Machine learning prediction of stalk lignin content using Fourier transform infrared spectroscopy in large scale maize germplasm.

Lignin has been recognized as a major factor contributing to lignocellulosic recalcitrance in biofuel production and attracted attentions as a high-value product in the biorefinery field. As the traditional wet chemical methods for detecting lignin content are labor-intensive, time-consuming and environment-toxic, it is an urgent need to develop high-throughput and environment-friendly techniques for large-scale crop germplasms screening. In this study, we conducted a Fourier transform infrared (FTIR) assay on 150 maize germplasms with a diverse lignin composition to build predictive models for lignin content in maize stalk. Principal component analysis (PCA) was applied to the FTIR spectra for use as model inputs. Classification and advanced gradient boosting machine (GBM) algorithms demonstrated higher predictive accuracy (0.82-0.96) compared to traditional linear and regularization algorithms (0.03-0.04) in the training set. Notably, two optimal models, built using the extreme gradient boosting (XGBoost) and light gradient boosting machine (LightGBM) algorithms, achieved R2 values of over 0.91 in the training set and over 0.82 in the test set. Overall, the combination of FTIR and machine learning (ML) algorithms offers a high-throughput and efficient method for predicting lignin content. This approach holds significant potential for genetic breeding and the effective utilization of maize in industrial production.

High-throughput prediction of stalk cellulose and hemicellulose content in maize using machine learning and Fourier transform infrared spectroscopy.

Cellulose and hemicellulose are key cross-linked carbohydrates affecting bioethanol production in maize stalks. Traditional wet chemical methods for their detection are labor-intensive, highlighting the need for high-throughput techniques. This study used Fourier transform infrared (FTIR) spectroscopy combined with machine learning (ML) algorithms on 200 large-scale maize germplasms to develop robust predictive models for stalk cellulose, hemicellulose and holocellulose content. We identified several peak height features correlated with three contents, used them as input data for model building. Four ML algorithms demonstrated higher predictive accuracy, achieving coefficient of determination (R2) ranging from 0.83 to 0.97. Notably, the Categorical Boosting algorithm yielded optimal models with coefficient of determination (R2) exceeding 0.91 for the training set and over 0.81 for the test set. The approach combined FTIR spectroscopy with ML algorithms offers a precise and high-throughput tool for predicting stalk cellulose, hemicellulose and holocellulose contents, benefiting maize genetic breeding for bioenergy and biofuels.

Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is addicted to glutaminolysis. Targeting this metabolic dependency has emerged as a potential therapeutic approach for HNSCC. In this study, we conducted a bioinformatic analysis of The Cancer Genome Atlas HNSCC cohort that revealed a robust correlation between expression of MYC (encoding the protein c-Myc) and glutaminase 1 (GLS1), which catalyzes the first step in glutaminolysis. Intriguingly, disruption of GLS1 signaling in HNSCC cells by genetic depletion or CB-839 treatment resulted in a reduction in c-Myc protein stability via a ubiquitin-specific peptidase 1-dependent ubiquitin-proteasome pathway. On the other hand, c-Myc directly binds to the promoter region of GLS1 and upregulates its transcription. Notably, the GLS1-c-Myc pathway enhanced acetyl-coenzyme A carboxylase-dependent Slug acetylation, prompting cancer cell invasion and metastasis. Thus, the GLS1-c-Myc axis emerged as a positive feedback loop critical for driving the aggressiveness of HNSCC. Therapeutically, combining CB-839 with the c-Myc inhibitor MYCi975 strongly suppressed GLS1-c-Myc signaling, resulting in a superior antitumor effect compared with either single agent in an orthotopic mouse model of HNSCC. These findings hold promise for the development of effective therapies for patients with HNSCC, addressing an urgent need arising from the significant incidence and high metastatic rate of the disease. Significance: GLS1 and c-Myc form a positive feedback loop that promotes head and neck cancer metastasis and can be targeted as a promising therapeutic strategy for this disease.

Exploring the impact of GSTM1 as a novel molecular determinant of survival in head and neck cancer patients of African descent.

