MAPK/ERK signaling in gliomas modulates interferon responses, T cell recruitment, microglia phenotype, and immune checkpoint blockade efficacy.

Background: Glioblastoma (GB) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) showing limited efficacy in unselected patients. We previously recently established that MAPK/ERK signaling is associated with overall survival following anti-PD-1 and anti-CTLA-4 treatment in recurrent GB. However, the causal relationship between MAPK/ERK signaling and susceptibility to ICB, as well as the mechanisms underlying this association, remain poorly understood. Method: We conducted in vivo kinome-wide CRISPR/Cas9 screenings in murine gliomas to identify key regulators of susceptibility to anti-PD-1 and CD8+ T cell responses and performed survival studies to validate the most relevant genes. Additionally, paired single cell RNA-sequencing (scRNA-seq) with p-ERK staining, spatial transcriptomics on GB samples, and ex-vivo slice culture of a BRAFV600E mutant GB tumor treated with BRAFi/MEKi were used to determine the causal relationship between MAPK signaling, tumor cell immunogenicity, and modulation of microglia phenotype. Results: CRISPR/Cas9 screens identified the MAPK pathway, particularly the RAF-MEK-ERK pathway, as the most critical modulator of glioma susceptibility to CD8+ T cells, and anti-PD-1 across all kinases. Experimentally-induced ERK phosphorylation in gliomas enhanced survival with ICB treatment, led to durable anti-tumoral immunity upon re-challenge and memory T cell infiltration in long-term survivors. Elevated p-ERK in glioma cells correlated with increased interferon responses, antigen presentation and T cell infiltration in GB. Moreover, spatial transcriptomics and scRNA-seq analysis revealed the modulation of interferon responses by the MAPK/ERK pathway in BRAFV600E human GB cells with ERK1/2 knockout and in slice cultures of human BRAFV600E GB tissue. Notably, BRAFi/MEKi treatment disrupted the interaction between tumor cells and tumor-associated macrophages/microglia in slice cultures from BRAFV600E mutant GB. Conclusion: Our data indicate that the MAPK/ERK pathway is a critical regulator of GB cell susceptibility to anti-tumoral immunity, modulating interferon responses, and antigen-presentation in glioma cells, as well as tumor cell interaction with microglia. These findings not only elucidate the mechanistic underpinnings of immunotherapy resistance in GB but also highlight the MAPK/ERK pathway as a promising target for enhancing immunotherapeutic efficacy in this challenging malignancy.

Inhibiting circ_0000673 blocks the progression of colorectal cancer through downregulating CPSF6 via targeting miR-548b-3p.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers, and its progression is regulated by several factors, including circular RNA (circRNA). OBJECTIVES: The objective of this study was to determine the role, or roles, of circ_0000673 in CRC. MATERIAL AND METHODS: We used quantitative real-time polymerase chain reaction (qPCR) to detect the expression of circ_0000673, miR-548b-3p and cleavage and polyadenylation specific factor 6 (CPSF6) in DLD-1 and RKO cells. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to determine circ_0000673 roles in proliferation. Wound healing and transwell assays were used to detect cell migration and invasion abilities. Expression of CPSF6 protein and stem cell-associated proteins were examined using western blot. The putative relationship between miR-548b-3p and circ_0000673 or CPSF6 was verified with dual-luciferase reporter assay. The role of circ_0000673 in CRC was also investigated in a tumor xenograft assay in nude mice. RESULTS: Circ_0000673 expression was increased in CRC tissues and cancer cells. Silencing circ_0000673 reduced tumor cell proliferation, migration and invasion, while also decreasing cell stemness. MiR-548b-3p was found to be a target of circ_0000673, while CPSF6 was a downstream target of miR-548b-3p. The tumor-regulatory effects of si-circ_0000673, anti-miR-548b-3p and oe-CPSF6 were partially reversed by anti-miR-548b-3p, si-CPSF6 and si-circ_0000673, respectively, in rescue assays. Downregulation of circ_0000673 reduced solid tumor growth in vivo. CONCLUSIONS: Circ_0000673 inhibition reduced CPSF6 expression by targeting miR-548b-3p, thereby blocking proliferation, migration and invasion of CRC tumor cells.

