallic nano-optical trapping forces by finite element-boundary integral method.

The hybrid of finite element and boundary integral (FE-BI) method is employed to predict nano-optical trapping forces of arbitrarily shaped metallic nanostructures. A preconditioning strategy is proposed to improve the convergence of the iterative solution. Skeletonization is employed to speed up the design and optimization where iteration has to be repeated for each beam configuration. The radiation pressure force (RPF) is computed by vector flux of the Maxwell's stress tensor. Numerical simulations are performed to validate the developed method in analyzing the plasmonic effects as well as the optical trapping forces. It is shown that the proposed method is capable of predicting the trapping forces of complex metallic nanostructures accurately and efficiently.

Elaboration of tubules with active hedgehog drives parenchymal fibrogenesis in gestational alloimmune liver disease.

Gestational alloimmune liver disease (GALD) produces severe neonatal liver disease that is notable for paucity of hepatocytes, large numbers of parenchymal tubules, and extensive fibrosis. Liver specimens from 19 GALD cases were studied in comparison with 14 infants without liver disease (normal newborn liver; NNL) to better understand the pathophysiology that would produce this characteristic histopathology. GALD liver parenchyma contained large numbers of tubules comprising epithelium expressing KRT7/19, EPCAM, and SOX9, suggesting biliary progenitor status. Quantitative morphometry demonstrated that in GALD, the area density of KRT19+ tubules was 16.4 ± 6.2 versus 2.0 ± 2.6 area% in NNL (P < .0001). Functional hepatocyte mass was markedly reduced in GALD, 16.3 ± 6.2 versus 61.9 ± 11.0 area% of CPS1+ cells in NNL (P < .0001). A strong inverse correlation was established between CPS1+ area density and KRT19+ area density (r(2) = 0.66, P < .0001). Tubules showed active hedgehog signaling as determined by SHH and nuclear GLI2 expression and expressed the profibrogenic cytokine SPP1. SPP1 protein content and SPP1 expression were greater in GALD than NNL (15- and 13-fold respectively; P = .002). GALD liver contained large numbers of activated myofibroblasts and showed greater than 10-fold more fibrosis than NNL. The extent of fibrosis correlated with the area density of KRT19+ tubules (r(2) = 0.387, P = .001). The data support a pathogenic model in which immune injury to fetal hepatocytes provides a stimulus for expansion of parenchymal tubules, which, by way of Hh activation, produce fibrogenic signals leading to vibrant fibrosis.

Prediction of radiation pressure force exerted on moving particles by the two-level skeletonization.

A fast full-wave method for computing radiation pressure force (RPF) exerted by shaped light beams on moving particles is presented. The problem of evaluating RPF exerted on a moving particle by a single excitation beam is converted into that of computing RPF's exerted on a static particle by multiple beams. The discretization of different beams leads to distinct right hand sides (RHS's) for the matrix system. To avoid solving each RHS by the brute-force manner, the algorithm conducts low-rank decomposition on the excitation matrix consisting of all RHS's to figure out the so-called skeleton light beams by interpolative decomposition (ID). The peak memory requirement of the skeletonization is a bottle-neck if the particle is large. A two-level skeletonization scheme is proposed to solve this problem. Some numerical experiments on arbitrarily shaped homogeneous particles are performed to illustrate the performance and capability of the developed method.

Neonatal liver cirrhosis without iron overload caused by gestational alloimmune liver disease.

Gestational alloimmune liver disease has emerged as the major cause of antenatal liver injury and failure. It usually manifests as neonatal liver failure with hepatic and extrahepatic iron overload, a clinical presentation called neonatal hemochromatosis. We report on a newborn in whom fetal hepatomegaly was detected during pregnancy and who presented at birth with liver cirrhosis and mild liver dysfunction. Liver biopsy showed the absence of iron overload but strong immunostaining of hepatocytes for the C5b-9 complex, the terminal complement cascade neoantigen occurring specifically during complement activation by the immunoglobulin G-mediated classic pathway, which established the alloimmune nature of the hepatocyte injury. The infant survived with no specific therapy, and follow-up until 36 months showed progressive normalization of all liver parameters. This case report expands the recognized clinical spectrum of congenital alloimmune liver disease to include neonatal liver disease and cirrhosis, even in the absence of siderosis. Such a diagnosis is of utmost importance regarding the necessity for immunotherapy in further pregnancies to avoid recurrence of alloimmune injury.

