Plasma MERTK is a promising biomarker for the diagnosis and prognosis of HBV-related acute-on-chronic liver failure.

BACKGROUND: Hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) has a high short-term mortality. This study aimed to determine the diagnostic and prognostic role of MER tyrosine kinase (MERTK) in HBV-ACLF patients. METHODS: Transcriptomics analysis evaluated MERTK expression and function during disease progression. The diagnostic and prognostic significance of MERTK for HBV-ACLF patients were verified by ELISA, the area under the receiver operating characteristic curve (AUROC) analysis, and immunohistochemistry (IHC) of liver tissues. RESULTS: MERTK mRNA was highly expressed in the HBV-ACLF compared to the liver cirrhosis (LC), chronic hepatitis B (CHB) and normal controls (NC) groups. Elevated MERTK mRNA predicted poor prognosis for HBV-ACLF at 28/90 days (AUROCs=0.814/0.731). Functional analysis showed MERTK was significantly associated with TLR and inflammatory signaling, and several key biological processes. External validation with 285 plasma subjects confirmed the high diagnostic accuracy of plasma MERTK for HBV-ACLF (AUROC=0.859) and potential prognostic value for 28/90-day mortality rates (AUROC=0.673 and 0.644, respectively). Risk stratification analysis indicated higher mortality risk for patients with plasma MERTK level above the cut-off value. Moreover, IHC staining showed increasing MERTK expression from NC, CHB and LC to HBV-ACLF patients. CONCLUSIONS: MERTK shows promise as a candidate biomarker for early diagnosis and prognosis of HBV-ACLF.

Open-Nanogap-Induced Strong Electromagnetic Enhancement in Au/AgAu Monolayer as a Stable and Uniform SERS Substrate for Ultrasensitive Detection.

Nanogap-based plasmonic metal nanocrystals have been applied in surface-enhanced Raman scattering detection, while the closed and insufficient electromagnetic fields as well as the nonreproducible Raman signal of the substrate greatly restrict the actual application. Herein, a highly uniform Au/AgAu monolayer with abundant nanogaps and huge electromagnetic enhancement is prepared, which shows ultrasensitive and reproducible SERS detection. Au/AgAu with an inner nanogap is first prepared based on Au nanotriangles, and the nanogap is opened from the three tips via a subsequent etching process. The open-gap Au/AgAu displays much higher SERS efficiency than Au and Au/AgAu with an inner nanogap on detecting crystal violet due to the open-gap induced electromagnetic enhancement and improved molecular absorption. Furthermore, the open-gap Au/AgAu monolayer is prepared via interfacial self-assembly, which shows further improved SERS due to the dense and strong hotspots in the nanocavities induced by the electromagnetic coupling between adjacent open gaps. The monolayer possesses excellent signal stability, uniformity, and reproducibility. The analytic enhancement factor and relative standard deviation reach to 2.12 × 108 and 4.65% on detecting crystal violet, respectively. Moreover, the monolayer achieves efficient detection of thiram in apple juice, biphenyl-4-thiol, 4-mercaptobenzoic, melamine, and a mixed solution of four different molecules, showing great promise in practical detection.

Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure.

BACKGROUND: The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis. METHODS: Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice. RESULTS: THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis. CONCLUSIONS: THBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.

Development of growth selection system and pocket engineering of d-amino acid oxidase to enhance selective deamination activity toward d-phosphinothricin.

