Comparative physiological and transcriptomic analysis of sono-biochemical control over post-acidification of Lactobacillus delbrueckii subsp. bulgaricus.

Thermosonication (UT) prestress treatments combining with varied fermentation patterns has been revealed as an effective method to regulate post-acidification as exerted by Lactobacillus delbrueckii subsp. bulgaricus (L. delbrueckii), but sono-biochemical controlling mechanisms remain elusive. This study employed physiological and transcriptomic analysis to explore the response mechanism of L. delbrueckii to UT-induced microstress (600 W, 33 kHz, 10 min). UT stress-induced inhibition of acidification of L. delbrueckii during (post)-fermentation was first confirmed, relying on the UT process parameters such as stress exposure duration and UT power. The significantly enhanced membrane permeability in cells treated by 600 W for 10 min than the microbes stressed by 420 W for 20 min suggested the higher dependence of UT-derived stresses on the treatment durations, relative to the ultrasonic powers. In addition, ultrasonication treatment-induced changes in cell membrane integrity enhanced and/or disrupted permeability of L. delbrueckii, resulting in an imbalance in intracellular conditions associated with corresponding alterations in metabolic behaviors and fermentation efficiencies. UT-prestressed inoculum exhibited a 21.46% decrease in the membrane potential during the lag phase compared to untreated samples, with an intracellular pH of 5.68 ± 0.12, attributed to the lower activities of H+-ATPase and lactate dehydrogenase due to UT stress pretreatments. Comparative transcriptomic analysis revealed that UT prestress influenced the genes related to glycolysis, pyruvate metabolism, fatty acid synthesis, and ABC transport. The genes encoding 3-oxoacyl-[acyl-carrier-protein] reductases I, II, and III, CoA carboxylase, lactate dehydrogenase, pyruvate oxidase, glucose-6-phosphate isomerase, and glycerol-3-phosphate dehydrogenase were downregulated, thus identifying the relevance of the UT microstresses-downregulated absorption and utilization of carbohydrates with the attenuated fatty acid production and energy metabolisms. These findings could contribute to provide a better understanding of the inactivated effects on the post-acidification of L. delbrueckii by ultrasonic pretreatments, thus providing theoretical basis for the targeted optimization of acidification inhibition efficiencies for yogurt products during chilled preservation processes.

Establishment and validation of a predictive model of immune tolerance after pediatric liver transplantation (ITPLT): A multicenter cohort study.

Side-effect of life-long immunosuppressants (IS) administration is a major obstacle for the long-term survival of pediatric liver transplantation (LT) recipients. Immunotolerance is the status that recipients discontinued IS with normal liver function and intrahepatic histology. So far, only a few clinical parameters were identified related with tolerance but failed to accurately discriminate tolerant recipients in clinical practice. Here we aimed to provide a comprehensive view of pre- and post-LT risk factors associated with the achievement of tolerance after pediatric LT and established a tolerance predictive nomogram (ITPLT) with high accuracy and specificity. We enrolled 2228 pediatric recipients who received LT in XX Hospital between October 2006 and December 2020. All participants survived over 3 years after transplantation with comprehensive and intact medical history and follow-up data. They were randomly assigned to training and validation cohorts in accordance with a ratio of 1:1. Univariate and multivariable Logistic regression were used to identify clinical factors associated with post-LT immune tolerance and establish a predictive model. The model was further validated in an independent external validation cohort from YY Hospital. Among all participants, 6% recipients successfully tapered IS with intact allograft function. The most common reason for IS discontinuity was pneumonia. Univariate analysis identified 15 clinical factors associated with tolerance achievement, including age at LT, follow-up time, preoperative total bilirubin, creatinine, INR, CYP polymorphism, types of transplantation, massive postoperative ascites, episodes of acute rejection, and the severity of EBV and CMV infection. Using multivariable Logistic regression, we established the predictive ITPLT model for post-LT tolerance, which included seven easily accessible clinical factors (age at LT, CYP3A5 genotype, types of transplantation, post-LT massive ascites, preoperative INR, creatinine, and total bilirubin levels). Then we visualized the model using nomogram. The c-statistics for predicting tolerance achievement in the training, internal validation, and external validation cohorts were 0.854, 0.787, and 0.746 respectively. Multiple pre- and post-LT clinical factors affected the process of immune remodeling after pediatric liver transplantation. The predictive ITPLT model, composed of seven easily accessible clinical factors, could comprehensively reveal the effect of these clinical parameters on immune remodeling and accurately identify tolerant recipients after pediatric LT. The application of ITPLT could facilitate the individualized IS strategy in the future.

