Prognostic value and drug sensitivity of F­box and leucine­rich repeat protein 6 in glioma.

Gliomas are highly malignant and invasive tumors lacking clear boundaries. Previous bioinformatics and experimental analyses have indicated that F-box and leucine-rich repeat protein 6 (FBXL6), a protein crucial for the cell cycle and tumorigenesis, is highly expressed in certain types of tumors. The high expression level of FBXL6 is reported to promote tumor growth and adversely affect patient survival. However, the molecular mechanism, prognostic value and drug sensitivity of FBXL6 in glioma remain unclear. To address this, the present study analyzed FBXL6 expression in gliomas, utilizing data from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Analysis of FBXL6 mRNA expression levels, combined with patient factors such as age, sex and tumor grade using Kaplan-Meier plots and nomograms, demonstrated a strong correlation between FBXL6 expression and glioma progression. Co-expression networks provided further insights into the biological function of FBXL6. Additionally, using CIBERSORT and TISDB tools, the correlation between FBXL6 expression correlation tumor-infiltrating immune cells and immune genes was demonstrated to be statistically significant. These findings were validated by examining FBXL6 mRNA and protein levels in glioma tissues using various techniques, including western blot, reverse transcription-quantitative PCR and immunohistochemistry. These assays demonstrated the role of FBXL6 in glioma progression. Furthermore, drug sensitivity analysis demonstrated a strong correlation between FBXL6 expression and various drugs, which indicated that FBXL6 may potentially act as a future promising therapeutic target in glioma treatment. Therefore, the present study identified FBXL6 as a diagnostic and prognostic marker in patients with gliomas and highlighted its potential role in glioma progression.

A soybean bZIP transcription factor is involved in submergence resistance.

Although the functions of basic leucine zipper (bZIP) family transcription factors in the regulation of various abiotic stresses are beginning to be unveiled, the precise roles of bZIP proteins in plants coping with submergence stress remain unclear. Here we identified a bZIP gene GmbZIP71-4 from soybean, which localized in the nucleus. The GmbZIP71-4 over-expressed tabocco line showed reduced submergence resistance due to the decreased abscisic acid (ABA) content. GO and KEGG pathway analysis based on chromatin immunoprecipitation assay sequencing (ChIP-seq) indicated that the differences expressed genes between submergence treatment and control groups were specially enriched in plant hormone signal transduction items, especially those in response to ABA. Electrophoretic mobility shift assays (EMSA) demonstrated that GmbZIP71-4 bound to the promoter of GmABF2 gene, which is consistent with the ChIP-qPCR results. GmbZIP71-4 function as a negative regulator of soybean in responding to submergence stress through manipulating ABA signaling pathway. This findings will set a solid foundation for the understanding of submergence resistance in plants.

Noncanonical WNT5A controls the activation of latent TGF-ß to drive fibroblast activation and tissue fibrosis.

Transforming growth factor ß (TGF-ß) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-ß remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-ß in fibrotic diseases. WNT5A was identified as a predominant noncanonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGF-ß. The activation of latent TGF-ß requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional ablation of WNT5A or its downstream targets prevented activation of latent TGF-ß, rebalanced TGF-ß signaling, and ameliorated experimental fibrosis. We thus uncovered what we believe to be a novel mechanism for the aberrant activation of latent TGF-ß in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.

Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis.

BACKGROUND: The interleukin (IL)-1 receptor accessory protein (IL1RAP) is an essential coreceptor required for signalling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). METHODS: The expression of IL1RAP-associated signalling molecules was determined by data mining of publicly available RNA sequencing (RNAseq) data as well as by imaging mass cytometry. The efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complementary mouse models: sclerodermatous chronic graft-versus-host disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. RESULTS: SSc skin showed upregulation of IL1RAP and IL1RAP-related signalling molecules on mRNA and protein level compared with normal skin. IL-1, IL-33 and IL-36 all regulate distinct gene sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33 and IL-36 were completely blocked by treatment with an anti-IL1RAP antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-induced, bleomycin-induced and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. CONCLUSION: This study provides the first evidence for the therapeutic benefits of targeting IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase one clinical trial.

