NiMOF-Derived MoSe2/NiSe Hollow Nanoflower Structures as Electrocatalysts for Hydrogen Evolution Reaction in Alkaline Medium.

Metal-organic frameworks (MOFs) are crystalline porous materials for storage and energy conversion applications with three-dimensional pore structure, high porosity, and specific surface area, which are widely utilized in electrocatalysis. Herein, MoSe2/NiSe composites were synthesized by selenization reaction using NiMOF as the precursor. The composites were hollow nanoflower structures with a synergistic effect between MoSe2 and NiSe to promote rapid electron transfer, which exhibited good hydrogen evolution reaction performance in an alkaline medium. At a current density of 10 mA/cm2, the HER overpotential reaches 80 mV, the Tafel slope is 33.86 mV/dec, and the material has good stability, with polarization curves remaining essentially unchanged after 3000 cycles. These results indicate that the method has a promising application in the preparation of efficient and sustainable catalysts for hydrogen production in alkaline medium.

Assessing the Relative Sustainability of Point-of-Use Water Disinfection Technologies for Off-Grid Communities.

Point-of-use (POU) water disinfection technologies can be adopted to provide access to safe drinking water by treating water at the household level; however, navigating various POU disinfection technologies can be difficult. While numerous conventional POU devices exist, emerging technologies using novel materials or advanced processes have been under development and claim to be of lower cost with higher treatment capacity. However, it is unclear if these claims are substantiated and how novel technologies compare to conventional ones in terms of cost and environmental impacts when providing the same service (i.e., achieving a necessary level of disinfection for safe drinking water). This research assessed the sustainability of four different POU technologies (chlorination using sodium hypochlorite, a silver-nanoparticle-enabled ceramic water filter, ultraviolet mercury lamps, and ultraviolet light-emitting diodes). Leveraging open-source Python packages (QSDsan and EXPOsan), the cost and environmental impacts of these POU technologies were assessed using techno-economic analysis and life cycle assessment as per capita cost (USD·cap-1·yr-1) and global warming potential (kg CO2 eq·cap-1·yr-1). Impacts of water quality parameters (e.g., turbidity, hardness) were quantified for both surface water and groundwater, and uncertainty and sensitivity analyses were used to identify which assumptions influence outcomes. All technologies were further evaluated across ranges of adoption times, and contextual analysis was performed to evaluate the implications of technology deployment across the world. Results of this study can potentially provide valuable insights for decision-makers, nonprofit organizations, and future researchers in developing sustainable approaches for ensuring access to safe drinking water through POU technologies.

Effects of γ-Aminobutyric Acid on Growth Performance, Immunity, Antioxidant Capacity, and Intestinal Microbiota of Growing Minks.

The present experiment was conducted to investigate the effects of γ-aminobutyric acid (GABA) on the growth performance, immunity, antioxidant capacity, and intestinal microbiota of growing minks. One hundred minks were evenly allocated across five groups, with each group consisting of 10 males and 10 females. The minks in these groups were fed a basal diet supplemented with γ-aminobutyric acid (GABA) at 0 (control), 10, 20, 30, and 40 mg/kg of diet, respectively. The experiment lasted for eight weeks. The results showed that GABA significantly affected immunity, antioxidant capacity, and intestinal microbiota (p < 0.05). Compared to the control minks, minks in 20, 30, and 40 mg/kg GABA group had greater total protein quantitative (TP), immunoglobulin A (IgA), immunoglobulin M (IgM) content, total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px) activities in serum as well as interleukin-4 (IL-4) level in jejunal mucosa (p < 0.05), and had less serum blood urea nitrogen (BUN) content (p < 0.05). Furthermore, compared with the control, the supplementation of GABA at 30 mg/kg of diet improved average daily feed intake (ADFI) (p < 0.05), increased immunoglobulin G (IgG) content in serum, interleukin-10 (IL-10) and secreted immunoglobulin A (SIgA) levels in jejunal mucosa, and decreased jejunal mucosal interleukin-2 (IL-2), interleukin-12 (IL-12), and interferon-γ (IFN-γ) levels (p < 0.05). The weight and feed intake of males were higher than females, and the feed/gain ratio (F/G) was lower than females (p < 0.05). Males also had greater serum superoxide dismutase (SOD) and GSH-Px activities, and jejunal mucosa IL-2, IL-4, IL-12, SIgA, and IFN-γ levels (p < 0.05), and males had less serum IgA, IgM, and T-AOC contents, and jejunal mucosal tumor necrosis factor-α (TNF-α) level (p < 0.05). The results suggest that the supplementation of GABA at 30 mg/kg of diet can improve immune status and antioxidant capacity, and modulate the intestinal microbiota abundance of growing minks.