BACKGROUND: Blacks/African American (BAA) patients diagnosed with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes than White patients. However, the mechanisms underlying racial disparities in HNSCC have not been thoroughly characterized. METHODS: Data on gene expression, copy number variants (CNVs), gene mutations, and methylation were obtained from 6 head and neck cancer datasets. Comparative bioinformatics analysis of the above genomic features was performed between BAAs and Whites. The expression pattern of GSTM1 was validated by immunohistochemistry using tumor tissue microarray (TMA). Effect of GSTM1 knockdown were assessed by cell proliferation, colony formation, and tumor development in an orthotopic mouse model. The changes in protein kinases were determined using the Proteome Profiler Human Phospho-Kinase Array Kit in HNSCC cells with or without GSTM1 knockdown. RESULTS: We identified ancestry-related differential genomic profiles in HNSCC. Specifically, in BAA HNSCC, FAT1 mutations were associated with its gene expression, SALL3 gene expression correlated with its gene CNVs, and RTP4 gene expression showed an inverse correlation with its methylation. Notably, GSTM1 emerged as a prognostic risk factor for BAA HNSCC, with high gene CNVs and expression levels correlating with poor overall survival in BAA patients. Immunohistochemistry results from newly developed in-house TMA validated the expression pattern of GSTM1 between BAA HNSCC and White HNSCC. In an orthotopic mouse model, GSTM1 knockdown significantly inhibited malignant progression in tumors derived from BAAs. In contrast, loss of GSTM1 did not affect the development of HNSCC originating in Whites. Mechanistically, GSTM1 knockdown suppressed HSP27 phosphorylation and ß-catenin in BAA HNSCC cells, but not in White HNSCC cells. This differential effect at least partially contributes to tumor development in BAA patients. CONCLUSION: This study identifies GSTM1 as a novel molecular determinant of survival in HNSCC patients of African descent. It also provides a molecular basis for future research focused on identifying molecular determinants and developing therapeutic interventions to improve outcomes for BAA patients with HNSCC.

Changing the order and ratio of substrate filling reduced CH4 and N2O emissions from the aerated constructed wetlands.

Constructed wetlands (CWs) have been used to enhance pollutant removal by filling several types of material as substrates. However, research on substrate filling order remains still limited, particularly regarding the effects of greenhouse gas (GHG) emissions. In this study, six CWs were constructed using zeolite and ferric­carbon micro-electrolysis (Fe-C) fillers to evaluate the effect of changing the filling order and ratio on pollutant removal, GHGs emissions, and associated microbial structure. The results showed that the order of substrate filling significantly impacted pollutant removal performance on CWs. Specifically, CWs filled with zeolite in the top layer exhibited superior NH4+-N removal compared to those filled in the lower layer. Moreover, the highest NH4+-N removal (95.0 % ± 1.9 %) was observed in CWs with a zeolite to Fe-C volume ratio of 8:2 (CWZe-1). Moreover, zeolite-filled at the top had lower GHGs emissions, with the lowest CH4 (0.22 ± 0.10 mg m-2 h-1) and N2O (167.03 ± 61.40 µg m-2 h-1) fluxes in the CWZe-1. In addition, it is worth noting that N2O is the major contributor to integrated global warming potential (GWP) in the six CWs, accounting for 81.7 %-90.8 %. The upper layer of CWs filled with zeolite exhibited higher abundances of nirK, nirS and nosZ genes. The order in which the substrate was filled affected the microbial community structure and the upper layer of CWs filled with zeolite had higher relative abundance of nitrifying genera (Nitrobacter, Nitrosomonas) and denitrifying genera (Zoogloea, Denitratisoma). Additionally, N2O emission was reduced by approximately 41.2 %-64.4 % when the location of the aeration of the CWs was changed from the bottom to the middle. This study showed that both the order of filling the substrate and the aeration position significantly affected the GHGs emissions from CWs, and that CWs had lower GHGs emissions when zeolites were filled in the upper layer and the aeration position was in the middle.

The protective effect of natural medicines in rheumatoid arthritis via inhibit angiogenesis.

