Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells.

BACKGROUND: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. METHODS: The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. RESULTS: HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. CONCLUSIONS: IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis.

γδ T cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity. However, the metabolic requirements and regulation of γδ T-cell development and function remain poorly understood. In this study, we investigated the role of liver kinase B1 (Lkb1), a serine/threonine kinase that links cellular metabolism with cell growth and proliferation, in γδ T-cell biology. Our findings demonstrate that Lkb1 is not only involved in regulating γδ T lineage commitment but also plays a critical role in γδ T-cell effector function. Specifically, T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations in γδ T-cell subsets in both the thymus and peripheral lymphoid tissues. Notably, loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4 γδ T cells, promoted the maturation of IL-17-producing Vγ6 γδ T cells, and led to the occurrence of fatal autoimmune hepatitis (AIH). Notably, clearance of γδ T cells or blockade of IL-17 significantly attenuated AIH. Mechanistically, Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity, accompanied by increased mTORC1 activation, thereby causing overactivation of γδ T cells and enhanced apoptosis. Interestingly, activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice. Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis of γδ T cells and preventing IL-17-mediated autoimmune diseases, providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymic γδ T cells.

Arthroscopy-assisted reduction and simultaneous robotic-assisted screw placement in the treatment of fractures of the posterior talar process.

PURPOSE: A fracture of the posterior talar process is easily missed because of its hidden position. Inappropriate treatment is likely to result in complications, such as nonunion of the fracture and traumatic arthritis. This study evaluated the outcomes of arthroscopy-assisted reduction combined with robotic-assisted screw placement in the treatment of fractures of the posterior talar process. METHODS: The clinical data for nine patients who underwent surgical treatment of a fracture of the posterior talar process at our institution between September 2017 and January 2021 were retrospectively reviewed. Arthroscopy-assisted reduction of the fracture was performed, and a cannulated screw was placed using three-dimensional orthopedic robotic-assisted navigation. RESULTS: The patients (seven men, two women) had a mean age of 36.33 ± 9.77 years and were followed up for 21 ± 5.43 months. The operation time was 106.67 ± 24.5 min with blood loss of 47.78 ± 9.05 ml. Primary healing was obtained in all cases, and no patient sustained a nerve or tendon injury, had fracture nonunion, or developed talar osteonecrosis. One patient developed subtalar arthritis, for which subtalar joint fusion was performed; pain was markedly less severe after cleaning. CONCLUSION: Arthroscopy-assisted reduction and robotic-assisted screw placement have the advantages of visualization of fracture reduction, minimal injury, and precise screw placement in the treatment of fractures of the posterior talar process.

Dihydro-ß-agarofuran-type sesquiterpenoids from the seeds of Tripterygium wilfordii (Thunder God Vine) and evaluation of their anti-osteoclastogenesis and immunosuppressive activities.

Extensive phytochemical investigation of the seeds of Tripterygium wilfordii led to the identification of 54 polyesterified dihydro-ß-agarofuran-type sesquiterpenoids, including 27 previously undescribed ones, named Tripwilin I-XXVII (1-27). Comprehensive spectroscopic and single-crystal X-ray diffraction analyses, along with electronic circular dichroism (ECD) calculations were used for the structural elucidation of the new compounds. Biological assay revealed that 37 compounds among the isolates exhibited significant inhibition against osteoclastogenesis induced by receptor activator of nuclear factor-κB ligand (RANKL) at 10 µM. Further investigation indicated that Triptogelin C-3 (54), with the most potent osteoclastogenesis inhibitory activity, regulated the osteoclast marker genes (MMP-9, c-Fos, CTSK, and TRAP) and proteins in a dose-dependent manner in vitro. Besides, celaforin D-1 (28), 1α,6ß,15-triacetoxy-8α,9α-dibenzoyloxy-2α-hydroxydihydro-ß-agarofuran (34), triptogelin A-2 (37), and chiapen D (49) showed moderate suppressive effects on the proliferation of T and B lymphocytes with IC50 values ranging between 8.1 ± 0.8 and 19.0 ± 0.9 µM.

SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.

Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1ß from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

Safety monitoring of oral iron supplements in pregnant women with anemia: a multi-center observational clinical study.

Aims: To investigate the safety of oral iron therapy in pregnant women with iron-deficiency anemia (IDA) in the real world. Methods: A retrospective analysis was performed on 1792 pregnant patients with IDA who received oral iron supplements from 12 hospitals in Shandong Province from 1 April to 31 June 2021; follow-up and adverse reactions were recorded. They were divided into six groups according to the treatment drugs. Results: The overall adverse reaction rate was 15.4%, and the main adverse reaction site was the digestive system. The incidence of all kinds of oral iron adverse reactions from high to low in order: compound ferrous sulfate and folic acid tablets (21.88%); iron proteinsuccinylate oral solution (20.90%); ferrous succinate tablets (19.76%); ferrous succinate sustained-release tablets (18.00%); iron polysaccharide complex capsule (12.06%); and iron dextran oral solution (6.94%). It was found that there was a significant difference in the incidence of adverse reactions among the six drugs (p < 0.05). Pairwise comparison showed that the incidence of adverse reactions was higher in the iron proteinsuccinylate oral solution than that in the iron polysaccharide complex capsule (p < 0.05). There was no significant difference in the incidence of adverse reactions in different ages (p > 0.05), but there was a significant difference in the incidence of adverse reactions in different gestational ages (p < 0.05). In Adverse Drug Reaction (ADR) patients, the adverse reaction result of most patients is recovery or improvement, and there was no serious adverse reaction outcome such as sequela and death. Conclusion: All the adverse reactions of oral iron were mainly gastrointestinal adverse reactions, and no heavy adverse reactions were found. Iron proteinsuccinylate oral solution has a higher incidence of adverse reactions than iron polysaccharide complex capsule. The results showed that oral iron was safer for anemia patients during pregnancy.

Safety of oral iron in the treatment of iron-deficiency anemia during pregnancy Introduction: The safety of different oral iron agents varies. At present, the safety evaluation of iron supplements in the treatment of anemia during pregnancy is mainly focused on intravenous iron supplements, and there is no comprehensive study on the safety of commonly used oral iron supplements. This study compared the safety of six commonly used oral iron supplements in the treatment of iron-deficiency anemia during pregnancy, aiming to provide a reference for clinical medication. Methods: We conducted a study involving 1792 patients in 12 hospitals in Shandong Province from 1 April to 31 June 2021. Results: Among the six groups, 276 ADR patients reported 302 adverse reactions. There were significant differences in the rates of adverse reactions among the six oral iron agents, and the incidence of adverse reactions in the iron proteinsuccinylate oral solution was significantly higher than that of iron polysaccharide complex capsules. The main incidence of adverse reactions was constipation (6.96%), and most of the outcomes were cured or improved. Conclusion: In this study, there were no heavy adverse reactions. The incidence of adverse reactions of iron proteinsuccinylate oral was higher than that of iron polysaccharide compound capsule. The results showed that oral iron had a good safety in patients with anemia during pregnancy.

METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells.

γδ T cells make key contributions to tissue physiology and immunosurveillance through two main functionally distinct subsets, γδ T1 and γδ T17. m6A methylation plays critical roles in controlling numerous aspects of mRNA metabolism that govern mRNA turnover, gene expression, and cellular functional specialization; however, its role in γδ T cells remains less well understood. Here, we find that m6A methylation controls the functional specification of γδ T17 vs. γδ T1 cells. Mechanistically, m6A methylation prevents the formation of endogenous double-stranded RNAs and promotes the degradation of Stat1 transcripts, which converge to prevent over-activation of STAT1 signaling and ensuing inhibition of γδ T17. Deleting Mettl3, the key enzyme in the m6A methyltransferases complex, in γδ T cells reduces interleukin-17 (IL-17) production and ameliorates γδ T17-mediated psoriasis. In summary, our work shows that METTL3-mediated m6A methylation orchestrates mRNA stability and double-stranded RNA (dsRNA) contents to equilibrate γδ T1 and γδ T17 cells.

The spatial variation and driving factors of soil total carbon and nitrogen in the Heihe River source region.

