Targeted delivery of NO donor and ROS scavenger for synergistic treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by high level of reactive oxygen species (ROS) and proinflammatory cytokines, which facilitate the activation of the inflammatory signaling such as NF-κB pathway and exacerbate the development of inflammation. Herein, we designed a nanodrug by encapsulating the NO donor S-nitrosoglutathione (GSNO) into an emulsion and coating the surface with a polydopamine (PDA) layer to yield GSNO@PDA, which simultaneously scavenged the extra ROS and suppressed NF-κB signaling for potent RA treatment. To enhance the cellular uptake and NO generation efficiency, dextran sulfate (DS) and Cu2+ were anchored on the surface of GSNO@PDA to obtain the final formulation GSNO@PDA@DS. Our results demonstrated that GSNO@PDA@DS were successfully prepared and the modification of DS effectively boosted the cellular uptake of GSNO@PDA@DS. Moreover, GSNO@PDA@DS lowered cellular ROS and elevated intracellular NO, resulting in a decrease of M1 phenotype, inhibition of NF-κB pathway and down-regulation of proinflammatory cytokine tumor necrosis factor-α (TNF-α). Further in vivo studies confirmed that GSNO@PDA@DS significantly relieved symptoms and bone erosion by regulating the microenvironment of RA, highlighting the potential of GSNO@PDA@DS for RA therapy through ROS scavenging and NO-mediated suppression of inflammatory signaling.

The Laccase Family Gene CsLAC37 Participates in Resistance to Colletotrichum gloeosporioides Infection in Tea Plants.

Fungal attacks have become a major obstacle in tea plantations. Colletotrichum gloeosporioides is one of the most devastating fungal pathogens in tea plantations that can severely affect tea yield and quality. However, the molecular mechanism of resistance genes involved in anthracnose is still largely unknown in tea plants. Here, we found that the laccase gene CsLAC37 was involved in the response to fungal infection based on a transcriptome analysis. The full-length CDS of CsLAC37 was cloned, and its protein sequence had the closest relationship with the Arabidopsis AtLAC15 protein compared to other AtLACs. Tissue-specific expression analysis showed that CsLAC37 had higher expression levels in mature leaves and stems than in the other tissues. Subcellular localization showed that the CsLAC37 protein was predominantly localized in the cell membrane. The expression levels of CsLAC37 were upregulated at different time points under cold, salt, SA, and ABA treatments. qRT-PCR confirmed that CsLAC37 responded to both Pestalotiopsis-like species and C. gloeosporioides infections. Functional validation showed that the hydrogen peroxide (H2O2) content increased significantly, and POD activity decreased in leaves after antisense oligonucleotide (AsODN) treatment compared to the controls. The results demonstrated that CsLAC37 may play an important role in resistance to anthracnose, and the findings provide a theoretical foundation for molecular breeding of tea varieties with resistance to fungal diseases.

[Risk factors for the failure of ibuprofen treatment in preterm infants with hemodynamically significant patent ductus arteriosus]. / æœ‰è¡€æµåŠ¨åŠ›å­¦æ„ä¹‰çš„åŠ¨è„‰å¯¼ç®¡æœªé—­æ—©äº§å„¿å¸ƒæ´›èŠ¬æ²»ç–—å¤±è´¥çš„å±é™©å› ç´ åˆ†æž.

OBJECTIVES: To investigate the risk factors for the failure of ibuprofen treatment in preterm infants with hemodynamically significant patent ductus arteriosus (hsPDA). METHODS: A retrospective collection of clinical data was conducted on preterm infants with a gestational age of <34 weeks who were diagnosed with hsPDA and treated at the Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, from January 2018 to June 2023. The subjects were divided into two groups based on the treatment approach: the ibuprofen group (95 cases) and the ibuprofen plus surgery group (44 cases). The risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA were identified by binary logistic regression analysis. RESULTS: The binary logistic regression analysis revealed that an increased diameter of the ductus arteriosus, a resistance index (RI) value of the middle cerebral artery ≥0.80, and prolonged total invasive mechanical ventilation time were risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). Receiver operating characteristic curve analysis showed that a ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days had significant predictive value for the failure of ibuprofen treatment in preterm infants with hsPDA (P<0.05). The combined predictive value of these three factors was the highest, with an area under the curve of 0.843, a sensitivity of 86.5%, and a specificity of 75.0% (P<0.05). CONCLUSIONS: A ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days are risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA, and they are of significant predictive value for the necessity of surgical treatment following the failure of ibuprofen treatment.