Characterised intron retention profiles in muscle tissue of idiopathic inflammatory myopathy subtypes.

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a group of heterogeneous autoimmune diseases. Intron retention (IR) serves as an important post-transcriptional and translational regulatory mechanism. This study aims to identify changes in IR profiles in IIM subtypes, investigating their influence on proteins and their correlations with clinical features. METHODS: RNA sequencing and liquid chromatography-tandem mass spectrometry were performed on muscle tissues obtained from 174 patients with IIM and 19 controls, following QC procedures. GTFtools and iREAD software were used for IR identification. An analysis of differentially expressed IRs (DEIs), exons and proteins was carried out using edgeR or DEP. Functional analysis was performed with clusterProfiler, and SPIRON was used to assess splicing factors. RESULTS: A total of 6783 IRs located in 3111 unique genes were identified in all IIM subtypes compared with controls. IIM subtype-specific DEIs were associated with the pathogenesis of respective IIM subtypes. Splicing factors YBX1 and HSPA2 exhibited the most changes in dermatomyositis and immune-mediated necrotising myopathy. Increased IR was associated with reduced protein expression. Some of the IIM-specific DEIs were correlated with clinical parameters (skin rash, MMT-8 scores and muscle enzymes) and muscle histopathological features (myofiber necrosis, regeneration and inflammation). IRs in IFIH1 and TRIM21 were strongly correlated with anti-MDA5+ antibody, while IRs in SRP14 were associated with anti-SRP+ antibody. CONCLUSION: This study revealed distinct IRs and specific splicing factors associated with IIM subtypes, which might be contributing to the pathogenesis of IIM. We also emphasised the potential impact of IR on protein expression in IIM muscles.

Protein profiling in systemic sclerosis patients with different pulmonary complications using proteomic antibody microarray.

BACKGROUND: Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are leading causes of systemic sclerosis (SSc)-related death. In this study, we aimed to identify biomarkers for detecting SSc pulmonary complications that are mild and in the early stages to improve the prognosis. METHODS: We screened for serum biomarkers using a proteomic antibody microarray that simultaneously assessed 1000 proteins. Differentially expressed proteins were further verified using ELISA. Finally, we performed a correlation analysis using clinical data. RESULTS: We identified 125 differentially expressed proteins, of which calcitonin, sclerostin (SOST), CD40, and fibronectin were selected for further verification. Serum calcitonin and SOST levels were significantly elevated in all SSc pulmonary complication subgroups, whereas serum calcitonin levels were higher in the SSc with PAH subgroup than in the SSc without PAH and ILD subgroup. Serum SOST levels were possibly associated with the presence of ILD and positively related to the presence of cardiac and gastrointestinal involvement. Serum CD40 and calcitonin levels appeared to be positively related to the presence of renal involvement, and serum calcitonin was also positively related to the presence of gastrointestinal involvement. CONCLUSIONS: This study indicated that serum calcitonin and SOST levels may be promising biomarkers for SSc-related PAH and ILD, respectively. Further research is needed to verify this result and understand the underlying mechanisms.

Glycerol/organic acid-based ternary deep eutectic solvents as a green approach to recover chitin with different molecular weight from seafood waste.

In this study, we designed a green and efficient approach for the fractionation of high-purity chitin with tunable molecular weights from seafood waste. This was achieved by using ternary deep eutectic solvents (TDESs) composed of choline chloride as a hydrogen bond acceptor, glycerol as the polyol-based hydrogen bond donor, together with lactic acid or malic acid. Two binary DESs and four TDESs were evaluated for their ability to recover chitin. The extracted chitin exhibited not only high yield with excellent protein and mineral removal, but also high purity with similar crystallinity patterns as standard chitin. However, the average molecular weights, viscosity behavior and morphology of chitin extracted by DESs were varied and influenced by organic acid to glycerol molar ratios. The molecular weights of chitin extracted by lactic acid-based TDES ranged from 264 kDa to 541 kDa, but malic acid-based TEDS displayed a stronger depolymerization effect, resulting in chitin with a smaller molecular weight of less than 300 kDa. Lactic acid-based TDES revealed that the purity of chitin remained higher than 92 % after three cycles. This sustainable and environmentally friendly extraction system holds great potential to recover chitin from seafood waste, opening a new era for chitin extraction and applications.