Long-term outcomes and risk factors for early bacterial infection after pediatric liver transplantation: a prospective cohort study.

BACKGROUND: Liver transplantation (LT) is the most efficient treatment for pediatric patients with end-stage liver diseases, while bacterial infection is the leading reason for posttransplant mortality. The present study is to explore the outcomes and risk factors of early bacterial infection (within 1 mo) after pediatric LT. METHODS: In this prospective cohort study, 1316 pediatric recipients (median [IQR] age: 9.1 [6.3-28.0] months; male: 48.0%; median [IQR] follow-up time: 40.6 [29.1-51.4] months) who received LT from September 2018 to April 2022 were included. Bacterial culture samples such as sputum, abdominal drainage, blood and so on were collected when recipients were presented with infective symptoms. Kaplan-Meier analysis was applied to estimate the long-term survival rates and logistic regression was used to identify independent risk factors. To explore the role of pretransplant rectal swab culture (RSC) in reducing posttransplant bacterial infection rate, 188 infant LT recipients (median [IQR] age: 6.8 [5.5-8.1] months; male: 50.5%) from May 2022 to September 2023 were included. Log-binomial regression was used to measure the association of pretransplant RSC screening and posttransplant bacterial infection. The "Expectation Maximization" algorithm was used to impute the missing data. RESULTS: Bacterial infection was the primary cause for early (38.9%) and overall mortality (35.6%) after pediatric LT. Kaplan-Meier analysis revealed inferior 1- and 5-year survival rates for recipients with posttransplant bacterial infection (92.6% vs. 97.1%, 91.8% vs. 96.4% respectively; P<0.001). Among all detected bacteria, Staphylococcus spp. (34.3%) and methicillin-resistant coagulase-negative Staphylococci (43.2%) were the dominant species and multi-drug resistant organisms, respectively. Multivariable analysis revealed that infant recipients (adjusted odds ratio [aOR], 1.49; 95% CI, 1.01-2.20), male recipients (aOR, 1.43; 95% CI, 1.08-1.89), high graft-to-recipient weight ratio (aOR, 1.64; 95% CI, 1.17-2.30), positive posttransplant RSC (aOR, 1.45; 95% CI, 1.04-2.02) and nasopharyngeal swab culture (aOR 2.46; 95% CI, 1.72-3.52) were independent risk factors for early bacterial infection. Furthermore, RSC screening and antibiotic prophylaxis before transplantation could result in a relatively lower posttransplant infection rate, albeit without statistical significance (adjusted RR, 0.53; 95% CI, 0.25-1.16). CONCLUSION: In this cohort study, posttransplant bacterial infection resulted in an inferior long-term patient survival rate. The five identified independent risk factors for posttransplant bacterial infection could guide the prophylaxis strategy of posttransplant bacterial infection in the future. Additionally, pretransplant RSC might decrease posttransplant bacterial infection rate.

CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer.

Driver genomic mutations in tumors define specific molecular subtypes that display distinct malignancy competence, therapeutic resistance and clinical outcome. Although TP53 mutation has been identified as the most common mutation in hepatocellular carcinoma (HCC), current understanding on the biological traits and therapeutic strategies of this subtype has been largely unknown. Here, we reveal that fatty acid ß oxidation (FAO) is remarkable repressed in TP53 mutant HCC and which links to poor prognosis in HCC patients. We further demonstrate that carnitine palmitoyltransferase 1 (CPT1A), the rate-limiting enzyme of FAO, is universally downregulated in liver tumor tissues, and which correlates with poor prognosis in HCC and promotes HCC progression in the de novo liver tumor and xenograft tumor models. Mechanically, hepatic Cpt1a loss disrupts lipid metabolism and acetyl-CoA production. Such reduction in acetyl-CoA reduced histone acetylation and epigenetically reprograms branched-chain amino acids (BCAA) catabolism, and leads to the accumulation of cellular BCAAs and hyperactivation of mTOR signaling. Importantly, we reveal that genetic ablation of CPT1A renders TP53 mutant liver cancer mTOR-addicted and sensitivity to mTOR inhibitor AZD-8055 treatment. Consistently, Cpt1a loss in HCC directs tumor cell therapeutic response to AZD-8055. CONCLUSION: Our results show genetic evidence for CPT1A as a metabolic tumor suppressor in HCC and provide a therapeutic approach for TP53 mutant HCC patients.