Expression of long non-coding RNA GAS5 by first trimester screening predicts the occurrence of gestational hypertension and pre-eclampsia.

AIMS: Hypertensive disorders of pregnancy (HDP) is a unique disease during gestational period, which is detrimental to pregnancy outcome. This study examined the clinical significance of long non-coding RNA GAS5 in gestational hypertension (GH) and preeclampsia (PE), aiming to explore potential biomarkers for the disease detection. METHODS: 180 pregnant women with HPD including 90 cases with GH and 90 cases with PE, and another 100 healthy pregnant women were enrolled. Serum GAS5 levels were measured by RT-qPCR method. The diagnostic performance of GAS5 was assessed in GH and PE through plotting receiver operating characteristic (ROC) curve. Logistic regression was applied for the identification of independent factors. RESULTS: Elevated serum GAS5 was identified in GH patients, and its diagnostic performance in discriminating GH cases from healthy people was determined by ROC curve. Serum GAS5 was positively associated with SBP, DBP, LDL-C and CRP values. Cases with PE had an increased serum GAS5 level relative to those with GH. Serum GAS5 was identified to be an independent predictor for PE, and can differentiate PE cases from GH ones. with a good diagnositc performance. Cases with high levels of serum GAS5 had a high risk of poor pregnancy outcomes. CONCLUSION: Elevated serum GAS5 could serve as an effective diagnostic biomarker in discriminating GH patients from healthy people by first trimester screening. Detection of serum GAS5 level has a certain predictive value for PE.

Critical factors driving spatiotemporal variability in the phytoplankton community structure of the coral habitat in Dongshan Bay, China.

This study investigated the spatiotemporal distribution of the phytoplankton in the coral habitat of Dongshan Bay (China), along with critical factors affecting the distribution, during June, August, and December 2022. Phytoplankton abundance in Dongshan Bay exhibited considerably temporal variation, peaking in June 2022, gradually decreasing thereafter, and reaching its lowest point in December 2022. The abundance of bottom-layer phytoplankton consistently exceeded that of the surface layer throughout all seasons. The average phytoplankton abundance in the coral habitat of Dongshan Bay was lower than that in non-coral habitat areas. Fluctuations in the Zhangjiang River and coastal upwelling influenced the diversity and community structure of the phytoplankton. Critical factors causing spatiotemporal variability in phytoplankton community structure included nutrient concentrations and seawater temperature. Nutrients played key roles in influencing various phytoplankton groups. Dominant diatom species, such as Thalassionema nitzschioides and Thalassiosira diporocyclus, were positively correlated with ammonia nitrogen, seawater salinity, coral cover, and the number of coral species present. In winter, Calanus sinicus exhibited a negative correlation with harmful algal bloom species. Additionally, it was found that both in the coral habitat and surrounding open sea, currents, nutrients, and zooplankton may play crucial roles in determining the spatiotemporal variability in the phytoplankton community structure.

Characterization of mung bean endogenous proteases and globulins and their effects on the production of mung bean protein.