D-amino acid oxidase (DAAO)-catalyzed selective oxidative deamination is a very promising process for synthesizing l-amino acids including l-phosphinothricin ( l-PPT, a high-efficiency and broad-spectrum herbicide). However, the wild-type DAAO's low activity toward unnatural substrates like d-phosphinothricin ( d-PPT) hampers its application. Herein, a DAAO from Caenorhabditis elegans (CeDAAO) was screened and engineered to improve the catalytic potential on d-PPT. First, we designed a novel growth selection system, taking into account the intricate relationship between the growth of Escherichia coli (E. coli) and the catalytic mechanism of DAAO. The developed system was used for high-throughput screening of gene libraries, resulting in the discovery of a variant (M6) with significantly increased catalytic activity against d-PPT. The variant displays different catalytic properties on substrates with varying hydrophobicity and hydrophilicity. Analysis using Alphafold2 modeling and molecular dynamic simulations showed that the reason for the enhanced activity was the substrate-binding pocket with enlarged size and suitable charge distribution. Further QM/MM calculations revealed that the crucial factor for enhancing activity lies in reducing the initial energy barrier of the reductive half reaction. Finally, a comprehensive binding-model index to predict the enhanced activity of DAAO toward d-PPT, and an enzymatic deracemization approach was developed, enabling the efficient synthesis of l-PPT with remarkable efficiency.

Double Cross-Linked Hydrogel Dressings Based on Triblock Copolymers Bearing Antifreezing, Antidrying, and Inherent Antibacterial Properties.

Bacterial infections typically invade the living tissue of wounds, thereby aggravating the inflammatory response, delaying wound healing, or causing further complications. In this paper, the antibacterial hydrogel (PNVBA) with antifreezing and antidrying properties was prepared by a two-step method using N-isopropylacrylamide (NIPAM), 1-butyl-3-vinylimidazolium bromide (VBIMBr), and 3-acrylamidophenylboronic acid (AAPBA). PNVBA hydrogels exhibited a high adsorption capacity of 280 mg·g-1 for bovine serum albumin (BSA) and can adhere to the surface of different materials through ion-dipole or hydrogen-bonding interactions. Meanwhile, the PNVBA hydrogels exhibited high viscoelasticity and good adhesion after freezing at -20 °C or heating at 70 °C for 24 h with a sterilizing rate of up to 98% against multidrug-resistant (MDR) Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). Moreover, a survival rate of up to 90% after incubation with L929 cells over 24 h was observed. Therefore, this inherent antibacterial hydrogel can be used as an excellent alternative material for wound dressings.

Effects of Early Versus Delayed Feeding in Patients With Acute Pancreatitis: A Systematic Review and Meta-analysis.

BACKGROUND: The aim of this study was to summarize the optimal strategy for early feeding in patients with acute pancreatitis. METHODS: The search was undertaken in electronic databases, which compared early with delayed feeding in acute pancreatitis. The primary outcome was the length of hospital stay (LOHS). The second outcomes were intolerance of refeeding, mortality, and total cost of each patient. This meta-analysis followed the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" guideline. Research is registered by PROSPERO, CRD42020192133. RESULTS: A total of 20 trials involving 2168 patients were included, randomly assigned to the early feeding group (N = 1033) and delayed feeding group (N = 1135). The LOHS was significantly lower in the early feeding group than the delayed feeding group (mean difference: -2.35, 95% CI: -2.89 to -1.80; P < 0.0001), no matter the mild or severe subgroup ( Pint = 0.69). The secondary outcome of feeding intolerance and mortality were no significant difference (risk ratio: 0.96, 0.40 to 2.16, P = 0.87 and 0.91, 0.57 to 1.46, P = 0.69; respectively). Moreover, the hospitalization cost was significantly less in the early feeding group, resulting in an average savings of 50%. In patients with severe pancreatitis, early feeding after 24 hours may be beneficial ( Pint = 0.001). CONCLUSION: Early oral feeding can significantly reduce the LOHS and hospitalization costs in patients with acute pancreatitis without increasing feeding intolerance or mortality. In patients with severe pancreatitis, early feeding after 24 hours may be beneficial.

Neurocomputational mechanisms of young children's observational learning of delayed gratification.