Fibroblast Subpopulations in Systemic Sclerosis: Functional Implications of Individual Subpopulations and Correlations with Clinical Features.

Fibroblasts constitute a heterogeneous population of cells. In this study, we integrated single-cell RNA-sequencing and bulk RNA-sequencing data as well as clinical information to study the role of individual fibroblast populations in systemic sclerosis (SSc). SSc skin demonstrated an increased abundance of COMP+, COL11A1+, MYOC+, CCL19+, SFRP4/SFRP2+, and PRSS23/SFRP2+ fibroblasts signatures and decreased proportions of CXCL12+ and PI16+ fibroblast signatures in the Prospective Registry of Early Systemic Sclerosis and Genetics versus Environment in Scleroderma Outcome Study cohorts. Numerical differences were confirmed by multicolor immunofluorescence for selected fibroblast populations. COMP+, COL11A1+, SFRP4/SFRP2+, PRSS23/SFRP2+, and PI16+ fibroblasts were similarly altered between normal wound healing and patients with SSc. The proportions of profibrotic COMP+, COL11A1+, SFRP4/SFRP2+, and PRSS23/SFRP2+ and proinflammatory CCL19+ fibroblast signatures were positively correlated with clinical and histopathological parameters of skin fibrosis, whereas signatures of CXCL12+ and PI16+ fibroblasts were inversely correlated. Incorporating the proportions of COMP+, COL11A1+, SFRP4/SFRP2+, and PRSS23/SFRP2+ fibroblast signatures into machine learning models improved the classification of patients with SSc into those with progressive versus stable skin fibrosis. In summary, the profound imbalance of fibroblast subpopulations in SSc may drive the progression of skin fibrosis. Specific targeting of disease-relevant fibroblast populations may offer opportunities for the treatment of SSc and other fibrotic diseases.

Predicting disease progression in cirrhotic patients after transjugular intrahepatic portosystemic shunt implantation: A sex-stratified analysis.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) has been extensively used to treat portal hypertension-associated complications, including cirrhosis. The prediction of post-TIPS prognosis is important for cirrhotic patients, as more aggressive liver transplantation is needed when the post-TIPS prognosis is poor. AIM: To construct a nutrition-based model that could predict the disease progression of cirrhotic patients after TIPS implantation in a sex-dependent manner. METHODS: This study retrospectively recruited cirrhotic patients undergoing TIPS implantation for analysis. Muscle quality was assessed by measuring the skeletal muscle index (SMI) by computed tomography. Multivariate Cox proportional hazard models were utilized to determine the association between SMI and disease progression in cirrhotic patients after TIPS implantation. RESULTS: This study eventually included 186 cirrhotic patients receiving TIPS who were followed up for 30.5 ± 18.8 mo. For male patients, the 30-mo survival rate was significantly lower and the probability of progressive events was higher (3.257-fold) in the low-level SMI group than in the high-level SMI group. According to the multivariate Cox analysis of male patients, SMI < 32.8 was an independent risk factor for long-term adverse outcomes after TIPS implantation. A model was constructed, which involved creatinine, plasma ammonia, SMI, and acute-on-chronic liver failure and hepatic encephalopathy occurring within half a year after surgery. This model had an area under the receiver operating characteristic curve of 0.852, sensitivity of 0.926, and specificity of 0.652. According to the results of the DeLong test, this model outperformed other models (Child-Turcotte-Pugh, Model for End-Stage Liver Disease, and Freiburg index of post-TIPS survival) (P < 0.05). CONCLUSION: SMI is strongly associated with poor long-term outcomes in male patients with cirrhosis who underwent TIPS implantation.