Rheumatoid arthritis is a chronic immunological disease leading to the progressive bone and joint destruction. Angiogenesis, accompanied by synovial hyperplasia and inflammation underlies joint destruction. Delaying or even blocking synovial angiogenesis has emerged as an important target of RA treatment. Natural medicines has a long history of treating RA, and numerous reports have suggested that natural medicines have a strong inhibitory activity on synovial angiogenesis, thereby improving the progression of RA. Natural medicines could regulate the following signaling pathways: HIF/VEGF/ANG, PI3K/Akt pathway, MAPKs pathway, NF-κB pathway, PPARγ pathway, JAK2/STAT3 pathway, etc., thereby inhibiting angiogenesis. Tripterygium wilfordii Hook. f. (TwHF), sinomenine, and total glucoside of Paeonia lactiflora Pall. Are currently the most representative of all natural products worthy of development and utilization. In this paper, the main factors affecting angiogenesis were discussed and different types of natural medicines that inhibit angiogenesis were systematically summarized. Their specific anti-angiogenesis mechanisms are also reviewed which aiming to provide new perspective and options for the management of RA by targeting angiogenesis.

Evaluation of pharmacist-led medication reconciliation at county hospitals in China: A multicentre, open-label, assessor-blinded, nonrandomised controlled study.

Background: Due to a lack of related research, we aimed to determine the effectiveness of a pharmacist-led medication reconciliation intervention in China. Methods: We conducted a multicentre, prospective, open-label, assessor-blinded, cluster, nonrandomised controlled study at six county-level hospitals, with hospital wards serving as the clusters. We included patients discharged from the sampled hospitals who were aged ≥60 years; had ≥1 studied diagnoses; and were prescribed with ≥3 medications at discharge. Patients in the intervention group received a pharmacist-led medication reconciliation intervention and those in the control group received standard care. We assessed the incidence of medication discrepancies at discharge, patients' medication adherence, and health care utilisation within 30 days after discharge. Results: There were 429 patients in the intervention group (mean age = 72.5 years, standard deviation (SD) = 7.0) and 526 patients in the control group (mean age = 73.6 years, SD = 7.1). Of the 1632 medication discrepancies identified at discharge, fewer occurred in the intervention group (1.9 per patient on average) than the control group (2.6 per patient on average).The intervention significantly reduced the incidence of medication discrepancy by 9.6% (95% confidence interval (CI) = -15.6, -3.6, P = 0.002) and improved patients' medication adherence, with an absolute decrease in the mean adherence score of 2.5 (95% CI = -2.8, -2.2, P < 0.001). There was no significant difference in readmission rates between the intervention and control groups. Conclusions: Pharmacist-led medication reconciliation at discharge from Chinese county-level hospitals reduced medication discrepancies and improved patients' adherence among patients aged 60 years or above, though no impact on readmission after discharge was observed. Registration: ChiCTR2100045668.

Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer.

BACKGROUND: While T cell-activating immunotherapies against recurrent head and neck squamous cell carcinoma (HNSCC) have shown impressive results in clinical trials, they are often ineffective in the majority of patients. NK cells are potential targets for immunotherapeutic intervention; however, the setback in monalizumab-based therapy in HNSCC highlights the need for an alternative treatment to enhance their antitumor activity. METHODS: Single-cell RNA sequencing (scRNA-seq) and TCGA HNSCC datasets were used to identify key molecular alterations in NK cells. Representative HPV-positive ( +) and HPV-negative ( -) HNSCC cell lines and orthotopic mouse models were used to validate the bioinformatic findings. Changes in immune cells were examined by flow cytometry and immunofluorescence. RESULTS: Through integration of scRNA-seq data with TCGA data, we found that the impact of IL6/IL6R and CCL2/CCR2 signaling pathways on evasion of immune attack by NK cells is more pronounced in the HPV - HNSCC cohort compared to the HPV + HNSCC cohort. In orthotopic mouse models, blocking IL6 with a neutralizing antibody suppressed HPV - but not HPV + tumors, which was accompanied by increased tumor infiltration and proliferation of CD161+ NK cells. Notably, combining the CCR2 chemokine receptor antagonist RS504393 with IL6 blockade resulted in a more pronounced antitumor effect that was associated with more activated intratumoral NK cells in HPV - HNSCC compared to either agent alone. CONCLUSIONS: These findings demonstrate that dual blockade of IL6 and CCR2 pathways effectively enhances the antitumor activity of NK cells in HPV-negative HNSCC, providing a novel strategy for treating this type of cancer.