Impact of HIV pre-exposure prophylaxis prescriptions on HIV diagnoses in New York city.

BACKGROUND: HIV preexposure prophylaxis (PrEP) has proven to be efficacious and effective in preventing HIV infections, but few studies have reported its impact in the real world. METHODS: We conducted an ecological analysis and compared the trends in HIV PrEP prescriptions with the trends in age-adjusted HIV diagnosis rates in New York City (NYC). Joinpoint regression analyses were used to identify any temporal trends in HIV diagnosis rates in NYC. RESULTS: The number of people filling at least one PrEP prescription in NYC increased from 2551 in 2014 to 35 742 in 2022. The overall age-adjusted HIV diagnosis rate steadily decreased from 48.1 per 100 000 in 2003 to 17.1 per 100 000 in 2022. After the rollout of PrEP, accelerated decreases were detected in some subpopulations including white men [2014-2019 annual percentage change (APC): -16.6%; 95% confidence interval (CI) -22.7 to -10.0], Asian/Pacific Islander men (2016-2022 APC: -9.8%), men aged 20-29 years (2017-2020 APC: -9.4%) and 40 -49 years (2014-2020 APC: -12.2%), Latino/Hispanic people aged 40-49 years (2015-2020 APC: -13.0%), white people aged 20-29 years (2012-2022 APC: -11.4%) and 40-49 years (2014-2018 APC: -27.8%), and Asian/Pacific Islander people aged 20-29 years (2017-2022 APC: -13.0). CONCLUSION: With a high coverage, PrEP can have a long-term impact in reducing HIV infections in a population, but if preexisting social determinants that contribute to racial, ethnic, and gender inequities are not well addressed, the implementation of PrEP can exacerbate these inequalities.

Efficient expansion and CRISPR-Cas9-mediated gene correction of patient-derived hepatocytes for treatment of inherited liver diseases.

Cell-based ex vivo gene therapy in solid organs, especially the liver, has proven technically challenging. Here, we report a feasible strategy for the clinical application of hepatocyte therapy. We first generated high-quality autologous hepatocytes through the large-scale expansion of patient-derived hepatocytes. Moreover, the proliferating patient-derived hepatocytes, together with the AAV2.7m8 variant identified through screening, enabled CRISPR-Cas9-mediated targeted integration efficiently, achieving functional correction of pathogenic mutations in FAH or OTC. Importantly, these edited hepatocytes repopulated the injured mouse liver at high repopulation levels and underwent maturation, successfully treating mice with tyrosinemia following transplantation. Our study combines ex vivo large-scale cell expansion and gene editing in patient-derived transplantable hepatocytes, which holds potential for treating human liver diseases.

Nutrition and Epstein-Barr viremia in children underwent liver transplantation: A retrospective, cross-sectional study.

BACKGROUND AND AIMS: We aimed to examine the association between nutritional status, assessed by height/length and body weight for age and sex, and Epstein-Barr virus (EBV) viremia in children underwent liver transplantation. METHODS: Nutritional status was determined by total score of age- and sex-specific height/length and body weight: < (-2 SD) as "2 points", (-2 SD to -1 SD) as "1 point", and ≥ (-1SD) as "0 point". Children were further classified into three groups: malnutrition (4 points), risk of malnutrition (1-3 points), and normal (0 point). EBV viremia were confirmed by real time quantitative PCR method if EBV burden was ≥400 copies/ml. RESULTS: A total number of 896 children (414 boys and 482 girls, medium age 8 months) were included in the study. The medium height was 65.0 cm while medium body weight was 7.0 kg. The prevalence of EBV viremia was 54.6% during follow up. Comparing with children with normal nutritional status, the adjusted odds ratios for the risk of EBV viremia was 2.14 (95% CI: 1.44, 3.19) in children with risk of malnutrition, and 2.29 (95% CI: 1.54, 3.40) in children with malnutrition. Each point increase of nutritional score was associated with a 21% higher risk of EBV viremia (odd ratios = 1.21; 95% CI: 1.10, 1.34) in fully adjusted model. CONCLUSIONS: Nutritional score was associated with EBV viremia in children underwent liver transplantation.

Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons.

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders (NDDs) in which children display differences in social interaction/communication and repetitive stereotyped behaviors along with variable associated features. Cul3, a gene linked to ASD, encodes CUL3 (CULLIN-3), a protein that serves as a key component of a ubiquitin ligase complex with unclear function in neurons. Cul3 homozygous deletion in mice is embryonic lethal; thus, we examine the role of Cul3 deletion in early synapse development and neuronal morphology in hippocampal primary neuronal cultures. Homozygous deletion of Cul3 significantly decreased dendritic complexity and dendritic length, as well as axon formation. Synaptic spine density significantly increased, mainly in thin and stubby spines along with decreased average spine volume in Cul3 knockouts. Both heterozygous and homozygous knockout of Cul3 caused significant reductions in the density and colocalization of gephyrin/vGAT puncta, providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged. Based on previous studies implicating elevated caspase-3 after Cul3 deletion, we demonstrated increased caspase-3 in our neuronal cultures and decreased neuronal cell viability. We then examined the efficacy of the caspase-3 inhibitor Z-DEVD-FMK to rescue the decrease in neuronal cell viability, demonstrating reversal of the cell viability phenotype with caspase-3 inhibition. Studies have also implicated caspase-3 in neuronal morphological changes. We found that caspase-3 inhibition largely reversed the dendrite, axon, and spine morphological changes along with the inhibitory synaptic puncta changes. Overall, these data provide additional evidence that Cul3 regulates the formation or maintenance of cell morphology, GABAergic synaptic puncta, and neuronal viability in developing hippocampal neurons in culture.

GPX4 transcriptionally promotes liver cancer metastasis via GRHL3/PTEN/PI3K/AKT axis.

Hepatocellular carcinoma (HCC) is among the most fatal types of malignancy, with a high prevalence of relapse and limited treatment options. As a critical regulator of ferroptosis and redox homeostasis, glutathione peroxidase 4 (GPX4) is commonly upregulated in HCC and is hypothesized to facilitate cancer metastasis, but this has not been fully explored in HCC. Here, we report that up-regulated GPX4 expression in HCC is strongly associated with tumor metastasis. FACS-based in vivo and in vitro analysis revealed that a cell subpopulation featuring lower cellular reactive oxygen species levels and ferroptosis resistance were involved in GPX4-mediated HCC metastasis. Mechanistically, GPX4 overexpressed in HCC tumor cells was enriched in the nucleus and transcriptionally silenced GRHL3 expression, thereby activating PTEN/PI3K/AKT signaling and promoting HCC metastasis. Functional studies demonstrated that GPX4 amino acids 110-145 are a binding site that interacts with the GRHL3 promoter. As AKT is a downstream target of GPX4, we combined the AKT inhibitor, AKT-IN3, with lenvatinib to effectively inhibit HCC tumor cell metastasis. Overall, these results indicate that the GPX4/GRHL3/PTEN/PI3K/AKT axis controls HCC cell metastasis and lenvatinib combined with AKT-IN3 represents a potential therapeutic strategy for patients with metastatic HCC.

Dexmedetomidine use during orthotopic liver transplantation surgery on early allograft dysfunction: A randomized controlled trial.