Neonatal iron overload and tissue siderosis due to gestational alloimmune liver disease.

BACKGROUND & AIMS: Gestational alloimmune liver disease is the main cause of the neonatal hemochromatosis phenotype, wherein severe neonatal liver disease is associated with iron overload and extrahepatic tissue siderosis. How fetal liver disease produces extrahepatic siderosis is not known. We hypothesized that fetal liver injury causes deficient hepcidin production and poor regulation of placental iron flux. Under the resulting conditions of iron overload, the tissue pattern of extrahepatic siderosis is determined by the normal expression of proteins involved in the import of non-transferrin-bound iron and the export of cellular iron. METHODS: Liver and extrahepatic tissues from infants with gestational alloimmune liver disease were examined and compared to normal age-appropriate tissues. RESULTS: Serum iron indices indicate iron overload and excess non-transferrin bound iron in gestational alloimmune liver disease. The diseased liver showed significantly reduced hepcidin, hemojuvulin, and transferrin gene expression compared to the normal fetal and neonatal liver. Those extrahepatic tissues that are typically involved in pathological siderosis in neonatal hemochromatosis, whether from normal or diseased newborns, consistently expressed solute carrier family 39 (zinc transporter), member 14 (ZIP14) for non-transferrin-bound iron uptake and expressed little ferroportin for iron export. CONCLUSIONS: Excess non-transferrin-bound iron in gestational alloimmune liver disease may result from fetal liver injury that causes reduced synthesis of key iron regulatory and transport proteins. Whereas, the pattern of extrahepatic siderosis appears to be determined by the normal capacity of various tissues to import non-transferrin-bound iron and not export cellular iron.

Gestational alloimmune liver disease in cases of fetal death.

OBJECTIVE: To determine whether alloimmune liver disease can be identified as a cause of fetal death. STUDY DESIGN: This is a retrospective examination of the autopsy tissue of 6 stillborn fetuses and 2 extreme preterm infants (gestational age, 20 to 34 weeks) drawn from families referred for suspected neonatal hemochromatosis. Thirteen appropriate nondisease controls and 8 cases of neonatal acute liver failure with known etiology were also examined. Liver sections were immunostained using anti-human C5b-9 complex. RESULTS: All of the study cases had died with no preceding evidence of fetal distress. Histopathology showed findings of acute liver injury, including global hepatocyte necrosis with minimal reticulum collapse and no fibrosis. Hepatocytes in cases stained strongly positively for C5b-9 complex, suggesting premortem lgG complement-mediated liver injury. Hepatocytes in acute liver failure case controls did not demonstrate a similar mechanism of liver injury. CONCLUSIONS: Alloimmune liver disease is sometimes associated with fetal death.

Novel mechanism of fetal hepatocyte injury in congenital alloimmune hepatitis involves the terminal complement cascade.

UNLABELLED: Evidence suggests that most neonatal hemochromatosis (NH) is the phenotypic expression of gestational alloimmune fetal liver injury. Gestational alloimmune diseases are induced by the placental passage of specific reactive immunoglobulin G and often involve the activation of fetal complement by the classical pathway leading to the formation of membrane attack complex (MAC) as the effector of cell injury. We examined liver specimens from cases of NH, from cases of non-NH liver disease, and from infants without liver disease to determine if they would provide evidence that MAC is involved in hepatocyte injury. Sections were immunostained with anti-human C5b-9 complex, the terminal complement cascade (TCC) neoantigen formed in the assembly of MAC. Fetal liver injury in NH cases is associated with a severe loss of hepatocytes. In all NH cases examined, most remaining hepatocytes showed intense staining for TCC neoantigen, whereas hepatocytes in non-NH liver disease cases showed variable light staining. The percentage of hepatocytes containing TCC neoantigen in NH was much greater than that in non-NH liver disease, and there was no overlap between the groups. Findings in both groups suggest that hepatocytes have mechanisms to protect against MAC, including a biliary pathway for its excretion. CONCLUSION: The finding that all cases of proven NH contained TCC neoantigen far in excess of cases of other neonatal liver diseases suggests that a single process, namely congenital alloimmune hepatitis, is the principal cause of NH. MAC-mediated alloimmune injury in congenital alloimmune hepatitis is a novel mechanism of liver injury that results from an interplay of maternal adaptive immunity and fetal innate immunity.