Environmental taxes, energy transition and sustainable environmental technologies: A comparative OECD region climate change analysis.

The integrated economic reforms in recent years have transformed human life, however, the subsequent rise in environmental challenges necessitates sustainable development goals to ensure net-zero transformation. Within the context of modern energy, economic, and environmental transformation, we deliberate how environmental taxes, energy transition, and sustainable environmental innovation impact climate change in 38 OECD economies. Our robust empirical investigation allows us to report that environmental taxation, sustainable environmental technology, and energy transition lower but GDP and trade openness exacerbate ecological challenges. We also divide the dataset in G7 and the rest of the OECD groups to document the varying impact of environmental policies within OECD economies. Our econometric analysis helps us report novel policy frameworks to solve climate challenges under the UN SDG agenda.

A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.

Assessment of the causal relationship between inflammatory bowel diseases and chronic kidney diseases: A two-sample bidirectional mendelian randomization study among European population.

BACKGROUND: Kidney function can be impaired in patients with inflammatory bowel diseases (IBD), including Crohn's diseases (CD) and ulcerative colitis (UC). However, the causal relationship between IBD and chronic kidney diseases (CKD) remains unclear. METHODS: We determined the causal association between IBD and CKD by performing two-sample bidirectional mendelian randomization (MR) analyses. Independent genetic variants were selected as instrumental variables (IVs) of the exposure from open-access genome-wide association studies (GWAS) among European ancestry. IVs-outcome estimates were extracted from three separate GWAS for IBD and two for CKD, respectively. Inverse-variance-weighted model was used as the primary MR method. The pleiotropic effect and heterogeneity were evaluated. For either direction, analyses were performed per outcome database and were subsequently meta-analysed. RESULTS: Genetically predicted IBD was associated with higher risk of CKD (OR: 1.045, 95% CI: 1.016-1.073, P = 0.002) by including 42 344 IBD cases and 229 164 controls. Further analyses showed genetic liability to CD increased the risk of CKD (OR: 1.057, 95% CI: 1.027-1.087, p < 0.001) whereas UC did not (OR: 0.999, 95% CI:0.969-1.031, p = 0.970). In contrast, genetically predicted CKD was not associated with IBD (OR: 1.010, 95% CI: 0.965-1.056, p = 0.676), UC (OR: 1.011, 95% CI: 0.948-1.078, p = 0.746) and CD (OR: 1.024; 95% CI: 0.963-1.089, p = 0.447). CONCLUSIONS: We concluded that CD, but not UC, can increase the risk of CKD causally. CD, but not UC, can increase the risk of chronic kidney disease causally. These findings enhance our understanding of the differential impact of IBD subtypes on CKD. It may be necessary to monitor kidney function regularly in patients with CD.

Predicting oral and esophageal cancers by one model in a Chinese prospective cohort study.

OBJECTIVE: Oral and esophageal cancers are both upper gastrointestinal cancers that share a number of risk factors. However, most previous risk prediction models only focused on one of these two types of cancer. There is no single model that could predict both cancers simultaneously. Our objective was to develop a model specifically tailored for oral and esophageal cancers. METHODS: From 1996 to 2007, a total of 431,460 subjects aged 20 and older without a history of cancer at baseline were included and were monitored for an average duration of 7.3 years in Taiwan, China. A total of 704 cases of oral and esophageal cancers were detected. We utilized both univariate and multivariate COX regression for screening predictors and constructing the model. We evaluated the goodness of fit of the model based on discriminatory accuracy, Harrell's C-index, and calibration. RESULTS: Finally, we developed a Cox regression model using the twelve most significant variables: age, gender, alcohol consumption, betel chewing, smoking status, history of oral ulceration, educational level, marital status, oropharynx status, family history of nasopharyngeal carcinoma, volume ratio of blood cell, and gamma-glutamyl transferase. The AUC (area under the curve) for the complete model was 0.82. Additionally, the C-index was 0.807 (with a 95 % confidence interval ranging from 0.789 to 0.824) and internal calibration results demonstrated that the model performed well. CONCLUSIONS: This study identified the twelve most significant common risk factors for oral and esophageal cancers and developed a single prediction model that performs well for both types of cancer.