The ability to delay gratification is crucial for a successful and healthy life. An effective way for young children to learn this ability is to observe the action of adult models. However, the underlying neurocomputational mechanism remains unknown. Here, we tested the hypotheses that children employed either the simple imitation strategy or the goal-inference strategy when learning from adult models in a high-uncertainty context. Results of computational modeling indicated that children used the goal-inference strategy regardless of whether the adult model was their mother or a stranger. At the neural level, results showed that successful learning of delayed gratification was associated with enhanced interpersonal neural synchronization (INS) between children and the adult models in the dorsal lateral prefrontal cortex but was not associated with children's own single-brain activity. Moreover, the discounting of future reward's value obtained from computational modeling of the goal-inference strategy was positively correlated with the strength of INS. These findings from our exploratory study suggest that, even for 3-year-olds, the goal-inference strategy is used to learn delayed gratification from adult models, and the learning strategy is associated with neural interaction between the brains of children and adult models.

UMI-77 Modulates the Complement Cascade Pathway and Inhibits Inflammatory Factor Storm in Sepsis Based on TMT Proteomics and Inflammation Array Glass Chip.

Sepsis is a systemic inflammatory response syndrome caused by infection, which has no specific drug at present. UMI-77 can significantly improve the survival rate of septic mice; the detailed role of UMI-77 and its underlying mechanisms in sepsis are not clear. Inflammation array glass chip and proteomic analyses were performed to elucidate the latent mechanism of UMI-77 in the treatment of sepsis. The results showed that 7.0 mg/kg UMI-77 improved the 5 day survival rate in septic mice compared to the LPS group (60.964 vs 9.779%) and ameliorated the pathological conditions. Inflammation array glass chip analysis showed that sepsis treatment with UMI-77 may eventually through the suppression of the characteristic inflammatory storm-related cytokines such as KC, RANTES, LIX, IL-6, eotaxin, TARC, IL-1ß, and so on. Proteomics analysis showed that 213 differential expression proteins and complement and coagulation cascades were significantly associated with the process for the UMI-77 treatment of sepsis. The top 10 proteins including Apoa2, Tgfb1, Serpinc1, Vtn, Apoa4, Cat, Hp, Serpinf2, Fgb, and Serpine1 were identified and verified, which play important roles in the mechanism of UMI-77 in the treatment of sepsis. Our findings indicate that UMI-77 exerts an antisepsis effect by modulating the complement cascade pathway and inhibiting inflammatory storm factors.

Biomarker Discovery for Early Diagnosis of Papillary Thyroid Carcinoma Using High-Throughput Enhanced Quantitative Plasma Proteomics.

The incidence of thyroid cancer (TC) has been increasing over the last 50 years worldwide. A higher rate of overdiagnosis in indolent thyroid lesions has resulted in unnecessary treatment. An accurate detection of TC at an early stage is highly demanded. We aim to develop an enhanced isobaric labeling-based high-throughput plasma quantitative proteomics to identify biomarkers in a discovery cohort. Selected candidates were tested by enzyme-linked immunosorbent assay (ELISA) in the training cohort and validation cohort. In total, 1063 proteins were quantified, and 129 proteins were differentially expressed between patients and healthy subjects. Serum levels of ISG15 and PLXNB2 were significantly elevated in patients with papillary thyroid cancer (PTC) or thyroid adenoma, compared to healthy subjects (p < 0.001) and patients with nodular goiter (p < 0.001). Receiver operating characteristic (ROC) analysis of combined markers (ISG15 and PLXNB2) significantly distinguished PTC from healthy control (HC) subjects. Similar differentiations were also found between thyroid adenoma and HC subjects. Notably, this combined marker could distinguish stage-I PTC from HC subjects (area under the curve (AUC) = 0.872). Our results revealed that ISG15 and PLXNB2 are independent diagnostic biomarkers for PTC and thyroid adenoma, showing a promising value for the early detection of PTC.

Ancient Demographics Determine the Effectiveness of Genetic Purging in Endangered Lizards.