BACKGROUND: Previous studies have shown a protective effect of dexmedetomidine use in kidney transplantation. In contrast, it is not known whether intraoperative administration of dexmedetomidine can reduce early allograft dysfunction incidence following liver transplantation. OBJECTIVE: To investigate the effect of dexmedetomidine use during surgery on early allograft dysfunction following orthotopic liver transplantation (OLT). STUDY DESIGN: This is a single-center, double-blinded, placebo-controlled randomized clinical trial. 330 adult patients undergoing orthotopic liver transplantation were enrolled from Jan 14th, 2019 to May 22nd, 2022. Patients received dexmedetomidine or normal saline during surgery. 1 year follow-ups were recorded. METHODS: Patients were randomized to two groups receiving either dexmedetomidine or normal saline intraoperatively. For patients in the dexmedetomidine group, a loading dose (1 µg/kg over 10 min) of dexmedetomidine was given after induction of anesthesia followed by a continuous infusion (0.5 µg/kg /h) until the end of surgery. For patients in the normal saline group, an equal volume loading dose of 0.9% saline was given after the induction of anesthesia followed by an equal volume continuous infusion until the end of surgery. The primary outcome was early allograft dysfunction. Secondary outcomes included primary graft non-function, acute kidney injury and acute lung injury/ acute respiratory distress syndrome. RESULTS: Of 330 patients included in the intention-to-treat analysis, 165 were in the dexmedetomidine group (mean [SD] age, 49 [10] years; 117 [70.9%] men), and 165 were in the normal saline group (mean SD age, 49 [9] years; 118 [74%] men). 39 (24.4%) patients in the dexmedetomidine group and 31 (19.4%) in normal saline group developed early allograft dysfunction and the difference was statistically insignificant (P=0.28). Secondary outcomes including primary graft non-function and acute kidney injury was similar between the two groups. CONCLUSION: Intraoperative administration of dexmedetomidine did not reduce early allograft dysfunction rate after orthotopic liver transplantation.

Hybrid Bioactive Hydrogel Promotes Liver Regeneration through the Activation of Kupffer Cells and ECM Remodeling After Partial Hepatectomy.

Partial hepatectomy is an essential surgical technique used to treat advanced liver diseases such as liver tumors, as well as for performing liver transplants from living donors. However, postoperative complications such as bleeding, abdominal adhesions, wound infections, and inadequate liver regeneration pose significant challenges and increase morbidity and mortality rates. A self-repairing mixed hydrogel (O5H2/Cu2+/SCCK), containing stem cell derived cytokine (SCCK) derived from human umbilical cord mesenchymal stem cells (HUMSCs) treated with the traditional Chinese remedy Tanshinone IIA (TSA), is developed. This SCCK, in conjunction with O5H2, demonstrates remarkable effects on Kupffer cell activation and extracellular matrix (ECM) remodeling. This leads to the secretion of critical growth factors promoting enhanced proliferation of hepatocytes and endothelial cells, thereby facilitating liver regeneration and repair after partial hepatectomy. Furthermore, the hydrogel, featuring macrophage-regulating properties, effectively mitigates inflammation and oxidative stress damage in the incision area, creating an optimal environment for postoperative liver regeneration. The injectability and strong adhesion of the hydrogel enables rapid hemostasis at the incision site, while its physical barrier function prevents postoperative abdominal adhesions. Furthermore, the hydrogel's incorporation of Cu2+ provides comprehensive antibacterial effects, protecting against a wide range of bacteria types and reducing the chances of infections after surgery.

A Novel Strategy for Topical Administration by Combining Chitosan Hydrogel Beads with Nanostructured Lipid Carriers: Preparation, Characterization, and Evaluation.

The objective of the present study was to develop and evaluate NLC-chitosan hydrogel beads for topical administration. The feasibility of the preparation technology was verified by investigating various formulation factors and the impact of chitosan hydrogel beads on the NLC. The encapsulation efficiency of NLC-chitosan hydrogel beads was above 95% in optimized process conditions. The physical characterization of the NLC-chitosan hydrogel beads showed that the NLC was distributed within the network of the chitosan hydrogel beads. Furthermore, the incorporation of NLC into the chitosan hydrogel beads was related to the electrostatic interaction between the surface of the NLC and chitosan, which influenced the lipid ordering degree of the NLC and contributed to the stability. The stability studies showed that the retention rate of quercetin in the NLC-chitosan hydrogel beads was 88.63 ± 2.57% after 10 months of storage under natural daylight. An in vitro permeation study showed that NLC-chitosan hydrogel beads exhibited superior ability in enhancing skin permeation by hydrophobic active ingredients compared to the NLC and significantly increased skin accumulation. These studies demonstrated that the use of NLC-chitosan hydrogel beads might be a promising strategy for the delivery of hydrophobic active ingredients in topical administration.