Excess Dally-like Induces Malformation of Drosophila Legs.

Glypicans are closely associated with organ development and tumorigenesis in animals. Dally-like (Dlp), a membrane-bound glypican, plays pivotal roles in various biological processes in Drosophila. In this study, we observed that an excess of Dlp led to the malformation of legs, particularly affecting the distal part. Accordingly, the leg disc was shrunken and frequently exhibited aberrant morphology. In addition, elevated Dlp levels induced ectopic cell death with no apparent cell proliferation changes. Furthermore, Dlp overexpression in the posterior compartment significantly altered Wingless (Wg) distribution. We observed a marked expansion of Wg distribution within the posterior compartment, accompanied by a corresponding decrease in the anterior compartment. It appears that excess Dlp guides Wg to diffuse to cells with higher Dlp levels. In addition, the distal-less (dll) gene, which is crucial for leg patterning, was up-regulated significantly. Notably, dachshund (dac) and homothorax (hth) expression, also essential for leg patterning and development, only appeared to be negligibly affected. Based on these findings, we speculate that excess Dlp may contribute to malformations of the distal leg region of Drosophila, possibly through its influence on Wg distribution, dll expression and induced cell death. Our research advances the understanding of Dlp function in Drosophila leg development.

Coaching ribosome biogenesis from the nuclear periphery.

Severe invagination of the nuclear envelope is a hallmark of cancers, aging, neurodegeneration, and infections. However, the outcomes of nuclear invagination remain unclear. This work identified a new function of nuclear invagination: regulating ribosome biogenesis. With expansion microscopy, we observed frequent physical contact between nuclear invaginations and nucleoli. Surprisingly, the higher the invagination curvature, the more ribosomal RNA and pre-ribosomes are made in the contacted nucleolus. By growing cells on nanopillars that generate nuclear invaginations with desired curvatures, we can increase and decrease ribosome biogenesis. Based on this causation, we repressed the ribosome levels in breast cancer and progeria cells by growing cells on low-curvature nanopillars, indicating that overactivated ribosome biogenesis can be rescued by reshaping nuclei. Mechanistically, high-curvature nuclear invaginations reduce heterochromatin and enrich nuclear pore complexes, which promote ribosome biogenesis. We anticipate that our findings will serve as a foundation for further studies on nuclear deformation.

The circadian syndrome is a better predictor for psoriasis than the metabolic syndrome via an explainable machine learning method - the NHANES survey during 2005-2006 and 2009-2014.

Objective: To explore the association between circadian syndrome (CircS) and Metabolic Syndrome (MetS) with psoriasis. Compare the performance of MetS and CircS in predicting psoriasis. Methods: An observational study used data from the NHANES surveys conducted in 2005-2006 and 2009-2014. We constructed three multiple logistic regression models to investigate the relationship between MetS, CircS, and their components with psoriasis. The performance of MetS and CircS in predicting psoriasis was compared using five machine-learning algorithms, and the best-performing model was explained via SHAP. Then, bidirectional Mendelian randomization analyses with the inverse variance weighted (IVW) as the primary method were employed to determine the causal effects of each component. Result: A total of 9,531 participants were eligible for the study. Both the MetS (OR = 1.53, 95%CI: 1.07-2.17, P = 0.02) and CircS (OR = 1.40, 95%CI: 1.02-1.91, P = 0.039) positively correlated with psoriasis. Each CircS algorithmic model performs better than MetS, with Categorical Features+Gradient Boosting for CircS (the area under the precision-recall curve = 0.969) having the best prediction effect on psoriasis. Among the components of CircS, elevated blood pressure, depression symptoms, elevated waist circumference (WC), and short sleep contributed more to predicting psoriasis. Under the IVW methods, there were significant causal relationships between WC (OR = 1.52, 95%CI: 1.34-1.73, P = 1.35e-10), hypertension (OR = 1.68, 95%CI: 1.19-2.37, P = 0.003), depression symptoms (OR = 1.39, 95%CI: 1.17-1.65, P = 1.51e-4), and short sleep (OR = 2.03, 95%CI: 1.21-3.39, p = 0.007) with psoriasis risk. Conclusion: CircS demonstrated superior predictive ability for prevalent psoriasis compared to MetS, with elevated blood pressure, depression symptoms, and elevated WC contributing more to the prediction.