Soil carbon and nitrogen levels are key indicators of soil fertility and are used to assess ecological value and safeguard the environment. Previous studies have focused on the contributions of vegetation, topography, physical and chemical qualities, and meteorology to soil carbon and nitrogen change, but there has been little consideration of landscape and ecological environment types as potential driving forces. The study investigated the horizontal and vertical distribution and influencing factors of total carbon and total nitrogen in soil at 0-20 and 20-50 cm depths in the source region of the Heihe River. A total of 16 influencing factors related to soil, vegetation, landscape, and ecological environment were selected, and their individual and synergistic effects on the distributions of total carbon and total nitrogen in soil were assessed. The results show gradually decreasing average values of soil total carbon and total nitrogen from the surface layer to the bottom layer, with larger values in the southeast part of the sampling region and smaller values in the northwest. Larger values of soil total carbon and total nitrogen at sampling points are distributed in areas with higher clay and silt and lower soil bulk density, pH, and sand. For environmental factors, larger values of soil total carbon and total nitrogen are distributed in areas with higher annual rainfall, net primary productivity, vegetation index, and urban building index, and lower surface moisture, maximum patch index, boundary density, and bare soil index. Among soil factors, soil bulk density and silt are most closely associated with soil total carbon and total nitrogen. Among surface factors, vegetation index, soil erosion, and urban building index have the greatest influence on vertical distribution, and maximum patch index, surface moisture, and net primary productivity have the greatest influence on horizontal distribution. In conclusion, vegetation, landscape, and soil physical properties all have a significant impact on the distribution of soil carbon and nitrogen, suggesting better strategies to improve soil fertility.

Single-cell RNA-seq and chromatin accessibility profiling decipher the heterogeneity of mouse γδ T cells.

The distinct characteristics of γδ T cells determine their vital roles in the formation of local immune responses and contribute to tissue homeostasis. However, the heterogeneity of γδ T cells across tissues remains unclear. By combining transcriptional and chromatin analyses with a truly unbiased fashion, we constructed a single-cell transcriptome and chromatin accessibility landscape of mouse γδ T cells in the lymph, spleen, and thymus. We also revealed the heterogeneity of γδ T1 and γδ T17 cells across these tissues and inferred their potential regulatory mechanisms. In the thymus, we reconstructed the developmental trajectory and gained further insights into the signature genes from the mature stage, intermediate stage, and immature stage of γδ T cells on the basis of single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing data. Notably, a novel Gzma+ γδ T cell subset was identified with immature properties and only localized to the thymus. Finally, NR1D1, a circadian transcription factor (TF), was validated as a key and negative regulator of γδ T17 cell differentiation by performing a combined analysis of TF motif enrichment, regulon enrichment, and Nr1d1 knockout mice. In summary, our data represent a comprehensive mapping on the transcriptome and chromatin accessibility dynamics of mouse γδ T cells, providing a valuable resource and reference for future studies on γδ T cells.

Potential Sources, Pollution, and Ecological Risk Assessment of Potentially Toxic Elements in Surface Soils on the North-Eastern Margin of the Tibetan Plateau.

