ABSTRACT
CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B12 levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology, and activity-based metabolomics, we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate, a recently identified human anti-microbial metabolite and immunomodulator. We report that CLYBL loss leads to a cell-autonomous defect in the mitochondrial B12 metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B12-dependent methylmalonyl-CoA mutase (MUT). Our work de-orphans the function of human CLYBL and reveals that a consequence of exposure to the immunomodulatory metabolite itaconate is B12 inactivation.
Subject(s)
Carbon-Carbon Lyases/metabolism , Succinates/metabolism , Vitamin B 12/metabolism , Carbon-Carbon Lyases/chemistry , Carbon-Carbon Lyases/genetics , Gene Knockout Techniques , Humans , Metabolic Networks and Pathways , Mitochondria/metabolism , Models, MolecularABSTRACT
RNA-binding proteins (RBPs) control messenger RNA fate in neurons. Here, we report a mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Mechanistically, YTHDF1 can condense with ribosomal proteins to promote the translation of its mRNA targets. FMRP regulates this process by sequestering YTHDF1 away from the ribosome; upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1 for translation upregulation. We show that a new small molecule inhibitor of YTHDF1 can reverse fragile X syndrome (FXS) developmental defects associated with FMRP deficiency in an organoid model. Our study thus reveals that FMRP and its phosphorylation are important regulators of activity-dependent translation during neuronal development and stimulation and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.
Subject(s)
Fragile X Mental Retardation Protein , Fragile X Syndrome , Humans , Phosphorylation , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/metabolism , Neurons/metabolism , Fragile X Syndrome/genetics , Fragile X Syndrome/metabolism , Ribosomal Proteins/metabolism , RNA, Messenger/genetics , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolismABSTRACT
The RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we examined the mechanisms whereby K63-polyUb chain regulate MDA5 activation. Only long unanchored K63-polyUbn (n ≥ 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 (MDA5CARDs). Cryoelectron microscopy structures of a polyUb13-bound MDA5CARDs tetramer and a polyUb11-bound MDA5CARDs-MAVSCARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging MDA5CARDs and MAVSCARD tetramers into proximity. ATP binding and hydrolysis promoted the stabilization of RNA-bound MDA5 prior to MAVS activation via allosteric effects on CARDs-polyUb complex. Abundant ATP prevented basal activation of apo MDA5. Our findings reveal the ordered assembly of a MDA5 signaling complex competent to recruit and activate MAVS and highlight differences with RIG-I in terms of CARD orientation and Ub sensing that suggest different abilities to induce antiviral responses.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Interferon-Induced Helicase, IFIH1/metabolism , Signal Transduction/physiology , Adaptor Proteins, Signal Transducing/chemistry , Cryoelectron Microscopy , HEK293 Cells , Humans , Immunity, Innate/physiology , Interferon-Induced Helicase, IFIH1/chemistry , Interferon-Induced Helicase, IFIH1/ultrastructure , Polyubiquitin/chemistry , Polyubiquitin/metabolism , Protein BindingABSTRACT
Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors1. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants2,3. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant4. Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.
Subject(s)
Cryoelectron Microscopy , Ketamine/chemistry , Ketamine/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/ultrastructure , Antidepressive Agents/chemistry , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacology , Asparagine/chemistry , Asparagine/metabolism , Binding Sites , Glutamic Acid/chemistry , Glutamic Acid/metabolism , Glutamic Acid/pharmacology , Glycine/chemistry , Glycine/metabolism , Glycine/pharmacology , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ketamine/metabolism , Leucine/chemistry , Leucine/metabolism , Molecular Dynamics Simulation , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/ultrastructure , Receptors, N-Methyl-D-Aspartate/chemistry , Receptors, N-Methyl-D-Aspartate/metabolismABSTRACT
Although interleukin 1 (IL-1) induces expression of the transcription factor IRF1 (interferon-regulatory factor 1), the roles of IRF1 in immune and inflammatory responses and mechanisms of its activation remain elusive. Here we found that IRF1 was essential for IL-1-induced expression of the chemokines CXCL10 and CCL5, which recruit mononuclear cells into sites of sterile inflammation. Newly synthesized IRF1 acquired Lys63 (K63)-linked polyubiquitination mediated by the apoptosis inhibitor cIAP2 that was enhanced by the bioactive lipid S1P. In response to IL-1, cIAP2 and the sphingosine kinase SphK1 (the enzyme that generates S1P) formed a complex with IRF1, which led to its activation. Thus, IL-1 triggered a hitherto unknown signaling cascade that controlled the induction of IRF1-dependent genes that encode molecules important for sterile inflammation.