HSP90 inhibition suppresses tumor glycolytic flux to potentiate the therapeutic efficacy of radiotherapy for head and neck cancer.

Glycolytic metabolism may account for antitumor immunity failure. Pyruvate kinase M2 (PKM2) and platelet phosphofructokinase (PFKP), two key enzymes involved in the glycolytic pathway, are hyperactivated in head and neck squamous cell carcinoma (HNSCC). Using ganetespib as a drug model for heat shock protein 90 (HSP90) inhibition and combining results from clinical trials and animal treatment, we demonstrated that HSP90 inhibition leads to a blockade of glycolytic flux in HNSCC cells by simultaneously suppressing PKM2 and PFKP at both the transcriptional and posttranslational levels. Down-regulation of tumor glycolysis facilitates tumor infiltration of cytotoxic T cells via suppression of glycolysis-dependent interleukin-8 signaling. The addition of ganetespib to radiation attenuates radiation-induced up-regulation of PKM2 and PFKP and potentiates T cell-mediated antitumor immunity, resulting in a more potent antitumor effect than either treatment alone, providing a molecular basis for exploring the combination of HSP90 inhibitors with radiotherapy to improve outcomes for patients with HNSCC.

Modulation of Dendritic Cell Function via Nanoparticle-Induced Cytosolic Calcium Changes.

Calcium nanoparticles have been investigated for applications, such as drug and gene delivery. Additionally, Ca2+ serves as a crucial second messenger in the activation of immune cells. However, few studies have systematically studied the effects of calcium nanoparticles on the calcium levels and functions within immune cells. In this study, we explore the potential of calcium nanoparticles as a vehicle to deliver calcium into the cytosol of dendritic cells (DCs) and influence their functions. We synthesized calcium hydroxide nanoparticles, coated them with a layer of silica to prevent rapid degradation, and further conjugated them with anti-CD205 antibodies to achieve targeted delivery to DCs. Our results indicate that these nanoparticles can efficiently enter DCs and release calcium ions in a controlled manner. This elevation in cytosolic calcium activates both the NFAT and NF-κB pathways, in turn promoting the expression of costimulatory molecules, antigen-presenting molecules, and pro-inflammatory cytokines. In mouse tumor models, the calcium nanoparticles enhanced the antitumor immune response and augmented the efficacy of both radiotherapy and chemotherapy without introducing additional toxicity. Our study introduces a safe nanoparticle immunomodulator with potential widespread applications in cancer therapy.

Biochemical and protein nutritional potential of mulberry (Morus alba L.) leaf: partial substitution improves the nutrition of conventional protein.

BACKGROUND: With the requirements of environmental, cost and economic sustainability, new sources of alternative proteins in the livestock industry are receiving increasing attention. Mulberry (Morus alba L.) leaves are a unique feed resource because of their high protein content and large availability. Therefore, mining sustainable protein suitable for the animal husbandry industry in sericulture resources could achieve a win-win situation. RESULTS: The protein content in mulberry leaves is 232.10-386.16 g kg-1 , and the mean value of crude fat content is 43.76 ± 8.48 g kg-1 , which has the advantages of protein content and energy. In addition, the average content of phytic acid in mulberry leaves is only 1.88 ± 0.56 g kg-1 , which means that it is not inhibited in terms of nutrient absorption. Meanwhile, the digestibility of protein was Bean pulp > Sample 8 ≈ Alfalfa ≈ Sample 13 ≈ Cottonseed meal > Fish meal, and the ß-turn and particle size of mulberry leaf protein are more conducive to digestion in vitro. Furthermore, the protein of Sample 13 had the richest essential amino acids (252.00 g kg-1 ) and the highest essential amino acid index (EAAI), which was superior to conventional feed protein. In addition, the partial substitution of mulberry leaf protein (15%) significantly increased the EAAI value of conventional feed protein. However, to balance nutrition, it is necessary to combine mulberry leaf protein with other proteins to further broaden its application field. CONCLUSION: Mulberry leaves are a new source of feed protein, which helps to alleviate the two major problems of mulberry resource surplus and feed protein resource shortage. © 2023 Society of Chemical Industry.

Occurrence and transport of novel and legacy poly- and perfluoroalkyl substances in coastal rivers along the Laizhou Bay, northern China.