Due to increased levels of human activity, various pollutants are frequently detected on the Tibetan Plateau, where the environment is extremely fragile and sensitive. Therefore, this study investigated the sources, pollution, and ecological risks of soil potentially toxic elements (PTEs) in different landscape areas within the Qaidam Basin in the northeastern part of the Qinghai−Tibet Plateau. The contents of seven PTEs (Cd, Cu, Pb, Zn, As, Cr, and Ni) in 32 topsoil samples (0−2 cm) were analyzed in different regions of the Qaidam Basin. The concentrations of As, Cd, Cr, Cu, Ni, Pb, and Zn were 10.4−29.9 mg/kg, 0.08−4.45 mg/kg, 19−66 mg/kg, 8.2−40 mg/kg, 11.7−30.8 mg/kg, 11.1−31.2 mg/kg, and 32−213 mg/kg, respectively. The correlation between Pb and Cd in unpopulated areas was 0.896 (p < 0.01). The correlations among Pb, Cd, and Zn in agricultural areas, among As, Cd, Cr, and Zn in saline lake areas, and among As, Cd, Cr, Cu, Ni, Pb, and Zn in residential areas were all greater than 0.65 (p < 0.05). The principal component analysis results showed that Pb and Cd in unpopulated areas, Pb, Cd, and Zn in agricultural areas, As, Cd, Cr, Zn, and Pb in saline lake areas, and As, Cd, Cr, Cu, Ni, Pb, and Zn in residential areas were affected by human activities (significant factor >0.70). Based on the geological accumulation index and single-factor pollution index results, the maximum Cd values were found to be 4.93 and 45.88, respectively; Cd was thus the most serious PTE pollutant. The comprehensive pollution index of Nemero showed that moderately and severely polluted areas accounted for 18.89% and 18.46% of the total area, respectively. The results of the potential risk index showed that very strong and strong ecological risk points together accounted for 18.8% of the total points. The spatial variations in PTE pollution and the potential ecological risk index had similar patterns; both increased from the unpopulated areas in the northeastern Qaidam Basin to Golmud city in the south-western Qaidam Basin. These results indicate that human activities negatively impacted the soil ecological environment in the Qaidam Basin during the rapid development of the economy and urbanization and that these negative impacts tended to spread to unpopulated areas. Therefore, it is necessary to emphasize the significant impacts of human activities on environmental quality and formulate preventive measures to reduce PTE pollution in the Qinghai−Tibet Plateau.

1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells.

BACKGROUND: Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in patients with cancer correlates with cytotoxic T-cell exhaustion is unknown. METHODS: Periphery blood samples from 172 patients with non-small cell lung cancer (NSCLC) were prospectively collected. Patients with NSCLC received one course of intravenous docetaxel (75 mg/m2) followed by treatment with or without rocaltrol at a dose of 0.5-2.0 µg/day for total of 3 weeks. We performed phenotypical and functional analysis of T-cell through flow cytometry. Vitamin D receptor (VDR) knockout and overexpression CD8+ and Vδ2+ T cells were constructed using Cas9-gRNA targeted and overexpressing approaches to identify 1α,25(OH)2D3/VDR-mediated transcription regulation for ICRs or antitumor activity in T cells. RESULTS: We show that serum level of vitamin D is negatively correlated with expression of programmed cell death-1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), but positively correlated with CD28 expression on CD8+ and Vγ9Vδ2+ T cells in patients with NSCLC. 1α,25(OH)2D3, the active form of vitamin D, promotes the nuclear translocation of VDR, which binds to the promoter region of Pdcd1, Tim3, and Tigit genes and inhibits their expression. Besides, 1α,25(OH)2D3 pretreatment also promotes the methylation of CpG island in the promoter region of the Pdcd1 gene and increases H3K27 acetylation at the promoter region of the Cd28 gene, which leads to surface PD-1 downregulation and CD28 upregulation, respectively. We further reveal that VDR-mediated Ca2+ influx enhanced expression of Th1 cytokines via T-cell receptor activation. Functionally, 1α,25(OH)2D3 pretreated CD8+ T cells or Vγ9Vδ2+ T cells showed increased Th1 cytokine production and enhanced antitumor immunity. Finally, oral 1α,25(OH)2D3 could also decrease expression of PD-1, Tim-3, TIGIT and increase expression of CD28, resulting in cytokine production (associated with antitumor immunity) by cytotoxic T cells of patients with NSCLC. CONCLUSIONS: Our findings uncover the pleiotropic effects of 1α,25(OH)2D3 in rescuing the exhausted phenotype of human cytotoxic T cells in patients with tumor and in promoting their antitumor immunity. TRIAL REGISTRATION NUMBER: ChiCTR2100051135.

Dihydro-ß-agarofuran-type sesquiterpenoids from the seeds of Celastrus virens with lifespan-extending effect on the nematode Caenorhabditis elegans.