Somatostatin signalling coordinates energy metabolism allocation to reproduction in zebrafish.

BACKGROUND: Energy allocation between growth and reproduction determines puberty onset and fertility. In mammals, peripheral hormones such as leptin, insulin and ghrelin signal metabolic information to the higher centres controlling gonadotrophin-releasing hormone neurone activity. However, these observations could not be confirmed in lower vertebrates, suggesting that other factors may mediate the energetic trade-off between growth and reproduction. A bioinformatic and experimental study suggested co-regulation of the circadian clock, reproductive axis and growth-regulating genes in zebrafish. While loss-of-function of most of the identified co-regulated genes had no effect or only had mild effects on reproduction, no such information existed about the co-regulated somatostatin, well-known for its actions on growth and metabolism. RESULTS: We show that somatostatin signalling is pivotal in regulating fecundity and metabolism. Knock-out of zebrafish somatostatin 1.1 (sst1.1) and somatostatin 1.2 (sst1.2) caused a 20-30% increase in embryonic primordial germ cells, and sst1.2-/- adults laid 40% more eggs than their wild-type siblings. The sst1.1-/- and sst1.2-/- mutants had divergent metabolic phenotypes: the former had 25% more pancreatic α-cells, were hyperglycaemic and glucose intolerant, and had increased adipocyte mass; the latter had 25% more pancreatic ß-cells, improved glucose clearance and reduced adipocyte mass. CONCLUSIONS: We conclude that somatostatin signalling regulates energy metabolism and fecundity through anti-proliferative and modulatory actions on primordial germ cells, pancreatic insulin and glucagon cells and the hypothalamus. The ancient origin of the somatostatin system suggests it could act as a switch linking metabolism and reproduction across vertebrates. The results raise the possibility of applications in human and animal fertility.

[Multi Scenario Carbon Peak Prediction and Emission Reduction Path Analysis of Xi'an Hi-tech Zone].

The fifth session of the 13th National People's Congress proposed to be committed to promoting carbon peaking and carbon neutrality, promoting the comprehensive green and low-carbon transformation of the economy and society and achieving high-quality development. As an important scientific and technological innovation and industrial cluster in Shaanxi Province, the economic development of the Xi'an Hi-tech Zone largely relies on energy consumption, making the task of carbon reduction particularly challenging. Firstly, taking the Xi'an Hi-tech Zone as the research object, through systematic accounting of carbon emissions within the park, we analyzed the current carbon emission status of enterprises in different energy types and industries. Then, using the Kaya model, multiple independent carbon peak scenarios were set up to predict the total carbon emissions and peak time under different scenarios. Finally, based on the development characteristics of the Xi'an Hi-tech Zone, we scientifically selected corresponding carbon emission reduction paths and provided reasonable emission reduction suggestions. The results showed that the proportion of carbon emissions consumed by electricity was currently the highest, and the share was increasing yearly. Industrial carbon emissions had always been dominant, and the development of the tertiary industry was becoming increasingly prosperous. In the scenario prediction, the carbon emission factor scenario, energy intensity scenario, and economic level scenario could reach the carbon peak by 2030. Among them, the economic development level had the greatest impact on the peak and time of the future carbon peak in the Xi'an Hi-tech Zone, whereas the industrial structure scenario, energy source structure scenario, and population size scenario had no peak before 2030. The future emission reduction path mainly started from decarbonization of the power sector, stable and high-quality economic development, green upgrading of energy and industrial structure, and building a green transportation system. This can reserve more preparation time for achieving carbon neutrality and provide decision-making reference for the low-carbon development of industrial parks in China.