Research on robust fault-tolerant control of the controllable suspension based on knowledge-data fusion driven.

For the robust fault-tolerant control of the controllable suspension system, a control strategy driven by knowledge-data fusion is proposed. Firstly, the boundary fuzziness between perturbation type uncertainty and gain type fault is analyzed, and then a data-driven method is introduced to avoid the state estimation of system uncertainty and fault. The proximal policy optimization algorithm in reinforcement learning is selected to construct a "data control law", to deal with uncertainty and fault. On the other hand, based on the classical sky-hook control, the "knowledge control law" for system performance optimization is designed, taking into account the nonlinear and non-stationary characteristics of the system. Furthermore, the dependency between robust fault tolerance and performance optimization control is revealed, and the two control laws are fused by numerical multiplication, to realize the performance matching optimization control of robust fault tolerance of controllable suspension system driven by knowledge-data fusion. Finally, the effectiveness and feasibility of the proposed method are verified by the simulation and real-time experiment of non-stationary excitation and near-stationary excitation under the combination of uncertainty and fault.

Assembly of highly efficient overall CO2 + H2O electrolysis cell with the matchup of CO2 reduction and water oxidation catalyst.

The exploitation of highly active and stable catalysts for reduction of CO2 and water oxidation is one of the approaches to facilitate scalable and sustainable CO2 reduction potentially at the industrial scale. Herein, a feasible strategy to rationally build an overall CO2 + H2O electrocatalytic reaction device is the preparation and matchup of a high-performance CO2 reduction catalyst and low-cost and highly active oxygen anode catalyst. A heterostructured nanosheet, γ-NiOOH/NiCO3/Ni(HCOO)2, exhibited superior catalytic activity in the oxygen evolution reaction, and was integrated with CoPc/Fe-N-C to build an overall CO2 + H2O cell with a current density of 10 mA cm-2 at a very low cell voltage of 1.97 V, and the faradaic deficiency of CO2 to CO was maintained at greater than 90% at 1.9 V.

The functions of FOXP transcription factors and their regulation by post-translational modifications.

The forkhead box subfamily P (FOXP) of transcription factors, consisting of FOXP1, FOXP2, FOXP3, and FOXP4, is involved in the regulation of multisystemic functioning. Disruption of the transcriptional activity of FOXP proteins leads to neurodevelopmental disorders and immunological diseases, as well as the suppression or promotion of carcinogenesis. The transcriptional activities of FOXP proteins are directly or indirectly regulated by diverse post-translational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, O-GlcNAcylation, and methylation. Here, we discuss how post-translational modifications modulate the multiple functions of FOXP proteins and examine the implications for tumorigenesis and cancer therapy.

The role and mechanism of myeloperoxidase in dermatomyositis.

OBJECTIVE: Dermatomyositis (DM) is the best known subtype of idiopathic inflammatory myopathies. The hallmarks of DM muscle pathology including microangiopathy, inflammatory infiltration, and perifascicular atrophy. Recent findings have revealed pathogenetic effects of myeloperoxidase (MPO) by causing oxidative damage and regulating abnormal immunity in multiple disease conditions. In this study, we aimed to explore the role of MPO in the pathogenesis of DM. METHODS: The peripheral blood mononuclear cell (PBMC) mRNA expression and DNA methylation of MPO were verified using real-time qPCR and bisulfite pyrosequencing, respectively. Plasma MPO levels were measured with enzyme-linked immunosorbent assay, and their relationships with clinical characteristics were analyzed. The expression and distribution of MPO in muscle were tested by immunofluorescence. Purified human native MPO protein was used to stimulate human dermal microvascular endothelial cells (HDMECs) and skeletal muscle myotubes. The cell viability, tube forming capacity, permeability, adhesion molecule expressions in HDMECs, and atrophy and programmed cell death pathways in myotubes were then observed. RESULTS: MPO gene methylation was decreased, while mRNA expression and plasma levels were increased in DM. Plasma MPO of DM patients was positively correlated with serum creatine kinase (CK). MPO mainly distributed around endomysia capillaries and perifascicular atrophy in DM muscle biopsies, and was co-localized with CD4+, CD8+ T cells and CD19+ B cells. MPO not only could influence the cell viability, tube forming capacity, permeability and expression of adhesion molecules (including ICAM 1, VCAM 1 and E-selectin) of HDMECs, but also could cause atrophy of myotubes. CONCLUSIONS: Our study disclosed, for the first time, that MPO plays an important role in promoting inflammatory infiltration and inducing muscle damage in DM patients. MPO may be a potential biomarker for DM muscle involvement and MPO targeted drugs may be promising in DM treatment.