The pollution profiles of 25 legacy and emerging poly- and perfluoroalkyl substances (PFASs) in the estuaries along the Laizhou Bay, northern China were investigated to better understand the new structure of PFASs under international regulations and to estimate the mass loadings of PFASs in coastal rivers. About 39.87 kg/d of PFASs were discharged into the Laizhou Bay by the Xiaoqing, Mi and Zhimai Rivers. Total PFAS concentrations in the Xiaoqing River decreased notably in recent years, but were still greater than the levels in 2011. Contribution of replacement substances exhibited an increasing trend in recent years. However, the long-chain chemicals were still the larger contributors of PFASs. Perfluoromethoxypropionic acid (PFMPA) was first detected with high concentrations ranging from 165.3 to 586.3 ng/L in the Xiaoqing River. The results of this study provided baseline data for ecological risk assessment, environmental management and corresponding development of pollution treatment technology.

Application of alkali-heated corncobs enhanced nitrogen removal and microbial diversity in constructed wetlands for treating low C/N ratio wastewater.

Lack of carbon source is the main limiting factor in the denitrification of low C/N ratio wastewater in the constructed wetlands (CWs). Agricultural waste has been considered as a supplementary carbon source but research is still limited. To solve this problem, ferric carbon (Fe-C) + zeolite, Fe-C + gravel, and gravel were used as substrates to build CWs in this experiment, aiming to investigate the effects of different carbon sources (rice straw, corncobs, alkali-heated corncobs) on nitrogen removal performance and microbial community structure in CWs for low C/N wastewater. The results demonstrated that the microbial community and effluent nitrogen concentration of CWs were mainly influenced by the carbon source rather than the substrate. Alkali-heated corncobs significantly enhanced the removal of NO2--N, NH4+-N, NO3-N, and TN. Carbon sources addition increased microbial diversity. Alkali-heated corncobs addition significantly increased the abundance of heterotrophic denitrifying bacteria (Proteobacteria and Bacteroidota). Furthermore, alkali-heated corncobs addition increased the copy number of nirS, nosZ, and nirK genes while greenhouse gas fluxes were lower than common corncobs. In summary, alkali-heated corncobs can be considered as an effective carbon source.

The Transcription Factor CsgD Contributes to Engineered Escherichia coli Resistance by Regulating Biofilm Formation and Stress Responses.

The high cell density, immobilization and stability of biofilms are ideal characteristics for bacteria in resisting antibiotic therapy. CsgD is a transcription activating factor that regulates the synthesis of curly fimbriae and cellulose in Escherichia coli, thereby enhancing bacterial adhesion and promoting biofilm formation. To investigate the role of CsgD in biofilm formation and stress resistance in bacteria, the csgD deletion mutant ΔcsgD was successfully constructed from the engineered strain E. coli BL21(DE3) using the CRISPR/Cas9 gene-editing system. The results demonstrated that the biofilm of ΔcsgD decreased by 70.07% (p < 0.05). Additionally, the mobility and adhesion of ΔcsgD were inhibited due to the decrease in curly fimbriae and extracellular polymeric substances. Furthermore, ΔcsgD exhibited a significantly decreased resistance to acid, alkali and osmotic stress conditions (p < 0.05). RNA-Seq results revealed 491 differentially expressed genes between the parent strain and ΔcsgD, with enrichment primarily observed in metabolism-related processes as well as cell membrane structure and catalytic activity categories. Moreover, CsgD influenced the expression of biofilm and stress response genes pgaA, motB, fimA, fimC, iraP, ompA, osmC, sufE and elaB, indicating that the CsgD participated in the resistance of E. coli by regulating the expression of biofilm and stress response. In brief, the transcription factor CsgD plays a key role in the stress resistance of E. coli, and is a potential target for treating and controlling biofilm.

Mechanistic insight into lysyl oxidase in vascular remodeling and angiogenesis.

Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. Lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.

Construction and validation of prognostic models in critically Ill patients with sepsis-associated acute kidney injury: interpretable machine learning approach.