Subject(s)
Chemokine CCL5/biosynthesis , Chemokine CXCL10/biosynthesis , Interferon Regulatory Factor-1/metabolism , Interleukin-1/metabolism , Signal Transduction/immunology , Animals , Chemokine CCL5/immunology , Chemokine CXCL10/immunology , Chemotaxis, Leukocyte/immunology , Enzyme-Linked Immunosorbent Assay , Humans , Immunoblotting , Immunoprecipitation , Inflammation/immunology , Inflammation/metabolism , Interferon Regulatory Factor-1/immunology , Interleukin-1/immunology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lysine , Mice , Mice, Knockout , Real-Time Polymerase Chain Reaction , UbiquitinationABSTRACT
BACKGROUND & AIMS: Portal hypertension (PH) is one of the most frequent complications of chronic liver disease. The peripheral 5-hydroxytryptamine (5-HT) level was increased in cirrhotic patients. We aimed to elucidate the function and mechanism of 5-HT receptor 1A (HTR1A) in the portal vein (PV) on PH. METHODS: PH models were induced by thioacetamide injection, bile duct ligation, or partial PV ligation. HTR1A expression was detected using real-time polymerase chain reaction, in situ hybridization, and immunofluorescence staining. In situ intraportal infusion was used to assess the effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP). Htr1a-knockout (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a-knockout (Htr1aΔVSMC) mice were used to confirm the regulatory role of HTR1A on PP. RESULTS: HTR1A expression was significantly increased in the hypertensive PV of PH model rats and cirrhotic patients. Additionally, 8-OH-DPAT increased, but WAY-100635 decreased, the PP in rats without affecting liver fibrosis and systemic hemodynamics. Furthermore, 5-HT or 8-OH-DPAT directly induced the contraction of isolated PVs. Genetic deletion of Htr1a in rats and VSMC-specific Htr1a knockout in mice prevented the development of PH. Moreover, 5-HT triggered adenosine 3',5'-cyclic monophosphate pathway-mediated PV smooth muscle cell contraction via HTR1A in the PV. We also confirmed alverine as an HTR1A antagonist and demonstrated its capacity to decrease PP in rats with thioacetamide-, bile duct ligation-, and partial PV ligation-induced PH. CONCLUSIONS: Our findings reveal that 5-HT promotes PH by inducing the contraction of the PV and identify HTR1A as a promising therapeutic target for attenuating PH. As an HTR1A antagonist, alverine is expected to become a candidate for clinical PH treatment.
ABSTRACT
Post-translational modifications (PTMs) fine-tune various signaling pathways not only by the modification of a single residue, but also by the interplay of different modifications on residue pairs within or between proteins, defined as PTM cross-talk. As a challenging question, less attention has been given to PTM dynamics underlying cross-talk residue pairs and structural information underlying protein-protein interaction (PPI) graph, limiting the progress in this PTM functional research. Here we propose a novel integrated deep neural network PPICT (Predictor for PTM Inter-protein Cross-Talk), which predicts PTM cross-talk by combining protein sequence-structure-dynamics information and structural information for PPI graph. We find that cross-talk events preferentially occur among residues with high co-evolution and high potential in allosteric regulation. To make full use of the complex associations between protein evolutionary and biophysical features, and protein pair features, a heterogeneous feature combination net is introduced in the final prediction of PPICT. The comprehensive test results show that the proposed PPICT method significantly improves the prediction performance with an AUC value of 0.869, outperforming the existing state-of-the-art methods. Additionally, the PPICT method can capture the potential PTM cross-talks involved in the functional regulatory PTMs on modifying enzymes and their catalyzed PTM substrates. Therefore, PPICT represents an effective tool for identifying PTM cross-talk between proteins at the proteome level and highlights the hints for cross-talk between different signal pathways introduced by PTMs.