Evaluation of the effectiveness and safety of sequential vaccination with inactivated SARS-CoV-2 vaccine and Ad5-nCoV booster in pediatric liver transplant recipients.

Amidst the COVID-19 pandemic, uncertainty persists among caregivers regarding the vaccination of pediatric liver transplant recipients (PLTRs). This study evaluates the immunogenicity and safety of COVID-19 vaccination in this vulnerable population. A cohort of 30 PLTRs underwent sequential vaccinations with an inactivated SARS-CoV-2 vaccine followed by an Ad5-nCoV booster. We collected and analyzed blood samples pre-vaccination and four weeks post-vaccination to quantify antibody and IGRA (IFN-γ Release Assay) levels. We also documented any adverse reactions occurring within seven days post-vaccination and monitored participants for infections over six months post-vaccination, culminating in a comprehensive statistical analysis. The Ad5-nCoV booster substantially elevated IgG (T1: 18.01, 20%; T2: 66.61, 55%) and nAb (T1: 119.29, 8%; T2: 3799.75, 80%) levels, as well as T-cell responses, in comparison to the initial dose. The first dose was associated with some common adverse reactions, such as injection site pain (13.3%) and fever (16.6%), but a low rate of systemic reactions (16.0%). There was no significant difference in Omicron infection rates or RTPCR conversion times between vaccinated and unvaccinated groups. Notably, following Omicron infection, vaccinated individuals exhibited significantly higher SARS-CoV-2 IgG and nAb titers (average IgG: 231.21 vs. 62.09 S/CO, p = 0.0003; nAb: 5246.11 vs. 2592.07 IU/mL, p = 0.0002). The use of inactivated vaccines followed by an Ad5-nCoV booster in PLTRs is generally safe and elicits a robust humoral response, albeit with limited T-cell responses.

Combining thermosonication microstress and pineapple peel extract addition to achieve quality and post-acidification control in yogurt fermentation.

This work investigated the effects of the combined use of thermosonication-preconditioned lactic acid bacteria (LAB) with the addition of ultrasound-assisted pineapple peel extracts (UU group) on the post-acidification potential, physicochemical and functional qualities of yogurt products, aimed at achieving prolonged preservation and enhancing functional attributes. Accordingly, the physical-chemical features, adhesion properties, and sensory profiles, acidification kinetics, the contents of major organic acids, and antioxidant activities of the differentially processed yogurts during refrigeration were characterized. Following a 14-day chilled storage process, UU group exhibited acidity levels of 0.5-2 oT lower than the control group and a higher lactose content of 0.07 mg/ml as well as unmodified adhesion potential, indicating that the proposed combination method efficiently inhibited post-acidification and delayed lactose metabolism without leading to significant impairment of the probiotic properties. The results of physicochemical analysis showed no significant changes in viscosity, hardness, and color of yogurt. Furthermore, the total phenolic content of UU-treated samples was 98 µg/mL, 1.78 times higher than that of the control, corresponding with the significantly lower IC50 values of DPPH and ABTS radical scavenging activities of the UU group than those of the control group. Observations by fluorescence inverted microscopy demonstrated the obvious adhesion phenomenon with no significant difference found among differentially prepared yogurts. The results of targeted metabolomics indicated the proposed combination strategy significantly modified the microbial metabolism, leading to the delayed utilization of lactose and the inhibited conversion into glucose during post-fermentation, as well as the decreased lactic acid production and a notable shift towards the formation of relatively weak acids such as succinic acid and citric acid. This study confirmed the feasibility of thermosonication-preconditioned LAB inocula, in combination with the use of natural active components from fruit processing byproducts, to alleviate post-acidification in yogurt and to enhance its antioxidant activities as well as simultaneously maintaining sensory features.

Influence of carboxymethyl cellulose on the stability, rheology, and curcumin bioaccessibility of high internal phase Pickering emulsions.