Epidemiology and genetic characterization of human parainfluenza virus-1 infection in pediatric patients from Hangzhou China, 2021-2022.

BACKGROUND: Human parainfluenza virus-1 (HPIV-1) is a notable pathogen instigating acute respiratory tract infections in children. The article is to elucidate the epidemiological and genetic characteristics of HPIV-1 circulating in Hangzhou during the period of 2021-2022. METHODS: A cohort of 2360 nasopharyngeal swabs were amassed and subsequently examined via RT-PCR, with HPIV-1 positive samples undergoing P gene sequencing. RESULTS: The highest HPIV-1 infection rates were found in children aged between 3 and 6 years. A pronounced positive rate persisted through the latter half of 2021, with a notable decline observed in the initial half of 2022. All HPIV-1 strains could be clustered into 2 groups: Cluster 1, with strains similar to those found in Japan (LC764865, LC764864), and Cluster 2, with strains similar to the Beijing strain (MW575643). CONCLUSION: In conclusion, our study contributes to the comprehensive data on the epidemiological and genetic characteristics of HPIV-1 in pediatric patients from Hangzhou, post the COVID-19 peak.

The research on the impact of industry governance on trust after group product-harm crisis.

The group product-harm crisis has much greater and longer negative impact, and its governance has become an important issue. To address this issue, this study proposed a new construct: industry governance. On the basis of clarifying the dimensions and measurements of industry governance, this study constructed a reflective-formative hierarchical model and collected data through a questionnaire. Utilizing convenience sampling, 329 valid samples at the University in Wuhan, China collected by survey were used to verify the hypotheses. With the help of Smart PLS 3.0, this study finds that the industry governance has a significant and positive impact on consumer's trust (enterprise trust, industry trust and government trust) after the group product-harm crisis. Industry governance plays an important role in the governance of group product-harm crisis. This study is the first time to explore the structure and measurement of industry governance, and verifies the impact of industry governance on group product-harm crisis, which enriches governance theory, and perfects product-harm crisis theory, providing a new direction and guidance for managers to better manage product-harm crisis.

Characterization of a novel phage against multidrug-resistant Klebsiella pneumoniae.

Multidrug-resistant Klebsiella pneumoniae (MDR-KP) poses a significant challenge in global healthcare, underscoring the urgency for innovative therapeutic approaches. Phage therapy emerges as a promising strategy amidst rising antibiotic resistance, emphasizing the crucial need to identify and characterize effective phage resources for clinical use. In this study, we introduce a novel lytic phage, RCIP0100, distinguished by its classification into the Chaoyangvirus genus and Fjlabviridae family based on International Committee on Taxonomy of Viruses (ICTV) criteria due to low genetic similarity to known phage families. Our findings demonstrate that RCIP0100 exhibits broad lytic activity against 15 out of 27 tested MDR-KP strains, including diverse profiles such as carbapenem-resistant K. pneumoniae (CR-KP). This positions phage RCIP0100 as a promising candidate for phage therapy. Strains resistant to RCIP0100 also showed increased susceptibility to various antibiotics, implying the potential for synergistic use of RCIP0100 and antibiotics as a strategic countermeasure against MDR-KP.

Lactiplantibacillus plantarum P9 for chronic diarrhea in young adults: a large double-blind, randomized, placebo-controlled trial.