Accelerating image reconstruction for multi-contrast MRI based on Y-Net3.

BACKGROUND: As one of the significant preoperative imaging modalities in medical diagnosis, Magnetic resonance imaging (MRI) takes a long scanning time due to its special imaging principle. OBJECTIVE: We propose an innovative MRI reconstruction strategy and data consistency method based on deep learning to reconstruct high-quality brain MRIs from down-sampled data and accelerate the MR imaging process. METHODS: Sixteen healthy subjects undergoing T1-weighted spin-echo (SE) and T2-weighted fast spin-echo (FSE) sequences by a 1.5T MRI scanner were recruited. A Y-Net3+ network was used to facilitate the high-quality MRI reconstruction through context information. In addition, the existing data consistency fidelity method was improved. The difference between the reconstructed K-space and the original K-space was shorten by the linear regression algorithm. Therefore, the redundant artifacts derived from under-sampling were avoided. The Structural Similarity (SSIM) and Peak Signal to Noise Ratio (PSNR) were applied to quantitatively evaluate image reconstruction performance of different down-sampling patterns. RESULTS: Compared with the classical Y-Net, Y-Net3+ network improved SSIM and PSNR of MRI images from 0.9164±0.0178 and 33.2216±3.2919 to 0.9387±0.0363 and 35.1785±3.3105, respectively, under compressed sensing reconstruction with acceleration factor of 4. The improved network increases signal-to-noise ratio and adds more image texture information in the reconstructed images. Furthermore, in the process of data consistency, linear regression analysis was used to reduce the difference between the reconstructed K-space and the original K-space, so that the SSIM and PSNR were increased to 0.9808±0.0081 and 40.9254±1.1911, respectively. CONCLUSIONS: The improved Y-Net combined with data consistency fidelity method elucidates its potential in reconstructing high-quality T2-weighted images from the down-sampled data by fully exploring the T1-weighted information. With the advantage of avoiding down-sampled artifacts, the improved network exhibits remarkable clinical promise for fast MRI applications.