Twelve dihydro-ß-agarofuran-type sesquiterpenoids, including five new ones (1-5), were purified from the seeds of Celastrus virens (Wang et Tang) C. Y. Chent et T. C. Kao. Their chemical structures were characterized via comprehensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and computational prediction of ECD, as well as comparison of observed and reported NMR spectral data. Among the isolates, nine abundant dihydro-ß-agarofuran-type sesquiterpenoids were evaluated for their lifespan-extending activity using the nematode Caenorhabditis elegans model. As a result, compounds 1, 2, 5, 6, 8, and 9 (50 µM) significantly extended the mean survival time of C. elegans, respectively, compared with the blank control group (p < 0.05). Further Quantitative RT-PCR showed that the prolonging of lifespan mediated by compounds 1, 6, 8, and 9 were dependent on the transcription factors skn-1 and hsf-1.

IL-27 signalling promotes adipocyte thermogenesis and energy expenditure.

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.

[Spatial-temporal differentiation of mountain-water-forest-farmland-lake-grass system in Qinghai area of the Qilian Mountain National Park, China]. / ç¥è¿žå±±å›½å®¶å ¬å›­é’æµ·ç‰‡åŒºå±±æ°´æž—ç”°æ¹–è‰çš„æ—¶ç©ºåˆ†å¼‚.

Higher and more precise requirements are critically needed for the protection, regulation, and restoration of ecological environment in the Qilian Mountain National Park after it is classified as a national park system pilot in China. Based on remote sensing data in 1980-2018, the spatial pattern map of mountain-water-forest-farmland-lake-grass system was constructed to analyze its spatial-temporal variations in the general control area and core conservation area in Qinghai area of the Qilian Mountain National Park. The results showed that grasslands, with an area of 8174.93 km2, were the main landscape in the park, and that grassland area in the core conservation area was 1.2 times as that of the general control area. The bare exposed rocks, a major type of unused land, accounted for 86.7% and 79.4% of the unused land in the core conservation area and the general control area, respectively. Forest area in the general control area was larger than that in the core conservation area. Water area in the core conservation area was 4.9 times as large as that in the general control area, with 90.4% of which being dominated by permanent glaciers and snowfields. The drylands were mainly concentrated in the general control area. From 1980 to 2018, the water area was decreasing and had been reduced by 186.75 km2. The area of permanent glaciers and snowfields decreased the most, with a drop of 12.05 and 175.88 km2 in the general control area and the core conservation area, respectively. The area of forests and grasslands were enlarged constantly. The changes of high-, medium-, and low-coverage grasslands in the core conservation area were greater than that in the general control area, which were the most significant during 1990-2000. Moreover, the degradation of high- and medium-coverage grasslands in the general control area as well as high- and low-coverage grasslands in the core conservation area was observed from 1980 to 2018. The area of bare exposed rocks was on the rise, while the permanent glaciers and snowfields displayed a decreasing trend. The permanent glaciers and snowfields and the bare exposed rocks exhibited the most obvious changes in the park. The glaciers in the core conservation area retreated remarkably faster than those in the general control area, which were transformed into the bare exposed rocks mainly in 1980-1990 and 2000-2010.

Yeast Shells Encapsulating Adjuvant AS04 as an Antigen Delivery System for a Novel Vaccine against Toxoplasma Gondii.

Toxoplasma gondii (T. gondii) infection causes severe zoonotic toxoplasmosis, which threatens the safety of almost one-third of the human population globally. However, there is no effective protective vaccine against human toxoplasmosis. This necessitates anti-T. gondii vaccine development, which is a main priority of public health. In this study, we optimized the adjuvant system 04 (AS04), a vaccine adjuvant constituted by 3-O-desacyl-4'-monophosphoryl lipid A (a TLR4 agonist) and aluminum salts, by packing it within natural extracts of ß-glucan particles (GPs) from Saccharomyces cerevisiae to form a GP-AS04 hybrid adjuvant system. Through a simple mixing procedure, we loaded GP-AS04 particles with the total extract (TE) of T. gondii lysate, forming a novel anti-T. gondii vaccine GP-AS04-TE. Results indicated that the hybrid adjuvant can efficiently and stably load antigens, mediate antigen delivery, facilitate the dendritic uptake of antigens, boost dendritic cell maturation and stimulation, and increase the secretion of pro-inflammatory cytokines. In the mouse inoculation model, GP-AS04-TE significantly stimulated the function of dendritic cells, induced a very strong TE-specific humoral and cellular immune response, and finally showed a strong and effective protection against toxoplasma chronic and acute infections. This work proves the potential of GP-AS04 for exploitation as a vaccine against a range of pathogens.

Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regeneration through activation of ferroptosis.

BACKGROUND: Satellite cells (SCs) are critical to skeletal muscle regeneration. Inactivation of SCs is linked to skeletal muscle loss. Transferrin receptor 1 (Tfr1) is associated with muscular dysfunction as muscle-specific deletion of Tfr1 results in growth retardation, metabolic disorder, and lethality, shedding light on the importance of Tfr1 in muscle physiology. However, its physiological function regarding skeletal muscle ageing and regeneration remains unexplored. METHODS: RNA sequencing is applied to skeletal muscles of different ages to identify Tfr1 associated to skeletal muscle ageing. Mice with conditional SC ablation of Tfr1 were generated. Between Tfr1SC/WT and Tfr1SC/KO (n = 6-8 mice per group), cardiotoxin was intramuscularly injected, and transverse abdominal muscle was dissected, weighted, and cryosectioned, followed by immunostaining, haematoxylin and eosin staining, and Masson staining. These phenotypical analyses were followed with functional analysis such as flow cytometry, tread mill, Prussian blue staining, and transmission electron microscopy to identify pathological pathways that contribute to regeneration defects. RESULTS: By comparing gene expression between young (2 weeks old, n = 3) and aged (80 weeks old, n = 3) mice among four types of muscles, we identified that Tfr1 expression is declined in muscles of aged mice (~80% reduction, P < 0.005), so as to its protein level in SCs of aged mice. From in vivo and ex vivo experiments, Tfr1 deletion in SCs results in an irreversible depletion of SCs (~60% reduction, P < 0.005) and cell-autonomous defect in SC proliferation and differentiation, leading to skeletal muscle regeneration impairment, followed by labile iron accumulation, lipogenesis, and decreased Gpx4 and Nrf2 protein levels leading to reactive oxygen species scavenger defects. These abnormal phenomena including iron accumulation, activation of unsaturated fatty acid biosynthesis, and lipid peroxidation are orchestrated with the occurrence of ferroptosis in skeletal muscle. Ferroptosis further exacerbates SC proliferation and skeletal muscle regeneration. Ferrostatin-1, a ferroptosis inhibitor, could not rescue ferroptosis. However, intramuscular administration of lentivirus-expressing Tfr1 could partially reduce labile iron accumulation, decrease lipogenesis, and promote skeletal muscle regeneration. Most importantly, declined Tfr1 but increased Slc39a14 protein level on cellular membrane contributes to labile iron accumulation in skeletal muscle of aged rodents (~80 weeks old), leading to activation of ferroptosis in aged skeletal muscle. This is inhibited by ferrostatin-1 to improve running time (P = 0.0257) and distance (P = 0.0248). CONCLUSIONS: Satellite cell-specific deletion of Tfr1 impairs skeletal muscle regeneration with activation of ferroptosis. This phenomenon is recapitulated in skeletal muscle of aged rodents and human sarcopenia. Our study provides mechanistic information for developing novel therapeutic strategies against muscular ageing and diseases.

CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity.

CFTR, a chloride channel and ion channel regulator studied mostly in epithelial cells, has been reported to participate in immune regulation and likely affect the risk of cancer development. However, little is known about the effects of CFTR on the differentiation and function of γδ T cells. In this study, we observed that CFTR was functionally expressed on the cell surface of γδ T cells. Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γ release by peripheral γδ T cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo. Interestingly, the molecular mechanisms underlying the regulation of γδ T cell IFN-γ production by CFTR were either TCR dependent or related to Ca2+ influx. CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling. In addition, CFTR was found to modulate TCR-induced Ca2+ influx and membrane potential (Vm)-induced Ca2+ influx and subsequently regulate the calcineurin-NFATc1 signaling pathway in γδ T cells. Thus, CFTR serves as a negative regulator of IFN-γ production in γδ T cells and the function of these cells in antitumor immunity. Our investigation suggests that modification of the CFTR activity of γδ T cells may be a potential immunotherapeutic strategy for cancer.

GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis.

Psoriasis is a severe disease associated with the disturbance of metabolism and inflammation, but the molecular mechanisms underlying these aspects of psoriasis pathology are poorly understood. Here, we report that glutaminase 1-mediated (GLS1-mediated) glutaminolysis was aberrantly activated in patients with psoriasis and in psoriasis-like mouse models, which promoted Th17 and γδ T17 (IL-17A-producing γδ T) cell differentiation through enhancement of histone H3 acetylation of the Il17a promoter, thereby contributing to the immune imbalance and development of psoriasis. We further demonstrate that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease was constitutively active in psoriatic CD4+ and γδ T cells, thereby supporting GLS1 expression by stabilizing c-Jun, which directly binds to the GLS1 promoter region. Blocking the activity of either GLS1 or MALT1 protease resolved Th17 and γδ T17 cell differentiation and epidermal hyperplasia in the psoriasis-like mouse models. Finally, IL-17A enhanced GLS1 expression via the MALT1/cJun pathway in keratinocytes, resulting in hyperproliferation of and chemokine production by keratinocytes. Our findings identify the role of the MALT1/cJun/GLS1/glutaminolysis/H3 acetylation/T17 axis in psoriasis pathogenesis and reveal potential therapeutic targets for this disease.

Perforin Acts as an Immune Regulator to Prevent the Progression of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of cirrhosis and major risk factors for hepatocellular carcinoma and liver-related death. Despite substantial clinical and basic research, the pathogenesis of obesity-related NAFLD remains poorly understood. In this study, we show that perforin can act as an immune regulator to prevent the progression of NAFLD. Aged perforin-deficient (Prf-/-) mice have increased lipid accumulation in the liver compared to WT mice. With high-fat diet (HFD) challenge, Prf-/- mice have increased liver weight, more severe liver damage, and increased liver inflammation when compared with WT controls. Mechanistic studies revealed that perforin specifically regulates intrinsic IFN-γ production in CD4 T cells, not CD8 T cells. We found that CD4 T cell depletion reduces liver injury and ameliorates the inflammation and metabolic morbidities in Prf-/- mice. Furthermore, improved liver characteristics in HFD Prf-/- and IFN-γR-/- double knockout mice confirmed that IFN-γ is a key factor for mediating perforin regulation of NAFLD progression. Overall, our findings reveal the important regulatory role perforin plays in the progression of obesity-related NAFLD and highlight novel strategies for treating NAFLD.

[Changes of growing season NDVI at different elevations, slopes, slope aspects and its relationship with meteorological factors in the southern slope of the Qilian Mountains, China from 1998 to 2017]. / 1998­2017年祁连山南坡不同海拔、坡度和坡向生长季NDVIå˜åŒ–åŠå ¶ä¸Žæ°”è±¡å› å­çš„å ³ç³».

Qilian Mountains is an important water conservation area in Northwest China, which is the boundary between the first and second steps of China's topography and is sensitive to climate change. Based on the data of temperature, precipitation, normal difference vegetation index (NDVI), and digital elevation model (DEM) data, we analyzed NDVI change and its relationship with temperature and precipitation along the elevation, slope and slope aspect in the southern slope of Qilian Mountains using tendency analysis method, wavelet analysis and correlation analysis. The results showed that, from 1998 to 2017, NDVI value of the growing season presented increasing trend by a rate of 0.023·10 a-1. Changes of NDVI differed at different elevations, slopes and slope aspects. NDVI increased first and then decreased with elevation. The vegetation coverage at 2700-3700 m was good, and degraded in the area of >4700 m. NDVI reduced with the increases of slope, which showed little difference in different slope aspects but was better in sunny slope than in shade slope. NDVI of the growing season was closely related with temperature and precipitation. NDVI, temperature and precipitation in growing season all had a 14-year cycle. Vegetation at different elevations, slopes and slope aspects was differently affected by temperature and precipitation. Vegetation in areas with altitude <3700 m, >4700 m, slope <25° and each slope direction was more sensitive to precipitation.