Current treatments for chronic diarrhea have limited efficacy and several side effects. Probiotics have the potential to alleviate symptoms of diarrhea. This randomized, double-blind, placebo-controlled trial evaluates the effects of administering the probiotic Lactiplantibacillus plantarum P9 (P9) strain in young adults with chronic diarrhea (Clinical Trial Registration Number: ChiCTR2000038410). The intervention period lasts for 28 days, followed by a 14-day post-intervention period. Participants are randomized into the P9 (n = 93) and placebo (n = 96) groups, with 170 individuals completing the double-blind intervention phase (n = 85 per group). The primary endpoint is the diarrhea symptom severity score. Both intention-to-treat (n = 189) and per-protocol (n = 170) analyses reveal a modest yet statistically significant reduction in diarrhea severity compared to the placebo group (20.0%, P = 0.050; 21.4%, P = 0.048, respectively). In conclusion, the results of this study support the use of probiotics in managing chronic diarrhea in young adults. However, the lack of blood parameter assessment and the short intervention period represent limitations of this study.

Effects of dietary supplementation of Enterococcus faecium postbiotics on growth performance and intestinal health of growing male mink.

Recent studies have demonstrated that postbiotics possess bioactivities comparable to those of probiotics. Therefore, our experiment aimed to evaluate the effects of postbiotics derived from Enterococcus faecium on the growth performance and intestinal health of growing male minks. A total of 120 growing male minks were randomly assigned to 4 groups, each with 15 replicates of 2 minks. The minks in the 4 groups were fed a basal diet supplemented with 0 (control), 0.05, 0.1, and 0.15% postbiotics derived from E. faecium (PEF), respectively. Compared to the control, PEF improved feed/gain (F/G) during the first 4 weeks and the entire 8 weeks of the study (p < 0.05); in addition, 0.1% PEF improved average daily gain (ADG) during the first 4 weeks and the entire 8 weeks of the study (p < 0.05), while 0.15% PEF improved ADG during the first 4 weeks of the study (p < 0.05). Consequently, 0.1% PEF minks displayed greater body weight (BW) at weeks 4 and 8 (p < 0.05), and 0.15% PEF minks had greater BW at week 4 (p < 0.05) than minks in the control. Furthermore, compared to the control, both 0.05 and 0.1% PEF enhanced the apparent digestibility of crude protein (CP) and ether extract (EE) (p < 0.05) in the initial 4 weeks, while both 0.1 and 0.15% PEF enhanced the apparent digestibility of CP and DM in the final 4 weeks (p < 0.05). Additionally, trypsin activity was elevated in the 0.1 and 0.15% PEF groups compared to the control (p < 0.05). In terms of intestinal morphology, PEF increased the villus height and villus/crypt (V/C) in the jejunum (p < 0.05), and both 0.1 and 0.15% PEF decreased the crypt depth and increased the villus height and V/C in the duodenum (p < 0.05) compared to the control group. Supplementation with 0.1% PEF increased the SIgA levels but decreased the IL-2, IL-8, and TNF-α levels in the jejunum (p < 0.05). Compared to the control, E. faecium postbiotics decreased the relative abundances of Serratia and Fusobacterium (p < 0.05). In conclusion, the results indicate that the growth performance, digestibility, immunity, and intestine development of minks are considerably affected by E. faecium postbiotics. In particular, dietary supplementation with 0.1% E. faecium postbiotics provides greater benefits than supplementation with 0.05 and 0.15%.

Effects of Mink-Origin Enterococcus faecium on Growth Performance, Antioxidant Capacity, Immunity, and Intestinal Microbiota of Growing Male Minks.