The purging of deleterious alleles has been hypothesized to mitigate inbreeding depression, but its effectiveness in endangered species remains debatable. To understand how deleterious alleles are purged during population contractions, we analyzed genomes of the endangered Chinese crocodile lizard (Shinisaurus crocodilurus), which is the only surviving species of its family and currently isolated into small populations. Population genomic analyses revealed four genetically distinct conservation units and sharp declines in both effective population size and genetic diversity. By comparing the relative genetic load across populations and conducting genomic simulations, we discovered that seriously deleterious alleles were effectively purged during population contractions in this relict species, although inbreeding generally enhanced the genetic burden. However, despite with the initial purging, our simulations also predicted that seriously deleterious alleles will gradually accumulate under prolonged bottlenecking. Therefore, we emphasize the importance of maintaining a minimum population capacity and increasing the functional genetic diversity in conservation efforts to preserve populations of the crocodile lizard and other endangered species.

Predicting the Onset of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome with rapid progression. This study aimed to develop and validate a prognostic score to predict the onset of ACLF in hepatitis B virus (HBV) etiology. METHODS: The prospective clinical data of 1373 patients with acute deterioration of HBV-related chronic liver disease were used to identify clinical characteristics and develop a prognostic score for the onset of ACLF. RESULTS: Of the patients assessed using the Chinese Group on the Study of Severe Hepatitis B (COSSH)-ACLF criteria, 903 patients with non-ACLF at admission (1 received transplantation at 5 days) were stratified: 71 with progression to ACLF and 831 without progression to ACLF at 7 days. Four predictors (total bilirubin, international normalized ratio, alanine aminotransferase, and ferritin) were associated significantly with ACLF onset at 7 days. The COSSH-onset-ACLF score was constituted as follows: (0.101 × ln [alanine aminotransferase] + 0.819 × ln [total bilirubin] + 2.820 × ln [international normalized ratio] + 0.016 × ln [ferritin]). The C-indexes of the new score for 7-/14-/28-day onset (0.928/0.925/0.913) were significantly higher than those of 5 other scores (Chronic Liver Failure Consortium ACLF development score/Model for End-stage Liver Disease score/Model for End-stage Liver Disease sodium score/COSSH-ACLF score/Chronic liver failure Consortium ACLF score; all P < .001). The improvement in predictive errors, time-dependent receiver operating characteristic, probability density function evaluation, and calibration curves of the new score showed the highest predictive value for ACLF onset at 7/14/28 days. Risk stratification of the new score showed 2 strata with high and low risk (≥6.3/<6.3) of ACLF onset. The external validation group further confirmed the earlier results. CONCLUSIONS: A new prognostic score based on 4 predictors can accurately predict the 7-/14-/28-day onset of ACLF in patients with acute deterioration of HBV-related chronic liver disease and might be used to guide clinical management.

Serum ferritin diagnosis and prediction of hepatitis B virus-related acute-on-chronic liver failure.

Early diagnosis and prediction of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is important to reduce mortality. This study aimed to assess the diagnostic and predictive value of serum ferritin (SF) in HBV-ACLF patients. Clinical data from 1905 hospitalized patients with acute deterioration of HBV-related chronic liver diseases were analyzed to explore the association between SF and ACLF. A co-expression network based on transcriptomics data for 20 HBV-ACLF patients was constructed to investigate biological processes related to ferritin. Of 1270 patients in the derivation group, 440 and 830 were diagnosed with and without ACLF, respectively, based on Chinese Group on the Study of Severe Hepatitis B-ACLF criteria. SF levels showed high diagnostic accuracy (area under the receiver operating characteristic [AUROC]: 0.820) for ACLF at admission. In patients with ACLF, SF was associated with liver and coagulation failure. In patients without ACLF, SF predicted risk for 28-day progression to ACLF (AUROC: 0.808). A validation group of 635 patients confirmed the above results. Moreover, SF was significantly associated with the immune response based on transcriptomics analysis. SF is a potential diagnostic and predictive marker for HBV-ACLF and might play a crucial role in immune disorders in HBV-ACLF.