BACKGROUND: Acute kidney injury (AKI) is a common complication in critically ill patients with sepsis and is often associated with a poor prognosis. We aimed to construct and validate an interpretable prognostic prediction model for patients with sepsis-associated AKI (S-AKI) using machine learning (ML) methods. METHODS: Data on the training cohort were collected from the Medical Information Mart for Intensive Care IV database version 2.2 to build the model, and data of patients were extracted from Hangzhou First People's Hospital Affiliated to Zhejiang University School of Medicine for external validation of model. Predictors of mortality were identified using Recursive Feature Elimination (RFE). Then, random forest, extreme gradient boosting (XGBoost), multilayer perceptron classifier, support vector classifier, and logistic regression were used to establish a prognosis prediction model for 7, 14, and 28 days after intensive care unit (ICU) admission, respectively. Prediction performance was assessed using the receiver operating characteristic (ROC) curve and decision curve analysis (DCA). SHapley Additive exPlanations (SHAP) were used to interpret the ML models. RESULTS: In total, 2599 patients with S-AKI were included in the analysis. Forty variables were selected for the model development. According to the areas under the ROC curve (AUC) and DCA results for the training cohort, XGBoost model exhibited excellent performance with F1 Score of 0.847, 0.715, 0.765 and AUC (95% CI) of 0.91 (0.90, 0.92), 0.78 (0.76, 0.80), and 0.83 (0.81, 0.85) in 7 days, 14 days and 28 days group, respectively. It also demonstrated excellent discrimination in the external validation cohort. Its AUC (95% CI) was 0.81 (0.79, 0.83), 0.75 (0.73, 0.77), 0.79 (0.77, 0.81) in 7 days, 14 days and 28 days group, respectively. SHAP-based summary plot and force plot were used to interpret the XGBoost model globally and locally. CONCLUSIONS: ML is a reliable tool for predicting the prognosis of patients with S-AKI. SHAP methods were used to explain intrinsic information of the XGBoost model, which may prove clinically useful and help clinicians tailor precise management.

Elevated Serum NOX2 Levels Contribute to Delayed Cerebral Ischemia and a Poor Prognosis After Aneurysmal Subarachnoid Hemorrhage: A Prospective Cohort Study.

Background: NADPH oxidase 2 (NOX2) is highly expressed in injured brain tissues. We determined serum NOX2 levels of aneurysmal subarachnoid hemorrhage (aSAH) patients and further investigated correlation of serum NOX2 levels with disease severity, delayed cerebral ischemia (DCI) plus prognosis after aSAH. Methods: Serum NOX2 levels were measured in 123 aSAH patients and 123 healthy controls. World Federation of Neurological Surgeons scale (WFNS) score and modified Fisher (mFisher) score were utilized to assess disease severity. Modified Rankin scale (mRS) score was used to evaluate the clinical prognosis at 90 days after aSAH. Relations of serum NOX2 levels to DCI and 90-day poor prognosis (mRS score of 3-6) were analyzed using multivariate analysis. Receiver operating characteristic curve (ROC) was built to evaluate the prognostic predictive capability. Results: Serum NOX2 levels in aSAH patients, compared with healthy controls, were significantly increased, and were independently correlated with WFNS score, mFisher score and post-stroke 90-day mRS score. Patients with poor prognosis or DCI had significantly higher serum NOX2 levels than other remainders, and serum NOX2 levels independently predicted 90-day poor prognosis and DCI. Serum NOX2 had high prognosis and DCI predictive abilities, and their areas under ROC curve were similar to those of WFNS score and mFisher score. Conclusion: Serum NOX2 levels are significantly associated with hemorrhage severity, poor 90-day prognosis and DCI in aSAH patients. Hence, complement NOX2 may serve as a potential prognostic biomarker after aSAH.

Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling.