The purpose of this experiment was to explore the effects of dietary Enterococcus faecium (EF) on the growth performance, antioxidant capacity, immunity, and intestinal microbiota of growing male minks. A total of 60 male Regal White minks at 12 weeks of age were randomly assigned to two groups, each with 15 replicates of two minks per replicate. The minks in two groups were fed the basal diets and the basal diets with viable Enterococcus faecium (more than 107 cfu/kg of diet), respectively. Compared with the minks in control, Enterococcus faecium minks had heavier body weight (BW) at week 4 and week 8 of the study (p < 0.05), greater average daily gain (ADG), and a lower feed/gain ratio (F/G) of male minks during the initial 4 weeks and the entire 8-week study period (p < 0.05). Furthermore, Enterococcus faecium increased the apparent digestibility of crude protein (CP) and dry matter (DM) compared to the control (p < 0.05). Moreover, Enterococcus faecium enhanced the serum superoxide dismutase (SOD) activity and decreased the malondialdehyde (MDA) contents (p < 0.05). The results also confirmed that Enterococcus faecium increased the levels of serum immunoglobulin A (IgA), immunoglobulin G (IgG), and the concentrations of secretory immunoglobulin A (SIgA) in the jejunal mucosa while decreasing the interleukin-8 (IL-8) and interleukin-1ß (IL-1ß) levels in the jejunal mucosa (p < 0.05). Intestinal microbiota analysis revealed that Enterococcus faecium increased the species numbers at the OUT level. Compared with the control, Enterococcus faecium had significant effects on the relative abundance of Paraclostridium, Brevinema, and Comamonas (p < 0.05). The results showed that Enterococcus faecium could improve the growth performance, increase the antioxidant capacity, improve the immunity of growing male minks, and also modulate the gut microbiota.

Can digital financial inclusion help reduce migrant workers' overwork? Evidence from China.

Introduction: Migrant workers in China are migrants from the rural to the urban areas who usually work in the cities and return to the countryside after a certain period. Due to China's strict household registration system, they differ significantly from urban residents' access to public services. However, at the same time, China's workers are facing a severe phenomenon of overwork, and the group of migrant workers is even more hard-hit by overwork, which will cause various adverse effects on workers and society and should attract the attention of all sectors of society. Methods: This paper focuses on the impact of digital financial inclusion on the overwork of migrant workers. This study considered cross-sectional data containing 98,047 samples based on the 2017 China Migrants Dynamic Survey 2017 (CMDS) and China Municipal Statistical Yearbook after robustness tests and heterogeneity analysis using probit models. Results: (1) digital financial inclusion can effectively alleviate overwork among migrant workers; (2) the impact of digital finance on overwork is more significant for the new generation, digitized industries, and self-employed migrant workers; it is also more significant for the South, East, and small and medium-sized cities than for the North, the Midwest, and large cities; (3) job quality and income are crucial factors in how digital financial inclusion affects overwork among migrant workers. Digital financial inclusion can improve the quality of employment for migrant workers and alleviate overwork. However, the income substitution effect partially reduces the inhibitory impact of digital financial inclusion on overwork. Conclusion: Continuously promote the development of digital inclusive finance, improve laws and regulations, and protect the labor rights and interests of migrant workers. At the same time, vocational training and skills upgrading for rural migrant workers should be strengthened to improve the quality of their employment so that they can leave the secondary labor market and enter the primary labor market.

Role of miRNAs in macrophage-mediated kidney injury.

Macrophages, crucial components of the human immune system, can be polarized into M1/M2 phenotypes, each with distinct functions and roles. Macrophage polarization has been reported to be significantly involved in the inflammation and fibrosis observed in kidney injury. MicroRNA (miRNA), a type of short RNA lacking protein-coding function, can inhibit specific mRNA by partially binding to its target mRNA. The intricate association between miRNAs and macrophages has been attracting increasing interest in recent years. This review discusses the role of miRNAs in regulating macrophage-mediated kidney injury. It shows how miRNAs can influence macrophage polarization, thereby altering the biological function of macrophages in the kidney. Furthermore, this review highlights the significance of miRNAs derived from exosomes and extracellular vesicles as a crucial mediator in the crosstalk between macrophages and kidney cells. The potential of miRNAs as treatment applications and biomarkers for macrophage-mediated kidney injury is also discussed.

Exploring the Mechanism of Yiwei Decoction in the Intervention of a Premature Ovarian Insufficiency Rat Based on Network Pharmacology and the miRNA-mRNA Regulatory Network.