Mung bean protein possesses several health benefits, and aqueous processing methods are used for its production. However, mung bean protein yields are different with different methods, which are actually different in conditions (e.g., pH, temperature, and time). Herein, liquid chromatography tandem mass spectrometry identified 28 endopeptidases and exopeptidases in mung bean protein extract, and the positions of 8S and 11S globulins on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel were confirmed in our experimental conditions. The SDS-PAGE, trichloroacetic acid-nitrogen solubility index, and free amino acid analysis revealed that (1) 8S globulins showed strong resistance to the endopeptidases (optimal at pH 5 and 50 °C) at pH 3-9, and 11S globulin exhibit strong resistance expect at pH 3-3.5; (2) the exopeptidases (optimal at pH 6 and 50 °C) preferred to liberate methionine and tryptophan. These proteases negatively affected protein yield, and short production time and low temperature were recommended.

Targeting IL-6/STAT3 signaling abrogates EGFR-TKI resistance through inhibiting Beclin-1 dependent autophagy in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is featured by notorious EGFR tyrosine kinase inhibitor (TKI) resistance attributable to activation of parallel pathways. The numerous phase I/II trials have rarely shown encouraging clinical outcomes of EGFR-TKIs during treatment in HNSCC patients with advanced tumors. A unique IL-6/STAT3 signaling axis is reported to regulate multiple cancer-related pathways, but whether this signaling is correlated with reduced EGFR-TKI responsiveness is unclear. Here, we found that STAT3 signaling is compensatorily upregulated after EGFR-TKI exposure and confers anti-EGFR therapy resistance during HNSCC therapy. Targeting STAT3 using small molecule inhibitors promotes complete recovery or sustained elimination of HNSCC tumors through combination with EGFR-TKIs both in vitro and in diverse animal models. Mechanistically, phosphorylated STAT3 was proven to enhance oncogenic autophagic flux, protecting cancer cells and preventing EGFR-TKI-induced tumor apoptosis. Thus, blockade of STAT3 signaling simultaneously disrupts several key interactions during tumor progression and remodels the autophagic degradation system, thereby rendering advanced HNSCC eradicable through combination with EGFR-TKI therapy. These findings provide a clinically actionable strategy and suggest STAT3 as a predictive biomarker with therapeutic potential for EGFR-TKI resistant HNSCC patients.

Nanoengineered Red Blood Cells Loaded with TMPRSS2 and Cathepsin L Inhibitors Block SARS-CoV-2 Pseudovirus Entry into Lung ACE2+ Cells.

The enzymatic activities of Furin, Transmembrane serine proteinase 2 (TMPRSS2), Cathepsin L (CTSL), and Angiotensin-converting enzyme 2 (ACE2) receptor binding are necessary for the entry of coronaviruses into host cells. Precise inhibition of these key proteases in ACE2+ lung cells during a viral infection cycle shall prevent viral Spike (S) protein activation and its fusion with a host cell membrane, consequently averting virus entry to the cells. In this study, dual-drug-combined (TMPRSS2 inhibitor Camostat and CTSL inhibitor E-64d) nanocarriers (NCs) are constructed conjugated with an anti-human ACE2 (hACE2) antibody and employ Red Blood Cell (RBC)-hitchhiking, termed "Nanoengineered RBCs," for targeting lung cells. The significant therapeutic efficacy of the dual-drug-loaded nanoengineered RBCs in pseudovirus-infected K18-hACE2 transgenic mice is reported. Notably, the modular nanoengineered RBCs (anti-receptor antibody+NCs+RBCs) precisely target key proteases of host cells in the lungs to block the entry of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), regardless of virus variations. These findings are anticipated to benefit the development of a series of novel and safe host-cell-protecting antiviral therapies.

Rebalancing TGF-ß/PGE2 breaks RT-induced immunosuppressive barriers by enhancing tumor-infiltrated dendritic cell homing.