Increased hepatic expression is a major determinant of serum alanine aminotransferase elevation in mice with nonalcoholic steatohepatitis.

BACKGROUND: Serum alanine aminotransferase (ALT) is a biomarker for hepatitis of various aetiologies including fatty liver disease. Increased serum ALT is thought to be related to its increased release from dying hepatocytes. AIM: We sought to understand the mechanisms by which serum ALT is elevated in a mouse model of experimental fatty liver disease where hepatocyte death is minimal. METHODS: To induce fatty liver disease, female A/J mice were fed a methionine-choline deficient (MCD) diet for up to 12 weeks. Serum and liver ALT expression and hepatic inflammation, necrosis and apoptosis were assessed and expressed relative to their expressions in control-diet-fed mice. RESULTS: Feeding mice the MCD diet produced hepatic steatosis with minimal hepatic inflammation or necrosis. Liver cell apoptosis was not significantly increased by MCD diet treatment. Conversely, serum ALT activity was approximately four-fold increased at 12 weeks of diet treatment, and ALT protein expressions in serum were correspondingly increased: ALT1 1.7-fold and ALT2 1.9-fold at 12 weeks. The expressions of ALT1 and ALT2 protein in liver increased over 2-12 weeks of MCD treatment. At 12 weeks, liver ALT1 protein was 2.27+/-0.31-fold increased and ALT2 protein 4.72+/-0.48-fold increased relative to their expressions in the mice fed a diet replete with methionine and choline. Liver ALT mRNA expressions were correspondingly increased: ALT1 mRNA 2.58-fold and ALT2 mRNA 4.97-fold at 12 weeks. Linear regression analysis showed a strong correlation between serum and liver tissue expressions for both ALT1 and ALT2. CONCLUSIONS: These findings suggest that induction of hepatic expression significantly contributes to increased serum ALT in this model of experimental fatty liver disease, whereas cell death appears not to.

Mitochondrial reactive oxygen species signal hepatocyte steatosis by regulating the phosphatidylinositol 3-kinase cell survival pathway.

Abnormal dietary intake of macronutrients is implicated in the development of obesity and fatty liver disease. Steatosis develops in cultured hepatocytes exposed to medium containing either a high concentration of long chain free fatty acids (HFFA) or medium deficient in methionine and choline (MCD). This study examined the mitochondrial reactive oxygen species (ROS)-dependent regulation of the phosphoinositol (PI) 3-kinase pathway in steatosis induced by exposure of AML-12 mouse hepatocytes to MCD or HFFA medium. Exposure to either MCD or HFFA medium resulted in increased production of superoxide anions and H(2)O(2), transduction of the PI 3-kinase pathway and steatosis. Inhibition of PI 3-kinase with LY294002 prevented steatosis. Pharmacologically inhibiting electron transport chain complex III production of ROS prevented activation of PI 3-kinase during macronutrient perturbation, whereas pharmacologically promoting electron transport chain complex III ROS production activated PI 3-kinase independent of nutrient input. The data suggest that H(2)O(2) is the ROS species involved in signal transduction; promoting the rapid conversion of superoxide to H(2)O(2) does not inhibit PI 3-kinase pathway activation during nutrient perturbation, and exogenous H(2)O(2) activates it independent of nutrient input. In addition to transducing PI 3-kinase, the ROS-dependent signal cascade amplifies the PI 3-kinase signal by maintaining phosphatase and tensin homolog in its inactive phosphorylated state. Knockdown of phosphatase and tensin homolog by small interfering RNA independently activated the PI 3-kinase pathway. Our findings suggest a common path for response to altered nutrition involving mitochondrial ROS-dependent PI 3-kinase pathway regulation, leading to steatosis.