Intra-Inter Graph Representation Learning for Protein-Protein Binding Sites Prediction.

Graph neural networks have drawn increasing attention and achieved remarkable progress recently due to their potential applications for a large amount of irregular data. It is a natural way to represent protein as a graph. In this work, we focus on protein-protein binding sites prediction between the ligand and receptor proteins. Previous work just simply adopts graph convolution to learn residue representations of ligand and receptor proteins, then concatenates them and feeds the concatenated representation into a fully connected layer to make predictions, losing much of the information contained in complexes and failing to obtain an optimal prediction. In this paper, we present Intra-Inter Graph Representation Learning for protein-protein binding sites prediction (IIGRL). Specifically, for intra-graph learning, we maximize the mutual information between local node representation and global graph summary to encourage node representation to embody the global information of protein graph. Then we explore fusing two separate ligand and receptor graphs as a whole graph and learning affinities between their residues/nodes to propagate information to each other, which could effectively capture inter-protein information and further enhance the discrimination of residue pairs. Extensive experiments on multiple benchmarks demonstrate that the proposed IIGRL model outperforms state-of-the-art methods.

Tomato Pectin Ameliorated Hepatic Steatosis in High-Fat-Diet Mice by Modulating Gut Microbiota and Bile Acid Metabolism.

Nonalcoholic fatty liver disease (NAFLD) is a worldwide public health issue. Changes in the gut microbiota structure and composition are closely related to host pathophysiology processes. Pectin is associated with several beneficial health effects. In the present study, we aimed at investigating the effect of tomato pectin (TP) on hepatic steatosis and exploring the underlying mechanisms by focusing on the regulation of the gut microbiota-bile acid axis. Our results showed that TP attenuated high-fat diet (HFD)-induced liver steatosis and inflammation. TP administration increased the diversity of gut microbiota, enhancing the abundance of beneficial bacteria and suppressing the abundance of harmful or conditional pathogenic bacteria. Further antibiotic-caused microbiome depletion confirmed that the anti-NAFLD activities of TP were dependent on the regulation of gut microbiota. Besides, TP intervention affected feces bile acid metabolism and caused significant changes in functional conjugated bile acids, which in turn inhibited the ileum FXR/FGF15 signaling, leading to stimulation of the hepatic bile acid (BA) production. Furthermore, TP treatment accelerated BA excretion, promoted BA transportation, inhibited BA reabsorption, and facilitated cholesterol efflux to relieve HFD-induced hyperlipidemia. These findings provide a potential dietary intervention strategy for TP against NAFLD via modulation of cross-talk between BAs and gut bacteria.

Effects of neonicotinoid residues on non-target soil animals: A case study of meta-analysis.

Neonicotinoids (NEOs) are currently the fastest-growing and most widely used insecticide class worldwide. Increasing evidence suggests that long-term NEO residues in the environment have toxic effects on non-target soil animals. However, few studies have conducted surveys on the effects of NEOs on soil animals, and only few have focused on global systematic reviews or meta-analysis to quantify the effects of NEOs on soil animals. Here, we present a meta-analysis of 2940 observations from 113 field and laboratory studies that investigated the effects of NEOs (at concentrations of 0.001-78,600.000 mg/kg) on different soil animals across five indicators (i.e., survival, growth, behavior, reproduction, and biochemical biomarkers). Furthermore, we quantify the effects of NEOs on different species of soil animals. Results show that NEOs inhibit the survival, growth rate, behavior, and reproduction of soil animals, and alter biochemical biomarkers. Both the survival rate and longevity of individuals decreased by 100 % with NEO residues. The mean values of juvenile survival, cocoon number, and egg hatchability were reduced by 97 %, 100 %, and 84 %, respectively. Both individual and cocoon weights were reduced by 82 %, while the growth rate decreased by 88 % with NEO residues. Our meta-analysis confirms that NEOs pose significant negative impacts on soil animals.