A better understanding of how tumor microenvironments shape immune responses after radiotherapy (RT) is required to improve patient outcomes. This study focuses on the observation that dendritic cells (DCs) infiltrating irradiated cervical tumors are retained in transforming growth factor (TGF)-ß-abundant regions. We report that TGF-ß secretion from cervical cancer cells was increased by irradiation in a dose-dependent manner and that this significantly suppressed the expression of allostimulatory markers and Th1 cytokines in DCs. To investigate further, we blocked the TGF-ß signal in DCs and observed that RT had a dose-dependent immune-promoting effect, improving DC maturation. This suggested that proinflammatory mediators may also be induced by RT, but their effects were being counteracted by the simultaneously increased levels of TGF-ß. Prostaglandin E2 (PGE2), a proinflammatory molecule, was shown to be one such mediator. Adjusting the TGF-ß/PGE2 ratio by inhibiting TGF-ß rebooted RT-induced DC cytoskeletal organization by stimulating myosin light chain (MLC) phosphorylation. Consequently, the homing of intra-tumorally infiltrated DCs to tumor-draining lymph nodes was enhanced, leading to the induction of more robust cytotoxic T cells. Ultimately, rebalancing the TGF-ß/PGE2 ratio amplified the therapeutic effects of RT, resulting in increased intra-tumoral infiltration and activation of CD8+ T cells, and improved tumor control and overall survival rate in mice. DC depletion experiments verified that the improvement in tumor control is directly correlated with the involvement of DCs via the PGE2-MLC pathway. This study emphasizes the importance of maintaining a balanced cytokine environment during RT, particularly hypofractionated RT; and it is advisable to block TGF-ß while preserving PGE2 in the tumor microenvironment in order to better stimulate DC homing and DC -T priming.

Clinical characteristics and risk factors for late-onset pneumocystis jirovecii pneumonia in kidney transplantation recipients.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a common and troublesome complication of kidney transplantation. In the era of prophylaxis, the peak incidence of PJP after kidney transplantation and specific characteristics of late-onset PJP have always been debated. METHODS: We performed a retrospective study by analysing the data of post-transplantation pneumonia in adult kidney transplantation recipients between March 2014 and December 2021 in The Affiliated First Hospital of University of Science and Technology of China (USTC). A total of 361 patients were included and divided into early-onset PJP, late-onset PJP and non-PJP groups. The characteristics of each group and related risk factors for the late-onset patients were investigated. RESULTS: Some patients developed PJP 9 months later with a second higher occurrence between month 10 and 15 after transplantation. Compared with non-PJP, ABO-incompatible and cytomegalovirus (CMV) viremia were significantly associated with late onset of PJP in multivariate analysis. The use of tacrolimus, CMV viremia, elevated CD8(+) T cell percent and hypoalbuminemia were risk factors for late PJP. Receiver operating characteristic curve analysis demonstrated that a combination of those factors could increase the sensitivity of prediction remarkably, with an area under the curve of 0.82, a sensitivity of 80% and a specificity of 83%. CONCLUSIONS: PJP could occur months after kidney transplantation. ABO-incompatible transplant recipients are at high risk of PJP. In the later stages of transplantation, CMV viremia, T lymphocyte subsets percentage and serum albumin levels should be monitored in patients using tacrolimus.

Deep learning, geometric characterization and hydrodynamic modeling for assessing sewer defect impacts on urban flooding: A case study in Guangzhou, China.

Deep learning techniques have offered innovative and efficient tools for accurate and automated detection of sewer defects by leveraging large-scale sewer data and advanced feature learning algorithms. However, there has been a lack of thorough characterization of the geometric properties of segmented defects, let alone systematically calculate the severity level of sewer defects and quantitatively evaluate their impacts on flood conditions in hydrodynamic models. This study proposed a comprehensive framework and related metrics to accurately and automatically detect, segment, characterize, and evaluate the impacts of sewer defects on flooded nodes and volumes by integrating a DeepLabv3+-based segmentation technique, an automated geometric characterization and severity quantification module, and a GIS and SWMM-based hydrodynamic modeling. The results clearly showed in details where and how much the urban flooding was affected by the different defect types. The segmentation model achieved satisfactory detection performance, with mean pixel accuracy (MPA), mean intersection over union (MIoU), and frequency weighted intersection over union (FWIoU) of 0.99, 0.74 and 0.95, respectively. In terms of severity level quantification, there were 98%, 90%, 90% and 83% of predictions consistent with real conditions for falling off, obstacle, disjoint and leakage. It was shown that the number of surcharging manholes and total flood volume (TFV) were greatly affected by sewer defects, with over 16% increase in TFVs under all investigated rainfall events. The results addressed the impacts of sewer defects on urban flooding and demonstrated the powerful tools provided by the proposed framework for decision-making on sewer defect detection and management.