Recently, there has been a focus on using biopolymer-based particles to stabilize high internal phase Pickering emulsions (HIPPEs) due to the notable advances in biocompatibility and biodegradability. In this work, the complex particles of peanut protein isolate and carboxymethyl cellulose (CMC) with various substitution degrees (DS; 0.7 and 0.9) and weight average molecular weights (Mw; 90, 250, and 700 kDa) were prepared and characterized as novel stabilizers. For the obtained four types of morphologically distinct particles, the complex particles formed by CMC (0.9 DS and 250 kDa) showed cluster structures with an average size of 1.271 µm, equally biphasic wettability with three-phase contact angles of 91.5°, and the highest diffusion rate at the oil-water interface. HIPPEs stabilized by these particles exhibited more elastic behavior due to the smaller tanδ and higher viscosity, as well as excellent thixotropic recovery properties and stability against heating, storage, and freeze-thawing. Furthermore, confocal laser scanning microscopy verified that these particles formed a dense interfacial layer around the oil droplets, which could resist flocculation and coalescence between oil droplets during in vitro digestion. The improved bioaccessibility of curcumin-loaded HIPPEs made these delivery systems potentially apply in functional foods.

Macroscopic inhibition of DNA damage repair pathways by targeting AP-2α with LEI110 eradicates hepatocellular carcinoma.

DNA damage repair (DDR) genes are known to be closely associated with the progression of Hepatocellular carcinoma (HCC). Here we report a unique cluster of "deletion-up" genes in HCC, which are accordantly overexpressed in HCC patients and predict the unfavorable prognosis. Binding motif analysis and further validation with ChIP-qPCR unveil that the AP-2α directly modulate the transcription of critical DNA repair genes including TOP2A, NUDT1, POLD1, and PARP1, which facilitates the sanitation of oxidized DNA lesions. Structural analysis and the following validation identify LEI110 as a potent AP-2α inhibitor. Together, we demonstrate that LEI110 stabilizes AP-2α and sensitizes HCC cells toward DNA-damaging reagents. Altogether, we identify AP-2α as a crucial transcription modulator in HCC and propose small-molecule inhibitors targeting AP-2α are a promising novel class of anticancer agents. Our study provides insights into the concept of macroscopic inhibition of DNA damage repair-related genes in cancer treatment.

Phosphate type dependent phosphorylation on the interfacial and emulsion stabilizing behaviors of goose liver protein: Perspective of protein charging.

Elucidation on the emulsifying behaviors of goose liver protein (GLP) from interfacial perspective was scarce when protein charging was altered. This work aimed to elucidate the role of phosphorylation on the interfacial associative interaction and then emulsion stabilizing properties of GLP using three structurally relevant phosphates of sodium trimetaphosphate (STMP), sodium tripolyphosphate (STPP) and sodium pyrophosphate (TSPP). A monotonic increment of protein charging treated from STMP, STPP to TSPP caused progressively increased particle de-aggregation, surface hydrophobicity and structural flexibility of GLP. Compared with STMP and TSPP, STPP phosphorylation rendered the most strengthened interfacial equilibrium pressure (11.98 ± 0.24 mN/m) due to sufficient unfolding but moderated charging character conveyed. Desorption curve and interfacial protein microstructure indicated that STPP phosphorylation caused the highest interfacial connectivity between proteins adsorbed onto the same droplet, as was also verified by interfacial elastic modulus (10.3 ± 0.21 mN/m). STPP treated GLP also yielded lowest droplet size (8.16 ± 0.10 µm), flocculation (8.18%) and Turbiscan stability index (8.78 ± 0.36) of emulsion but most improved microrheological properties. Overall, phosphorylation functioned itself in fortifying the intradroplet protein-protein interaction but restraining the interdroplet aggregation, and STPP phosphorylation endowed the protein with most enhanced interfacial stabilization and emulsifying efficiency.