Subject(s)
Neural Networks, Computer , Protein Processing, Post-Translational , Proteome/metabolism , Signal Transduction , Protein DomainsABSTRACT
Omics data from clinical samples are the predominant source of target discovery and drug development. Typically, hundreds or thousands of differentially expressed genes or proteins can be identified from omics data. This scale of possibilities is overwhelming for target discovery and validation using biochemical or cellular experiments. Most of these proteins and genes have no corresponding drugs or even active compounds. Moreover, a proportion of them may have been previously reported as being relevant to the disease of interest. To facilitate translational drug discovery from omics data, we have developed a new classification tool named Omics and Text driven Translational Medicine (OTTM). This tool can markedly narrow the range of proteins or genes that merit further validation via drug availability assessment and literature mining. For the 4489 candidate proteins identified in our previous proteomics study, OTTM recommended 40 FDA-approved or clinical trial drugs. Of these, 15 are available commercially and were tested on hepatocellular carcinoma Hep-G2 cells. Two drugs-tafenoquine succinate (an FDA-approved antimalarial drug targeting CYC1) and branaplam (a Phase 3 clinical drug targeting SMN1 for the treatment of spinal muscular atrophy)-showed potent inhibitory activity against Hep-G2 cell viability, suggesting that CYC1 and SMN1 may be potential therapeutic target proteins for hepatocellular carcinoma. In summary, OTTM is an efficient classification tool that can accelerate the discovery of effective drugs and targets using thousands of candidate proteins identified from omics data. The online and local versions of OTTM are available at http://otter-simm.com/ottm.html.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Translational Science, Biomedical , Proteomics , Drug DiscoveryABSTRACT
Machine learning including modern deep learning models has been extensively used in drug design and screening. However, reliable prediction of molecular properties is still challenging when exploring out-of-domain regimes, even for deep neural networks. Therefore, it is important to understand the uncertainty of model predictions, especially when the predictions are used to guide further experiments. In this study, we explored the utility and effectiveness of evidential uncertainty in compound screening. The evidential Graphormer model was proposed for uncertainty-guided discovery of KDM1A/LSD1 inhibitors. The benchmarking results illustrated that (i) Graphormer exhibited comparative predictive power to state-of-the-art models, and (ii) evidential regression enabled well-ranked uncertainty estimates and calibrated predictions. Subsequently, we leveraged time-splitting on the curated KDM1A/LSD1 dataset to simulate out-of-distribution predictions. The retrospective virtual screening showed that the evidential uncertainties helped reduce false positives among the top-acquired compounds and thus enabled higher experimental validation rates. The trained model was then used to virtually screen an independent in-house compound set. The top 50 compounds ranked by two different ranking strategies were experimentally validated, respectively. In general, our study highlighted the importance to understand the uncertainty in prediction, which can be recognized as an interpretable dimension to model predictions.
Subject(s)
Histones , Lysine , Retrospective Studies , Uncertainty , Histone Demethylases/metabolismABSTRACT
Dance and music are well known to improve sensorimotor skills and cognitive functions. To reveal the underlying mechanism, previous studies focus on the brain plastic structural and functional effects of dance and music training. However, the discrepancy training effects on brain structure-function relationship are still blurred. Thus, proficient dancers, musicians, and controls were recruited in this study. The graph signal processing framework was employed to quantify the region-level and network-level relationship between brain function and structure. The results showed the increased coupling strength of the right ventromedial putamen in the dance and music groups. Distinctly, enhanced coupling strength of the ventral attention network, increased coupling strength of the right inferior frontal gyrus opercular area, and increased function connectivity of coupling function signal between the right and left middle frontal gyrus were only found in the dance group. Besides, the dance group indicated enhanced coupling function connectivity between the left inferior parietal lobule caudal area and the left superior parietal lobule intraparietal area compared with the music groups. The results might illustrate dance and music training's discrepant effect on the structure-function relationship of the subcortical and cortical attention networks. Furthermore, dance training seemed to have a greater impact on these networks.