Dual thermal ecotypes coexist within a nearly genetically identical population of the unicellular marine cyanobacterium Synechococcus.

The extent and ecological significance of intraspecific functional diversity within marine microbial populations is still poorly understood, and it remains unclear if such strain-level microdiversity will affect fitness and persistence in a rapidly changing ocean environment. In this study, we cultured 11 sympatric strains of the ubiquitous marine picocyanobacterium Synechococcus isolated from a Narragansett Bay (RI) phytoplankton community thermal selection experiment. Thermal performance curves revealed selection at cool and warm temperatures had subdivided the initial population into thermotypes with pronounced differences in maximum growth temperatures. Curiously, the genomes of all 11 isolates were almost identical (average nucleotide identities of >99.99%, with >99% of the genome aligning) and no differences in gene content or single nucleotide variants were associated with either cool or warm temperature phenotypes. Despite a very high level of genomic similarity, sequenced epigenomes for two strains showed differences in methylation on genes associated with photosynthesis. These corresponded to measured differences in photophysiology, suggesting a potential pathway for future mechanistic research into thermal microdiversity. Our study demonstrates that present-day marine microbial populations can harbor cryptic but environmentally relevant thermotypes which may increase their resilience to future rising temperatures.

Three-dimensional solitons in Rydberg-dressed cold atomic gases with spin-orbit coupling.

We present numerical results for three-dimensional (3D) solitons with symmetries of the semi-vortex (SV) and mixed-mode (MM) types, which can be created in spinor Bose-Einstein condensates of Rydberg atoms under the action of the spin-orbit coupling (SOC). By means of systematic numerical computations, we demonstrate that the interplay of SOC and long-range spherically symmetric Rydberg interactions stabilize the 3D solitons, improving their resistance to collapse. We find how the stability range depends on the strengths of the SOC and Rydberg interactions and the soft-core atomic radius.

Host genetics and gut microbiota jointly regulate blood biochemical indicators in chickens.

Blood biochemical indicators play a crucial role in assessing an individual's overall health status and metabolic function. In this study, we measured five blood biochemical indicators, including total cholesterol (CHOL), low-density lipoprotein cholesterol (LDL-CH), triglycerides (TG), high-density lipoprotein cholesterol (HDL-CH), and blood glucose (BG), as well as 19 growth traits of 206 male chickens. By integrating host whole-genome information and 16S rRNA sequencing of the duodenum, jejunum, ileum, cecum, and feces microbiota, we assessed the contributions of host genetics and gut microbiota to blood biochemical indicators and their interrelationships. Our results demonstrated significant negative phenotypic and genetic correlations (r = - 0.20 ~ - 0.67) between CHOL and LDL-CH with growth traits such as body weight, abdominal fat content, muscle content, and shin circumference. The results of heritability and microbiability indicated that blood biochemical indicators were jointly regulated by host genetics and gut microbiota. Notably, the heritability of HDL-CH was estimated to be 0.24, while the jejunal microbiability for BG and TG reached 0.45 and 0.23. Furthermore, by conducting genome-wide association study (GWAS) with the single-nucleotide polymorphism (SNPs), insertion/deletion (indels), and structural variation (SV), we identified RAP2C, member of the RAS oncogene family (RAP2C), dedicator of cytokinesis 11 (DOCK11), neurotensin (NTS) and BOP1 ribosomal biogenesis factor (BOP1) as regulators of HDL-CH, and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5), dihydrodiol dehydrogenase (DHDH), and potassium voltage-gated channel interacting protein 1 (KCNIP1) as candidate genes of BG. Moreover, our findings suggest that cecal RF39 and Clostridia_UCG_014 may be linked to the regulation of CHOL, and jejunal Streptococcaceae may be involved in the regulation of TG. Additionally, microbial GWAS results indicated that the presence of gut microbiota was under host genetic regulation. Our findings provide valuable insights into the complex interaction between host genetics and microbiota in shaping the blood biochemical profile of chickens. KEY POINTS: • Multiple candidate genes were identified for the regulation of CHOL, HDL-CH, and BG. • RF39, Clostridia_UCG_014, and Streptococcaceae were implicated in CHOL and TG modulation. • The composition of gut microbiota is influenced by host genetics.