Outcomes in pediatric extracorporeal cardiopulmonary resuscitation: A single-center retrospective study from 2007 to 2022 in China.

OBJECTIVE: We aimed to investigate the prognostic factors of pediatric extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: The retrospective study included a total of 77 pediatric cases (7 neonates and 70 children) who underwent ECPR after in-hospital and out-of-hospital cardiac arrest between July 2007 and December 2022. Primary endpoints were complications, while secondary endpoints included all-cause in-hospital mortality. RESULTS: Among the 45 cases experiencing complications, 4 neonates and 41 children had multiple simultaneous complications, primarily neurological issues in 25 cases. Additionally, organ failure occurred in 11 cases, and immunodeficiency was present in two cases. Furthermore, 9 cases experienced bleeding events, and 13 cases showed thrombosis. Patients with complications had lower weight, shorter ECMO durations, and longer CPR durations. Non-survivors had longer CPR durations and shorter durations of ECMO, ICU stay, and mechanical ventilation compared to survivors. Complications were more prevalent in non-survivors, particularly organ failure and bleeding events. CONCLUSION: Weight, CPR duration, and ECMO duration were associated with complications, suggesting areas for treatment optimization. The higher occurrence of complications in non-survivors underscores the importance of early detection and management to improve survival rates. Our findings suggest clinicians consider these factors in prognostic assessments to enhance the effectiveness of ECPR programs.

Black Ultrathin Single-Crystalline Flakes of CuVP2S6 and CuCrP2S6 for Near-Infrared-Driven Photocatalytic Hydrogen Evolution.

The development of new near-infrared-responsive photocatalysts is a fascinating and challenging approach to acquire high photocatalytic hydrogen evolution (PHE) performance. Herein, near-infrared-responsive black CuVP2S6 and CuCrP2S6 flakes, as well as CuInP2S6 flakes, are designed and constructed for PHE. Atom-resolved scanning transmission electron microscopy images and X-ray absorption fine structure evidence the formation of ultrathin single-crystalline sheet-like structure of CuVP2S6 and CuCrP2S6. The synthetic CuVP2S6 and CuCrP2S6, with a narrow bandgap of ≈1.0 eV, shows the high light-absorption edge exceeding 1100 nm. Moreover, through the femtosecond-resolved transient absorption spectroscopy, CuCrP2S6 displays the efficient charge transfer and long charge lifetime (18318.1 ps), which is nearly 3 and 29 times longer than that of CuVP2S6 and CuInP2S6, respectively. In addition, CuCrP2S6, with the appropriate d-band and p-band, is thermodynamically favorable for the H+ adsorption and H2 desorption by contrast with CuVP2S6 and CuInP2S6. As a result, CuCrP2S6 exhibits high PHE rates of 9.12 and 0.66 mmol h-1 g-1 under simulated sunlight and near-infrared light irradiation, respectively, far exceeding other layered metal phospho-sulfides. This work offers a distinctive perspective for the development of new near-infrared-responsive photocatalysts.

Foxo1 is an iron-responsive transcriptional factor regulating systemic iron homeostasis.