OBJECTIVE: our aim is to explore the mechanism of action of Yiwei decoction (YWD) in addressing premature ovarian insufficiency (POI) through a combination of transcriptomics and network pharmacology. By doing so, we hope to identify important pathways of action, key targets, and active components that contribute to the efficacy of YWD. MATERIALS AND METHODS: group A comprised of the model + traditional Chinese medicine group, while group B was the model control group and group C was the normal control group. After gavage, serum AMH and E2 levels were measured by using ELISA. HE staining was used to study the impact of YWD on ovarian follicle recovery in POI rats. Additionally, RNA-seq sequencing technology was employed to analyze the transcription levels of mRNAs and miRNAs in the ovarian tissues of each group, and the resulting data were examined using R. YWD used UPLC-Q-TOF-HRMS to analyze its active ingredients. Upon obtaining the sequencing results, the miRWalk database was utilized to forecast the targets of DEmiRNAs. Network pharmacology was then applied to predict the targets of active ingredients present in YWD, ultimately constructing a regulatory network consisting of active ingredients-mRNA-miRNA. The coexpression relationship between mRNAs and miRNAs was calculated using the Pearson correlation coefficient, and high correlation coefficients between miRNA-mRNA were confirmed through miRanda sequence combination. RESULTS: the application of YWD resulted in improved serum levels of AMH and E2, as well as an increased number of ovarian follicles in rats with POI. However, there was a minimal impact on the infiltration of ovarian lymphocytes. Through GSEA pathway enrichment analysis, we found that YWD may have a regulatory effect on PI3K-Akt, ovarian steroidogenesis, and protein digestion and absorption, which could aid in the treatment of POI. Additionally, our research discovered a total of 6 DEmiRNAs between groups A and B, including 2 new DEmiRNAs. YWD contains 111 active compounds, and our analysis of the active component-mRNA regulatory network revealed 27 active components and 73 mRNAs. Furthermore, the coexpression network included 5 miRNAs and 18 mRNAs. Our verification of MiRanda binding demonstrated that 12 of the sequence binding sites were stable. CONCLUSIONS: our research has uncovered the regulatory network mechanism of active ingredients, mRNA, and miRNA in YWD POI treatment. However, further research is needed to determine the effect of the active ingredients on key miRNAs and mRNAs.

Inhibition of survivin by 2'-O-methyl phosphorothioate-modified steric-blocking antisense oligonucleotides.

Chemically modified antisense oligonucleotide (ASO) has been established as a successful therapeutic strategy for treating various human diseases. To date, ten ASO drugs, which are capable of either inducing mRNA degradation via RNase H recruitment (fomivirsen, mipomersen, inotersen, volanesorsen and tofersen) or splice modulation (eteplirsen, nusinersen, golodirsen, viltolarsen and casimersen), have been approved by the regulatory agencies for market entry. Nonetheless, none of these approved drugs are prescribed as cancer therapy. Towards this, we have developed steric-blocking ASOs targeting BIRC5 - a well-validated oncogene. Initial screening was performed by transfection of HepG2 cells with seven BIRC5 exon-2 targeting, uniformly 2'-OMe-PS modified ASOs at 400 nM respectively, leading to the identification of two best-performing candidates ASO-2 and ASO-7 in reducing the production of BIRC5 mRNA. Subsequent dose-response assay was conducted via transfection of HepG2 cells by different concentrations (400, 200, 100, 50, 25 nM) of ASO-2 and ASO-7 respectively, showing that both ASOs consistently and efficiently inhibited BIRC5 mRNA expression in a dose-dependent manner. Furthermore, western blot analysis confirmed that ASO-7 could significantly repress survivin production on protein level. Based on our preliminary results, we believe that ASO-7 could be a useful BIRC5 inhibitor for both research purpose and therapeutic development.

Intensive Microalgal Cultivation and Tertiary Phosphorus Recovery from Wastewaters via the EcoRecover Process.