Elucidation of the melitidin biosynthesis pathway in pummelo.

Specialized plant metabolism is a rich resource of compounds for drug discovery. The acylated flavonoid glycoside melitidin is being developed as an anti-cholesterol statin drug candidate, but its biosynthetic route in plants has not yet been fully characterized. Here, we describe the gene discovery and functional characterization of a new flavonoid gene cluster (UDP-glucuronosyltransferases (CgUGTs), 1,2 rhamnosyltransferase (Cg1,2RhaT), acyltransferases (CgATs)) that is responsible for melitidin biosynthesis in pummelo (Citrus grandis (L.) Osbeck). Population variation analysis indicated that the tailoring of acyltransferases, specific for bitter substrates, mainly determine the natural abundance of melitidin. Moreover, 3-hydroxy-3-methylglutaryl-CoA reductase enzyme inhibition assays showed that the product from this metabolic gene cluster, melitidin, may be an effective anti-cholesterol statin drug candidate. Co-expression of these clustered genes in Nicotiana benthamiana resulted in the formation of melitidin, demonstrating the potential for metabolic engineering of melitidin in a heterologous plant system. This study establishes a biosynthetic pathway for melitidin, which provides genetic resources for the breeding and genetic improvement of pummelo aimed at fortifying the content of biologically active metabolites.

Design and synthesis of 1H-pyrazolo[3,4-d]pyrimidine derivatives as hematopoietic progenitor kinase 1 (HPK1) inhibitors.

Despite immune checkpoint inhibitors' tremendous success in the treatment of tumors, the moderate response rate limits their widespread use. Hematopoietic progenitor kinase 1 (HPK1) is served as an essential negative regulator of T-cell receptor, which has been identified as a promising target for enhancing antitumor immunity. However, the development of a selective HPK1 inhibitor is still challenging. Herein, we reported a novel series of 1H-pyrazolo[3,4-d]pyrimidine derivatives as HPK1 inhibitors by structure-based rational design. The optimal compound 10n significantly inhibited HPK1 with an IC50 value of 29.0 nM and the phosphorylation of SLP76 at a concentration as low as 0.1 µM. Furthermore, compound 10n exhibited good selectivity over a panel of 25 kinases, including GLK from the same MAP4K family. Together, the current study provided a novel, potent, and selective HPK1 inhibitor, acting as a lead compound for the future development of cancer immunotherapy.

Construction of Multifunctional Hierarchical Biofilms for Highly Sensitive and Weather-Resistant Fire Warning.