ETS2 alleviates acute-on-chronic liver failure by suppressing excessive inflammation.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a syndrome with high short-term mortality. The mechanism of the transcription factor ETS2 in ACLF remains unclear. This study aimed to clarify the molecular basis of ETS2 in ACLF pathogenesis. Peripheral blood mononuclear cells from patients with HBV-ACLF (n = 50) were subjected to RNA sequencing. Transcriptome analysis showed that ETS2 expression was significantly higher in ACLF patients than in patients with chronic liver diseases and healthy subjects (all p < 0.001). Area-under-ROC analysis of ETS2 demonstrated high values for the prediction of 28-/90-day mortality in ACLF patients (0.908/0.773). Significantly upregulated signatures of the innate immune response (monocytes/neutrophils/inflammation-related pathways) were observed in ACLF patients with high ETS2 expression. Myeloid-specific ETS2 deficiency in liver failure mice resulted in deterioration of biofunctions and increased expression of pro-inflammatory cytokines (IL-6/IL-1ß/TNF-α). Knockout of ETS2 in macrophages confirmed the downregulation of IL-6 and IL-1ß caused by both HMGB1 and lipopolysaccharide, and an NF-κB inhibitor reversed the suppressive effect of ETS2. ETS2 is a potential prognostic biomarker of ACLF patients that alleviates liver failure by downregulating the HMGB1-/lipopolysaccharide-triggered inflammatory response and may serve as a therapeutic target for ACLF.

Effects of temperature and charged vacancies on electronic and optical properties of ß-Ga2O3 after radiation damage.

ß-Ga2O3 as an ultra-wide bandgap material is widely used in space missions and nuclear reactor environments. It is well established that the physical properties of ß-Ga2O3 would be affected by radiation damage and temperature in such application scenarios. Defects are inevitably created in ß-Ga2O3 upon irradiation and their dynamic evolution is positively correlated with the thermal motion of atoms as temperature increases. This work utilizes first-principles calculations to investigate how temperature influences the electronic and optical properties of ß-Ga2O3 after radiation damage. It finds that the effect of p-type defects caused by Ga vacancies on optical absorption diminishes as temperature increases. The high temperature amplifies the effect of oxygen vacancies to ß-Ga2O3, however, making n-type defects more pronounced and accompanied by an increase in the absorption peak in the visible band. The self-compensation effect varies when ß-Ga2O3 contains both Ga vacancies and O vacancies at different temperatures. Moreover, in the case of Ga3- (O2+) vacancies, the main characters of p(n)-type defects caused by uncharged Ga0 (O0) vacancies disappear. This work aims to understand the evolution of physical properties of ß-Ga2O3 under irradiation especially at high temperatures, and help analyze the damage mechanism in ß-Ga2O3-based devices.

Omics in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a critical syndrome that develops in patients with chronic liver disease and is characterized by acute decompensation, single- or multiple-organ failure and high short-term mortality. Over the past few decades, ACLF has been progressively recognized as an independent clinical entity, and several criteria and prognostic scores have been proposed and validated by different scientific societies. However, controversies still exist in some aspects across regions, which mainly involve whether the definition of underlying liver diseases should include cirrhosis and non-cirrhosis. The pathophysiology of ACLF is complicated and remains unclear, although accumulating evidence based on different aetiologies of ACLF shows that it is closely associated with intense systemic inflammation and immune-metabolism disorder, which result in mitochondrial dysfunction and microenvironment imbalance, leading to disease development and organ failure. In-depth insight into the biological pathways involved in the mechanisms of ACLF and potential mechanistic targets that improve patient survival still needs to be investigated. Omics-based analytical techniques, including genomics, transcriptomics, proteomics, metabolomics and microbiomes, have developed rapidly and can offer novel insights into the essential pathophysiologic process of ACLF. In this paper, we briefly reviewed and summarized the current knowledge and recent advances in the definitions, criteria and prognostic assessments of ACLF; we also described the omics techniques and how omics-based analyses have been applied to investigate and characterize the biological mechanisms of ACLF and identify potential predictive biomarkers and therapeutic targets for ACLF. We also outline the challenges, future directions and limitations presented by omics-based analyses in clinical ACLF research.