BACKGROUND: Ufm1-specific ligase 1 (Ufl1) and Ufm1-binding protein 1 (Ufbp1), as putative targets of ubiquitin-fold modifier 1 (Ufm1), have been implicated in several pathogenesis-related signaling pathways. However, little is known about their functional roles in liver disease. METHODS: Hepatocyte-specific Ufl1Δ/Δhep and Ufbp1Δ/Δhep mice were used to study their role in liver injury. Fatty liver disease and liver cancer were induced by high-fat diet (HFD) and diethylnitrosamine (DEN) administration, respectively. iTRAQ analysis was employed to screen for downstream targets affected by Ufbp1 deletion. Co-immunoprecipitation was used to determine the interactions between the Ufl1/Ufbp1 complex and the mTOR/GßL complex. RESULTS: Ufl1Δ/Δhep or Ufbp1Δ/Δhep mice exhibited hepatocyte apoptosis and mild steatosis at 2 months of age and hepatocellular ballooning, extensive fibrosis, and steatohepatitis at 6-8 months of age. More than 50% of Ufl1Δ/Δhep and Ufbp1Δ/Δhep mice developed spontaneous hepatocellular carcinoma (HCC) by 14 months of age. Moreover, Ufl1Δ/Δhep and Ufbp1Δ/Δhep mice were more susceptible to HFD-induced fatty liver and DEN-induced HCC. Mechanistically, the Ufl1/Ufbp1 complex directly interacts with the mTOR/GßL complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/GßL complex and activates oncogenic mTOR signaling to drive HCC development. CONCLUSIONS: These findings reveal the potential role of Ufl1 and Ufbp1 as gatekeepers to prevent liver fibrosis and subsequent steatohepatitis and HCC development by inhibiting the mTOR pathway.

Adaptive c-Met-PLXDC2 Signaling Axis Mediates Cancer Stem Cell Plasticity to Confer Radioresistance-associated Aggressiveness in Head and Neck Cancer.

Radiotherapy plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSCC), yet radioresistance remains a major barrier to therapeutic efficacy. A better understanding of the predominant pathways determining radiotherapy response could help develop mechanism-informed therapies to improve cancer management. Here we report that radioresistant HNSCC cells exhibit increased tumor aggressiveness. Using unbiased proteome profiler antibody arrays, we identify that upregulation of c-Met phosphorylation is one of the critical mechanisms for radioresistance in HNSCC cells. We further uncover that radioresistance-associated HNSCC aggressiveness is effectively exacerbated by c-Met but is suppressed by its genetic knockdown and pharmacologic inactivation. Mechanistically, the resulting upregulation of c-Met promotes elevated expression of plexin domain containing 2 (PLXDC2) through activating ERK1/2-ELK1 signaling, which in turn modulates cancer cell plasticity by epithelial-mesenchymal transition (EMT) induction and enrichment of the cancer stem cell (CSC) subpopulation, leading to resistance of HNSCC cells to radiotherapy. Depletion of PLXDC2 overcomes c-Met-mediated radioresistance through reversing the EMT progress and blunting the self-renewal capacity of CSCs. Therapeutically, the addition of SU11274, a selective and potent c-Met inhibitor, to radiation induces tumor shrinkage and limits tumor metastasis to lymph nodes in an orthotopic mouse model. Collectively, these significant findings not only demonstrate a novel mechanism underpinning radioresistance-associated aggressiveness but also provide a possible therapeutic strategy to target radioresistance in patients with HNSCC. Significance: This work provides novel insights into c-Met-PLXDC2 signaling in radioresistance-associated aggressiveness and suggests a new mechanism-informed therapeutic strategy to overcome failure of radiotherapy in patients with HNSCC.

UFL1, a UFMylation E3 ligase, plays a crucial role in multiple cellular stress responses.

The UFM1 conjugation system(UFMylation)is a novel type of ubiquitin-like system that plays an indispensable role in maintaining cell homeostasis under various cellular stress. Similar to ubiquitination, UFMylation consists of a three-step enzymatic reaction with E1-like enzymes ubiquitin-like modifier activating enzyme5 (UBA5), E2-like enzymes ubiquitin-fold modifier-conjugating enzyme 1(UFC1), and E3-like ligase UFM1-specific ligase 1 (UFL1). As the only identified E3 ligase, UFL1 is responsible for specific binding and modification of the substrates to mediate numerous hormone signaling pathways and endocrine regulation under different physiological or pathological stress, such as ER stress, genotoxic stress, oncogenic stress, and inflammation. Further elucidation of the UFL1 working mechanism in multiple cellular stress responses is essential for revealing the disease pathogenesis and providing novel potential therapeutic targets. In this short review, we summarize the recent advances in novel UFL1 functions and shed light on the potential challenges ahead, thus hopefully providing a better understanding of UFMylation-mediated cellular stress.