Mixed community microalgal wastewater treatment technologies have the potential to advance the limits of technology for biological nutrient recovery while producing a renewable carbon feedstock, but a deeper understanding of their performance is required for system optimization and control. In this study, we characterized the performance of a 568 m3·day-1 Clearas EcoRecover system for tertiary phosphorus removal (and recovery as biomass) at an operating water resource recovery facility (WRRF). The process consists of a (dark) mix tank, photobioreactors (PBRs), and a membrane tank with ultrafiltration membranes for the separation of hydraulic and solids residence times. Through continuous online monitoring, long-term on-site monitoring, and on-site batch experiments, we demonstrate (i) the importance of carbohydrate storage in PBRs to support phosphorus uptake under dark conditions in the mix tank and (ii) the potential for polyphosphate accumulation in the mixed algal communities. Over a 3-month winter period with limited outside influences (e.g., no major upstream process changes), the effluent total phosphorus (TP) concentration was 0.03 ± 0.03 mg-P·L-1 (0.01 ± 0.02 mg-P·L-1 orthophosphate). Core microbial community taxa included Chlorella spp., Scenedesmus spp., and Monoraphidium spp., and key indicators of stable performance included near-neutral pH, sufficient alkalinity, and a diel rhythm in dissolved oxygen.

Chemoselective Synthesis of 3-Bromomethyloxindoles via Visible-Light-Induced Radical Cascade Bromocyclization of Alkenes.

A novel visible-light-induced radical cascade bromocyclization of N-arylacrylamides has been accomplished. This reaction overcomes the overbromination at the benzene rings suffered in traditional electrophilic reactions, thus enabling the first highly chemoselective synthesis of valuable 3-bromomethyloxindoles. The combination of pyridine and anhydrous medium is identified as the key factor for the high chemoselectivity in the current photoreaction system, which might work by suppressing the in situ generation of low-concentration Br2 from N-bromosuccinimide. Moreover, the mild reaction conditions ensure the generation of a wide range of the new desired products with excellent functional group tolerance.

The First High-Quality Genome Assembly of Freshwater Pearl Mussel Sinohyriopsis cumingii: New Insights into Pearl Biomineralization.

China leads the world in freshwater pearl production, an industry in which the triangle sail mussel (Sinohyriopsis cumingii) plays a pivotal role. In this paper, we report a high-quality chromosome-level genome assembly of S. cumingii with a size of 2.90 Gb-the largest yet reported among bivalves-and 89.92% anchorage onto 19 linkage groups. The assembled genome has 37,696 protein-coding genes and 50.86% repeat elements. A comparative genomic analysis revealed expansions of 752 gene families, mostly associated with biomineralization, and 237 genes under strong positive selection. Notably, the fibrillin gene family exhibited gene family expansion and positive selection simultaneously, and it also exhibited multiple high expressions after mantle implantation by transcriptome analysis. Furthermore, RNA silencing and an in vitro calcium carbonate crystallization assay highlighted the pivotal role played by one fibrillin gene in calcium carbonate deposition and aragonite transformation. This study provides a valuable genomic resource and offers new insights into the mechanism of pearl biomineralization.

Numerical Simulations of Combined Dielectrophoresis and Alternating Current Electrothermal Flow for High-Efficient Separation of (Bio)Microparticles.

High-efficient separation of (bio)microparticles has important applications in chemical analysis, environmental monitoring, drug screening, and disease diagnosis and treatment. As a label-free and high-precision separation scheme, dielectrophoresis (DEP) has become a research hotspot in microparticle separation, especially for biological cells. When processing cells with DEP, relatively high electric conductivities of suspending media are sometimes required to maintain the biological activities of the biosample, which results in high temperature rises within the system caused by Joule heating. The induced temperature gradient generates a localized alternating current electrothermal (ACET) flow disturbance, which seriously impacts the DEP manipulation of cells. Based on this, we propose a novel design of the (bio)microparticle separator by combining DEP with ACET flow to intensify the separation process. A coupling model that incorporates electric, fluid flow, and temperature fields as well as particle tracking is established to predict (bio)microparticle trajectories within the separator. Numerical simulations reveal that both ACET flow and DEP motion act in the same plane but in different directions to achieve high-precision separation between particles. This work provides new design ideas for solving the very tricky Joule heating interference in the DEP separation process, which paves the way for further improving the throughput of the DEP-based (bio)microparticle separation system.

TGF-ß1 induces PD-1 expression in macrophages through SMAD3/STAT3 cooperative signaling in chronic inflammation.