Transcriptomics confirm the establishment of a liver-immune dual-humanized mouse model after transplantation of a single type of human bone marrow mesenchymal stem cell.

BACKGROUND AND AIMS: Human bone marrow mesenchymal stem cells (hBMSCs) are important for developing a dual-humanized mouse model to clarify disease pathogenesis. We aimed to elucidate the characteristics of hBMSC transdifferentiation into liver and immune cells. METHODS: A single type of hBMSCs was transplanted into immunodeficient Fah-/- Rag2-/- IL-2Rγc-/- SCID (FRGS) mice with fulminant hepatic failure (FHF). Liver transcriptional data from the hBMSC-transplanted mice were analysed to identify transdifferentiation with traces of liver and immune chimerism. RESULTS: Mice with FHF were rescued by implanted hBMSCs. Human albumin/leukocyte antigen (HLA) and CD45/HLA double-positive hepatocytes and immune cells were observed in the rescued mice during the initial 3 days. The transcriptomics analysis of liver tissues from dual-humanized mice identified two transdifferentiation phases (cellular proliferation at 1-5 days and cellular differentiation/maturation at 5-14 days) and ten cell lineages transdifferentiated from hBMSCs: human hepatocytes, cholangiocytes, stellate cells, myofibroblasts, endothelial cells and immune cells (T/B/NK/NKT/Kupffer cells). Two biological processes, hepatic metabolism and liver regeneration, were characterized in the first phase, and two additional biological processes, immune cell growth and extracellular matrix (ECM) regulation, were observed in the second phase. Immunohistochemistry verified that the ten hBMSC-derived liver and immune cells were present in the livers of dual-humanized mice. CONCLUSIONS: A syngeneic liver-immune dual-humanized mouse model was developed by transplanting a single type of hBMSC. Four biological processes linked to the transdifferentiation and biological functions of ten human liver and immune cell lineages were identified, which may help to elucidate the molecular basis of this dual-humanized mouse model for further clarifying disease pathogenesis.

Assessing the Use of Probes and Quenchers for Understanding the Reactive Species in Advanced Oxidation Processes.

Advanced oxidation processes (AOPs) are increasingly applied in water and wastewater treatment. Understanding the role of reactive species using probes and quenchers is one of the main requirements for good process design. However, much fundamental kinetic data for the reactions of probes and quenchers with reactive species is lacking, probably leading to inappropriate probe and quencher selection and dosing. In this work, second-order rate constants for over 150 reactions of probes and quenchers with reactive species such as •OH, SO4•-, and Cl• and chemical oxidants such as free chlorine and persulfate were determined. Some previously ill-quantified reactions (e.g., furfuryl alcohol and methyl phenyl sulfoxide reactions with certain chemical oxidants, nitrobenzene and 1,4-dioxane reactions with certain halogen radicals) were found to be kinetically favorable. The selection of specific probes can be guided by the improved kinetic database. The criteria for properly choosing dosages of probes and quenchers were proposed along with a procedure for quantifying reactive species free of interference from probe addition. The limitations of probe and quencher approaches were explicated, and possible solutions (e.g., the combination with other tools) were proposed. Overall, the kinetic database and protocols provided in this work benefit future research in understanding the radical chemistry in AOPs as well as other radical-involved processes.

Acute-on-chronic liver failure: far to go-a review.