Global burden and trends of acute viral hepatitis among children and adolescents from 1990 to 2019: a systematic analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Children and adolescents are at high risk for acute viral hepatitis (AVH), but epidemiological research focusing on them has been overshadowed by adult chronic B and C. We provide global, regional, and national estimates of the AVH burden and their trends on people under 20 years from 1990 to 2019. METHODS: AVH data from Global Burden of Disease Study (GBD) 2019 was used. Incidence and disability-adjusted life years (DALYs) were calculated, analyzing trends with estimated annual percentage change (EAPC) and Joinpoint regression. RESULTS: In 2019, 156.39 (95% uncertainty interval 145.20-167.16) million new cases of AVH were reported among children and adolescents globally, resulting in 1.98 (1.50-2.55) million DALYs. Incidence rates for young children (< 5 years), older children (5-9 years), and adolescents (10-19 years) were 12,799 (11,068-14,513), 5,108 (4829-5411), and 3020 (2724-3339) per 100,000 population, respectively. The global AVH incidence displayed a linear decline with an EAPC of - 0.66 (- 0.68 to - 0.65). High-incidence regions included sub-Saharan Africa, Oceania, South Asia, and Central Asia, with India, Pakistan, and Nigeria facing the greatest burden. Leading causes were hepatitis A, followed by hepatitis E, B, and C. All hepatitis types showed declining trends, especially hepatitis B. Furthermore, we confirmed the association between the AVH incidence and the socioeconomics, vaccine, and advanced liver diseases. CONCLUSION: Effective vaccines and treatments for hepatitis B and C offer eradication opportunities. Broadening diagnostic and therapeutic coverage is vital to address disparities in service provision for children and adolescents.

Food off-odor generation, characterization and recent advances in novel mitigation strategies.

The pronounced perception of off-odors poses a prevalent issue across various categories of food ingredients and processed products, significantly exerting negative effects on the overall quality, processability, and consumer acceptability of both food items and raw materials. Conventional methods such as brining, marinating, and baking, are the main approaches to remove the fishy odor. Although these methods have shown notable efficacy, there are simultaneously inherent drawbacks that ultimately diminish the processability of raw materials, encompassing alterations in the original flavor profiles, the potential generation of harmful substances, restricted application scopes, and the promotion of excessive protein/lipid oxidation. In response to these challenges, recent endeavors have sought to explore innovative deodorization techniques, including emerging physical processing approaches, the development of high-efficiency adsorbent material, biological fermentation methods, and ozone water rinsing. However, the specific mechanisms underpinning the efficacy of these deodorization techniques remain not fully elucidated. This chapter covers the composition of major odor-causing substances in food, the methodologies for their detection, the mechanisms governing their formation, and the ongoing development of deodorization techniques associated with the comparison of their advantages, disadvantages, and application mechanisms. The objective of this chapter is to furnish a theoretical framework for enhancing deodorization efficiency through fostering the development of suitable deodorization technologies in the future.

High intra-patient variability of tacrolimus within post-operative 1 month predicted worse 1-year outcomes in pediatric liver transplant recipients.

BACKGROUND: The pharmacokinetics of tacrolimus (TAC) show high intra-patient variability (IPV), which is associated with poor long-term outcomes following adult liver transplantation (LT). However, this relationship remains to be confirmed in pediatric liver transplant (PLT) recipients. The present study aimed to investigate the association between TAC IPV and grafts or patient outcomes after pediatric liver transplantion. METHODS: This retrospective study included 848 PLT recipients (including infants) between January, 2016, and June, 2021. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of trough concentrations in whole blood within 1 month after transplantation. Patients were categorized into two groups, low IPV (CV < 45%) and high IPV (CV ≥ 45%), based on the third quartile of the CV distribution. RESULTS: A total of 848 patients were included in our study. The low CV group included 614 patients, with a mean TAC trough concentration of 8.59 ± 1.65 ng/ml and a median CV of 32.37%. In contrast, the high CV group included 214 patients, the mean TAC trough concentration and median CV were 8.81 ± 2.00 ng/ml and 54.88%, respectively. The median hospital duration was significantly higher in the high CV group (22 days vs. 20 days, P = 0.01). Univariate analysis was performed to evaluate the significant differences in 1-year recipient survival (P = 0.041) and 1-year graft survival (P = 0.005) between the high- and low-CV groups. Moreover, high CV (HR 2.316, 95%CI 1.026-5.231, P = 0.043) and persistent EBV viremia (HR 13.165, 95%CI 3.090-56.081, P < 0.001) were identified as independent risk factors for 1- year mortality after PLT. CONCLUSIONS: PLT recipients with high TAC trough concentration of CV in the first month were associated with poor 1-year outcomes. This CV calculation provides a valuable strategy to monitor TAC exposure.