Multifunctional biofilms with early fire-warning capabilities are highly necessary for various indoor and outdoor applications, but a rational design of intelligent fire alarm films with strong weather resistance remains a major challenge. Herein, a multiscale hierarchical biofilm based on lignocellulose nanofibrils (LCNFs), carbon nanotubes (CNTs) and TiO2 was developed through a vacuum-assisted alternate self-assembly and dipping method. Then, an early fire-warning system that changes from an insulating state to a conductive one was designed, relying on the rapid carbonization of LCNFs together with the unique electronic excitation characteristics of TiO2. Typically, the L-CNT-TiO2 film exhibited an ultrasensitive fire-response signal of ~0.30 s and a long-term warning time of ~1238 s when a fire disaster was about to occur, demonstrating a reliable fire-alarm performance and promising flame-resistance ability. More importantly, the L-CNT-TiO2 biofilm also possessed a water contact angle (WCA) of 166 ± 1° and an ultraviolet protection factor (UPF) as high as 2000, resulting in excellent superhydrophobicity, antifouling, self-cleaning as well as incredible anti-ultraviolet (UV) capabilities. This work offers an innovative strategy for developing advanced intelligent films for fire safety and prevention applications, which holds great promise for the field of building materials.

Laponite Lights Calcium Flickers by Reprogramming Lysosomes to Steer DC Migration for An Effective Antiviral CD8+ T-Cell Response.

Immunotherapy using dendritic cell (DC)-based vaccination is an established approach for treating cancer and infectious diseases; however, its efficacy is limited. Therefore, targeting the restricted migratory capacity of the DCs may enhance their therapeutic efficacy. In this study, the effect of laponite (Lap) on DCs, which can be internalized into lysosomes and induce cytoskeletal reorganization via the lysosomal reprogramming-calcium flicker axis, is evaluated, and it is found that Lap dramatically improves the in vivo homing ability of these DCs to lymphoid tissues. In addition, Lap improves antigen cross-presentation by DCs and increases DC-T-cell synapse formation, resulting in enhanced antigen-specific CD8+ T-cell activation. Furthermore, a Lap-modified cocktail (Lap@cytokine cocktail [C-C]) is constructed based on the gold standard, C-C, as an adjuvant for DC vaccines. Lap@C-C-adjuvanted DCs initiated a robust cytotoxic T-cell immune response against hepatitis B infection, resulting in > 99.6% clearance of viral DNA and successful hepatitis B surface antigen seroconversion. These findings highlight the potential value of Lap as a DC vaccine adjuvant that can regulate DC homing, and provide a basis for the development of effective DC vaccines.

Hepatic steatosis is associated with dysregulated cholesterol metabolism and altered protein acetylation dynamics in chickens.

BACKGROUND: Hepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed to systematically investigate the genetic regulatory mechanisms of hepatic steatosis in laying hens. METHODS: Ninety individuals with the most prominent characteristics were selected from 686 laying hens according to the accumulation of lipid droplets in the liver, and were graded into three groups, including the control, mild hepatic steatosis and severe hepatic steatosis groups. A combination of transcriptome, proteome, acetylome and lipidome analyses, along with bioinformatics analysis were used to screen the key biological processes, modifications and lipids associated with hepatic steatosis. RESULTS: The rationality of the hepatic steatosis grouping was verified through liver biochemical assays and RNA-seq. Hepatic steatosis was characterized by increased lipid deposition and multiple metabolic abnormalities. Integration of proteome and acetylome revealed that differentially expressed proteins (DEPs) interacted with differentially acetylated proteins (DAPs) and were involved in maintaining the metabolic balance in the liver. Acetylation alterations mainly occurred in the progression from mild to severe hepatic steatosis, i.e., the enzymes in the fatty acid oxidation and bile acid synthesis pathways were significantly less acetylated in severe hepatic steatosis group than that in mild group (P < 0.05). Lipidomics detected a variety of sphingolipids (SPs) and glycerophospholipids (GPs) were negatively correlated with hepatic steatosis (r ≤ -0.5, P < 0.05). Furthermore, the severity of hepatic steatosis was associated with a decrease in cholesterol and bile acid synthesis and an increase in exogenous cholesterol transport. CONCLUSIONS: In addition to acquiring a global and thorough picture of hepatic steatosis in laying hens, we were able to reveal the role of acetylation in hepatic steatosis and depict the changes in hepatic cholesterol metabolism. The findings provides a wealth of information to facilitate a deeper understanding of the pathophysiology of fatty liver and contributes to the development of therapeutic strategies.