Serum metabolomic profiling reveals potential biomarkers in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a chronic and systemic autoimmune disease marked by the skin and visceral fibrosis. Metabolic alterations have been found in SSc patients; however, serum metabolomic profiling has not been thoroughly conducted. Our study aimed to identify alterations in the metabolic profile in both SSc patients before and during treatment, as well as in mouse models of fibrosis. Furthermore, the associations between metabolites and clinical parameters and disease progression were explored. METHODS: High-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS)/MS was performed in the serum of 326 human samples and 33 mouse samples. Human samples were collected from 142 healthy controls (HC), 127 newly diagnosed SSc patients without treatment (SSc baseline), and 57 treated SSc patients (SSc treatment). Mouse serum samples were collected from 11 control mice (NaCl), 11 mice with bleomycin (BLM)-induced fibrosis and 11 mice with hypochlorous acid (HOCl)-induced fibrosis. Both univariate analysis and multivariate analysis (orthogonal partial least-squares discriminate analysis (OPLS-DA)) were conducted to unravel differently expressed metabolites. KEGG pathway enrichment analysis was performed to characterize the dysregulated metabolic pathways in SSc. Associations between metabolites and clinical parameters of SSc patients were identified by Pearson's or Spearman's correlation analysis. Machine learning (ML) algorithms were applied to identify the important metabolites that have the potential to predict the progression of skin fibrosis. RESULTS: The newly diagnosed SSc patients without treatment showed a unique serum metabolic profile compared to HC. Treatment partially corrected the metabolic changes in SSc. Some metabolites (phloretin 2'-O-glucuronide, retinoyl b-glucuronide, all-trans-retinoic acid, and betaine) and metabolic pathways (starch and sucrose metabolism, proline metabolism, androgen and estrogen metabolism, and tryptophan metabolism) were dysregulated in new-onset SSc, but restored upon treatment. Some metabolic changes were associated with treatment response in SSc patients. Metabolic changes observed in SSc patients were mimicked in murine models of SSc, indicating that they may reflect general metabolic changes associated with fibrotic tissue remodeling. Several metabolic changes were associated with SSc clinical parameters. The levels of allysine and all-trans-retinoic acid were negatively correlated, while D-glucuronic acid and hexanoyl carnitine were positively correlated with modified Rodnan skin score (mRSS). In addition, a panel of metabolites including proline betaine, phloretin 2'-O-glucuronide, gamma-linolenic acid and L-cystathionine were associated with the presence of interstitial lung disease (ILD) in SSc. Specific metabolites identified by ML algorithms, such as medicagenic acid 3-O-b-D-glucuronide, 4'-O-methyl-(-)-epicatechin-3'-O-beta-glucuronide, valproic acid glucuronide, have the potential to predict the progression of skin fibrosis. CONCLUSIONS: Serum of SSc patients demonstrates profound metabolic changes. Treatment partially restored the metabolic changes in SSc. Moreover, certain metabolic changes were associated with clinical manifestations such as skin fibrosis and ILD, and could predict the progression of skin fibrosis.

A Novel Manner of Anchoring Cobalt Phthalocyanine on Edge-Defected Carbon for Highly Electrocatalytic CO2 Reduction.

Cobalt phthalocyanine anchored on carbon material has attracted an enormous amount of attention due to its superior performance in electrocatalytic CO2 reduction. However, the interaction between cobalt phthalocyanine and the carbon substrate remains problematic, and the role of intrinsic carbon defects is unfortunately ignored in the anchoring of cobalt phthalocyanine on carbon. Herein, new interactions between the bridging N atoms of cobalt phthalocyanine and the edge defects of carbon have been discovered, which result in a novel model of anchoring of cobalt phthalocyanine on ketjen black carbon. Such anchored cobalt phthalocyanine has been found to be responsible for superior catalysis for electrochemical reduction of CO2 to CO with high selectivity and low overpotential.

The proportion of C1q-high and ISG15-high monocytes in the skin of patients with Behçet disease.

Behçet disease (BD) is a chronic systemic vasculitis that is clinically characterized by recurrent oral ulcers, genital ulcers, uveitis, and skin lesions. Here, we conducted bulk RNA-seq of skin samples from 4 BD patients and 4 normal controls (NCs). A total of 260 differentially expressed genes (DEGs), including 99 upregulated and 161 downregulated genes, were detected in the skin lesions of BD patients compared to NCs. These DEGs were mainly enriched in the following biological processes: the activation and migration of immune cells, the release of proinflammatory factors, and the IFN-γ signaling pathway. The top upregulated DEGs were CXCL10, CXCL9, FCGR3A, GBP5, GBP4, LILRB2, ADIPOQ, PLIN1, SLC43A2, and MYO1G. Using the deconvolution method CIBERSORT, we analyzed the immune cells subtypes in the skin of BD by integrating the single cell RNA-seq data from PBMC (GSE198616) and bulk RNA-seq data of skin. There was a higher proportion of C1q+ and ISG15 + monocyte subtypes in skin of BD. IHC staining of CD14 and CD16 showed that the monocyte number increased in the skin of BD. IF staining confirmed there was a higher proportion of the C1Q + Mono and ISG15 + Mono subsets in the skin of BD patients. Moreover, we analyzed the average expression level of the top upregulated genes in immune cell types found in PBMC from BD patients and NCs. Almost all the top upregulated genes expressed in monocytes. CXCL10 was specifically expressed in ISG15 + monocyte, and GBP5, GBP4 and IFI44L were expressed more strongly in ISG15 + monocytes. LILRB2 was expressed more strongly in CD16+ monocytes and C1Q + monocytes. In conclusion, our study identified that the IFN-γ pathway was activated in skin of BD and the proportion of C1q+ and ISG15 + monocyte subtype increased in the skin of BD.