Acute-on-chronic liver failure (ACLF) has been recognized as a severe clinical syndrome based on the acute deterioration of chronic liver disease and is characterized by organ failure and high short-term mortality. Heterogeneous definitions and diagnostic criteria for the clinical condition have been proposed in different geographic regions due to the differences in aetiologies and precipitating events. Several predictive and prognostic scores have been developed and validated to guide clinical management. The specific pathophysiology of ACLF remains uncertain and is mainly associated with an intense systemic inflammatory response and immune-metabolism disorder based on current evidence. For ACLF patients, standardization of the treatment paradigm is required for different disease stages that may provide targeted treatment strategies for individual needs.

[Effect of aqueous extract of Corni Fructus on Aß_(25-35)-induced brain injury and neuroinflammation in mice with Alzheimer's disease].

The purpose of this study was to investigate the effect of aqueous extract of Corni Fructus on ß-amyloid protein 25-35(Aß_(25-35))-induced brain injury and neuroinflammation in Alzheimer's disease(AD) mice to provide an experimental basis for the treatment of AD by aqueous extract of Corni Fructus. Sixty C57BL/6J male mice were randomly divided into a sham group, a model group, a positive control group(huperizine A, 0.2 mg·kg~(-1)), a low-dose aqueous extract of Corni Fructus group(1.3 g·kg~(-1)), a medium-dose aqueous extract of Corni Fructus group(2.6 g·kg~(-1)), and a high-dose aqueous extract of Corni Fructus group(5.2 g·kg~(-1)). The AD model was induced by lateral ventricular injection of Aß_(25-35) in mice except for those in the sham group, and AD model mice were treated with corresponding drugs by gavage for 24 days. The behavioral test was performed one week before animal dissection. Hematoxylin-eosin(HE) staining was performed to observe the morphology of neurons in the hippocampal region. Flow cytometry was used to detect the apoptosis level of primary hippocampal cells in mice. ELISA kits were used to detect the levels of ß-amyloid protein 1-42(Aß_(1-42)) and phosphorylated microtubule-associated protein Tau(p-Tau) in mouse brain tissues. Immunofluorescence and Western blot were used to detect the expression of related proteins in mouse brain tissues. MTT assay was used to detect the effect of compounds in aqueous extract of Corni Fructus on Aß_(25-35)-induced N9 cell injury. Molecular docking was employed to analyze the interactions of caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-ß-D-glucopyranoside, esculetin, and(+)-lyoniresinol with ß-amyloid precursor protein(APP), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α). Aqueous extract of Corni Fructus could improve the learning and memory abilities of Aß_(25-35)-induced mice by increasing the duration of the autonomous activity, the rate of autonomous alternation, the preference coefficient, and the discrimination coefficient, and reduce Aß_(25-35)-induced brain injury and neuroinflammation in mice by increasing the expression levels of interleukin-10(IL-10) and B-cell lymphoma-2(Bcl-2) in brain tissues, decreasing the expression levels of Aß_(1-42), p-Tau, IL-6, TNF-α, cysteine aspartate-specific protease 3(caspase-3), cysteine aspartate-specific protease 9(caspase-9), and Bcl-2-associated X protein(Bax), and decreasing the number of activated glial cells in brain tissues. The results of cell experiments showed that esculetin and(+)-lyoniresinol could improve Aß_(25-35)-induced N9 cell injury. Molecular docking results showed that caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-ß-D-glucopyranoside, esculetin, and(+)-lyoniresinol had good binding affinity with APP and weak binding affinity with IL-6 and TNF-α. Aqueous extract of Corni Fructus could ameliorate cognitive dysfunction and brain damage in Aß_(25-35)-induced mice by reducing the number of apoptotic cells and activated glial cells in the brain and decreasing the expression level of inflammatory factors. Caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-ß-D-glucopyranoside, esculetin, and(+)-lyoniresinol may be the material basis for the anti-AD effect of aqueous extract of Corni Fructus.

PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF.

OBJECTIVE: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics. METHODS: Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs). RESULTS: The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis. CONCLUSIONS: This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.