ABSTRACT: The liver plays a crucial role in maintaining systemic iron homeostasis by secreting hepcidin, which is essential for coordinating iron levels in the body. Imbalances in iron homeostasis are associated with various clinical disorders related to iron deficiency or iron overload. Despite the clinical significance, the mechanisms underlying how hepatocytes sense extracellular iron levels to regulate hepcidin synthesis and iron storage are not fully understood. In this study, we identified Foxo1, a well-known regulator of macronutrient metabolism, which translocates to the nucleus of hepatocytes in response to high-iron feeding, holo-transferrin, and bone morphogenetic protein 6 (BMP6) treatment. Furthermore, Foxo1 plays a crucial role in mediating hepcidin induction in response to both iron and BMP signals by directly interacting with evolutionally conserved Foxo binding sites within the hepcidin promoter region. These binding sites were found to colocalize with Smad-binding sites. To investigate the physiological relevance of Foxo1 in iron metabolism, we generated mice with hepatocyte-specific deletion of Foxo1. These mice exhibited reduced hepatic hepcidin expression and serum hepcidin levels, accompanied by elevated serum iron and liver nonheme iron concentrations. Moreover, high-iron diet further exacerbated these abnormalities in iron metabolism in mice lacking hepatic Foxo1. Conversely, hepatocyte-specific Foxo1 overexpression increased hepatic hepcidin expression and serum hepcidin levels, thereby ameliorating iron overload in a murine model of hereditary hemochromatosis (Hfe-/- mice). In summary, our study identifies Foxo1 as a critical regulator of hepcidin and systemic iron homeostasis. Targeting Foxo1 may offer therapeutic opportunities for managing conditions associated with aberrant iron metabolism.

Peripheral Soluble Immune Checkpoint-Related Proteins Were Associated with Survival and Treatment Efficacy of Osteosarcoma Patients, a Cohort Study.

BACKGROUND: The immune checkpoint blockade remains obscure in osteosarcoma (OS). We aim to explore the clinical significance of soluble immune checkpoint (ICK)-related proteins in OS. METHODS: We profiled 14 soluble ICK-related proteins (BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, CD28, CD80, CD137, CD27, and CTLA-4) in the plasma of 76 OS patients and matched controls. We evaluated the associations between the biomarkers and the risk of OS using unconditional multivariate logistic regression. The multivariate Cox model was utilized to develop the prediction model of OS. Immune subtypes were established from the identified biomarkers. Transcriptional data from GEO were analyzed to elucidate potential mechanisms. RESULTS: We found that sTIM3, sCD137, sIDO, and sCTLA4 were significantly correlated with OS risk (all p < 0.05). sBTLA, sPDL2, and sCD27 were significantly associated with the risk of lung metastasis, whereas sBTLA and sTIM3 were associated with the risk of disease progression. We also established an immune subtype based on sBTLA, sPD1, sTIM3, and sPDL2. Patients in the sICK-type2 subtype had significantly decreased progression-free survival (PFS) and lung metastasis-free survival (LMFS) than those in the sICK-type1 subtype (log-rank p = 2.8 × 10-2, 1.7 × 10-2, respectively). Interestingly, we found that the trend of LMFS and PFS in the subtypes of corresponding ICK genes' expression was opposite to the results in the blood (log-rank p = 2.6 × 10-4, 9.5 × 10-4, respectively). CONCLUSION: Four soluble ICK-related proteins were associated with the survival of OS patients. Soluble ICK-related proteins could be promising biomarkers for the outcomes and immunotherapy of OS patients, though more research is warranted.

Transcriptome analysis integrated with changes in cell wall polysaccharides of different fresh-cut chili pepper cultivars during storage reveals the softening mechanism.

Cell wall disassembly and transcriptomic changes during storage of two fresh-cut chili pepper cultivars displaying contrasting softening rates were investigated. Results showed that Hangjiao No. 2 (HJ-2) softened more rapidly than Lafeng No. 3 (LF-3). Compared with LF-3, HJ-2 had a higher content of WSP, more side chains of RG-I in three pectin fractions, and higher activities of PME, PL, and ß-Gal at day-0. During storage, HJ-2 showed more markable pectin solubilization, more severe degradation in CSP and NSP, and greater loss of side chains from RG-I in three pectin fractions, which were correlated with increased activities of PG and α-L-Af. Furthermore, the higher up-regulation of PG (LOC107870605, LOC107851416) and α-L-Af (LOC107848776, LOC107856612) were screened in HJ-2. In conclusion, the different softening rate between cultivars was not only due to the fundamental differences in pectin structure but also pectin degradation regulated by related enzymes and gene expression levels.