Programmed cell death protein 1 (PD-1), a coinhibitory T cell checkpoint, is also expressed on macrophages in pathogen- or tumor-driven chronic inflammation. Increasing evidence underscores the importance of PD-1 on macrophages for dampening immune responses. However, the mechanism governing PD-1 expression in macrophages in chronic inflammation remains largely unknown. TGF-ß1 is abundant within chronic inflammatory microenvironments. Here, based on public databases, significantly positive correlations between PDCD1 and TGFB1 gene expression were observed in most human tumors. Of note, among immune infiltrates, macrophages as the predominant infiltrate expressed higher PDCD1 and TGFBR1/TGFBR2 genes. MC38 colon cancer and Schistosoma japonicum infection were used as experimental models for chronic inflammation. PD-1hi macrophages from chronic inflammatory tissues displayed an immunoregulatory pattern and expressed a higher level of TGF-ß receptors. Either TGF-ß1-neutralizing antibody administration or macrophage-specific Tgfbr1 knockdown largely reduced PD-1 expression on macrophages in animal models. We further demonstrated that TGF-ß1 directly induced PD-1 expression on macrophages. Mechanistically, TGF-ß1-induced PD-1 expression on macrophages was dependent on SMAD3 and STAT3, which formed a complex at the Pdcd1 promoter. Collectively, our study shows that macrophages adapt to chronic inflammation through TGF-ß1-triggered cooperative SMAD3/STAT3 signaling that induces PD-1 expression and modulates macrophage function.

CD1d protects against hepatocyte apoptosis in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Hepatocyte apoptosis, a well-defined form of cell death in non-alcoholic steatohepatitis (NASH), is considered the primary cause of liver inflammation and fibrosis. However, the mechanisms underlying the regulation of hepatocyte apoptosis in NASH remain largely unclear. We explored the anti-apoptotic effect of hepatocyte CD1d in NASH. METHODS: Hepatocyte CD1d expression was analyzed in patients with NASH and mouse models. Hepatocyte-specific gene overexpression or knockdown and anti-CD1d crosslinking were used to investigate the anti-apoptotic effect of hepatocyte CD1d on lipotoxicity-, Fas-, and concanavalin (ConA)-mediated liver injuries. A high-fat diet, a methionine-choline-deficient diet, a Fas agonist, and ConA were used to induce lipotoxic and/or apoptotic liver injuries. Palmitic acid was used to mimic lipotoxicity-induced apoptosis in vitro. RESULTS: We identified a dramatic decrease in CD1d expression in hepatocytes of patients with NASH and mouse models. Hepatocyte-specific CD1d overexpression and knockdown experiments collectively demonstrated that hepatocyte CD1d protected against hepatocyte apoptosis and alleviated hepatic inflammation and injuries in NASH mice. Furthermore, decreased JAK2-STAT3 signaling was observed in NASH patient livers. Mechanistically, anti-CD1d crosslinking on hepatocytes induced tyrosine phosphorylation of the CD1d cytoplasmic tail, leading to the recruitment and phosphorylation of JAK2. Phosphorylated JAK2 activated STAT3 and subsequently reduced apoptosis in hepatocytes, which was associated with an increase in anti-apoptotic effectors (Bcl-xL and Mcl-1) and a decrease in pro-apoptotic effectors (cleaved-caspase 3/7). Moreover, anti-CD1d crosslinking effectively protected against Fas- or ConA-mediated hepatocyte apoptosis and liver injury in mice. CONCLUSIONS: Our study uncovered a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 axis in hepatocytes that conferred hepatoprotection and highlighted the potential of hepatocyte CD1d-directed therapy for liver injury and fibrosis in NASH, as well as in other liver diseases associated with hepatocyte apoptosis. IMPACT AND IMPLICATIONS: Excessive and/or sustained hepatocyte apoptosis is critical in driving liver inflammation and injury. The mechanisms underlying the regulation of hepatocyte apoptosis in non-alcoholic steatohepatitis (NASH) remain largely unclear. Here, we found that CD1d expression in hepatocytes substantially decreases and negatively correlates with the severity of liver injury in patients with NASH. We further revealed a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 signaling axis in hepatocytes, which confers significant protection against liver injury in NASH and acute liver diseases. Thus, hepatocyte CD1d-targeted therapy could be a promising strategy to manipulate liver injury in both NASH and other hepatocyte apoptosis-related liver diseases.