Removal of anionic and cationic dyes using porous chitosan/carboxymethyl cellulose-PEG hydrogels: Optimization, adsorption kinetics, isotherm and thermodynamics studies.

Chitosan (CS)/carboxymethyl cellulose (CMC) porous hydrogels chemically crosslinked by epichlorohydrin were synthesized using polyethylene glycol (PEG) as a pore-forming agent for anionic (Congo red, CR) and cationic (methylene blue, MB) dyes removal from aqueous solutions. The swelling ratio of hydrogels prepared with 2 % CS and 2 % CMC (CS2/CMC2) exhibited optimal performance at different pHs. The addition of PEG into hydrogels (denoted as CS2/CMC2-PEG1.25) exhibited a significantly higher adsorption for CR and MB, increasing from 117.83 to 159.12 mg/g and 110.2 to 136 mg/g, respectively. The comprehensive analyses of Fourier transform infrared spectroscopy, thermalgravimetric study and scanning electron microscopy showed that CS2/CMC2-PEG1.25 hydrogels became more porous with no significant changes in intermolecular and intramolecular interactions, compared with CS2/CMC2 hydrogels. The adsorption process for CR and MB conformed to the pseudo-second-order and pseudo-first-order kinetics models, respectively. The results of adsorption isotherm for CR followed both Freundlich and Langmuir models with the maximum adsorption capacities of 1053.88 mg/g, whereas the isotherm for MB fitted the Langmuir model better with the maximum adsorption capacities of 331.72 mg/g. The thermodynamic study results proved that the CR and MB adsorption by hydrogels was spontaneous, but the CR adsorption was endothermic and the MB adsorption was exothermic.

Association of KMT2C/D loss-of-function variants with response to immune checkpoint blockades in colorectal cancer.

Immune checkpoint inhibitors (ICIs) have become important treatment strategies, yet responses vary among patients and predictive biomarkers are urgently needed. Mutations in KMT2C and KMT2D lead to increased levels of genomic instability. Therefore, we aimed to examine whether KMT2C/D mutations might be a predictor of immunotherapeutic efficacy. Here, we investigated the associations of KMT2C/D loss-of-function (LOF) variants with tumor mutation burden (TMB), MSI-H, PD-L1 expression, the levels of tumor-infiltrating leukocytes (TILs), and clinical response to ICIs. It was found that KMT2C/D LOF variants were associated with higher TMB. Compared with the non-LOF group, the proportion of patients with MSI-H tumors was larger in the LOF group. PD-L1 expression was higher in the LOF group only for colorectal cancer in both the Chinese and The Cancer Genome Atlas cohorts. Importantly, KMT2C/D LOF variants were associated with decreased regulatory T cells and increased levels of CD8+ T cells, activated NK cells, M1 macrophages, and M2 macrophages in colorectal cancer. However, there was no significant association between KMT2C/D LOF and TILs levels in other cancer types. Consistently, the results showed that KMT2C/D LOF variants were associated with prolonged overall survival only in colorectal cancer (p = 0.0485). We also presented that patients with KMT2C/D LOF mutations exhibited a better clinical response to anti-PD-1 therapy in a Chinese colorectal cancer cohort (p = 0.002). Taken together, these results suggested that KMT2C/D LOF variants could be a useful predictor for ICIs efficacy in colorectal cancer. In addition, the predictive value of KMT2C/D LOF variants was consistent with their association with TILs levels.