Subject(s)
Music , Brain/diagnostic imaging , Brain Mapping , Parietal Lobe , Frontal Lobe , Magnetic Resonance Imaging/methodsABSTRACT
Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation, glucolipid metabolism, and inflammation. Thiazolidinediones are PPARγ full agonists with potent insulin-sensitizing effects, whereas their oral usage is restricted because of unwanted side effects, including obesity and cardiovascular risks. Here, via virtual screening, microscale thermophoresis analysis, and molecular confirmation, we demonstrate that diosmin, a natural compound of wide and long-term clinical use, is a selective PPARγ modulator that binds to PPARγ and blocks PPARγ phosphorylation with weak transcriptional activity. Local diosmin administration in subcutaneous fat (inguinal white adipose tissue [iWAT]) improved insulin sensitivity and attenuated obesity via enhancing browning of white fat and energy expenditure. Besides, diosmin ameliorated inflammation in WAT and liver and reduced hepatic steatosis. Of note, we determined that iWAT local administration of diosmin did not exhibit obvious side effects. Taken together, the present study demonstrated that iWAT local delivery of diosmin protected mice from diet-induced insulin resistance, obesity, and fatty liver by blocking PPARγ phosphorylation, without apparent side effects, making it a potential therapeutic agent for the treatment of metabolic diseases.
Subject(s)
Adipose Tissue, Brown , Adipose Tissue, White , Diosmin , Fatty Liver , Insulin Resistance , PPAR gamma , Animals , Mice , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Diet, High-Fat , Diosmin/pharmacology , Diosmin/metabolism , Diosmin/therapeutic use , Fatty Liver/metabolism , Inflammation/metabolism , Mice, Inbred C57BL , Obesity/metabolism , PPAR gamma/metabolism , Adipose Tissue, Brown/metabolismABSTRACT
The interaction between cerebellum and cerebrum participates widely in function from motor processing to high-level cognitive and affective processing. Because of the motor symptom, idiopathic generalized epilepsy (IGE) patients with generalized tonic-clonic seizure have been recognized to associate with motor abnormalities, but the functional interaction in the cerebello-cerebral circuit is still poorly understood. Resting-state functional magnetic resonance imaging data were collected for 101 IGE patients and 106 healthy controls. The voxel-based functional connectivity (FC) between cerebral cortex and the cerebellum was contacted. The functional gradient and independent components analysis were applied to evaluate cerebello-cerebral functional integration on the voxel-based FC. Cerebellar motor components were further linked to cerebellar gradient. Results revealed cerebellar motor functional modules were closely related to cerebral motor components. The altered mapping of cerebral motor components to cerebellum was observed in motor module in patients with IGE. In addition, patients also showed compression in cerebello-cerebral functional gradient between motor and cognition modules. Interestingly, the contribution of the motor components to the gradient was unbalanced between bilateral primary sensorimotor components in patients: the increase was observed in cerebellar cognitive module for the dominant hemisphere primary sensorimotor, but the decrease was found in the cerebellar cognitive module for the nondominant hemisphere primary sensorimotor. The present findings suggest that the cerebral primary motor system affects the hierarchical architecture of cerebellum, and substantially contributes to the functional integration evidence to understand the motor functional abnormality in IGE patients.
Subject(s)
Epilepsy, Generalized , Magnetic Resonance Imaging , Humans , Neural Pathways , Brain Mapping/methods , Epilepsy, Generalized/diagnostic imaging , Epilepsy, Generalized/pathology , Cerebral Cortex/diagnostic imaging , Cerebellum/diagnostic imaging , Immunoglobulin EABSTRACT
OBJECTIVE: To evaluate the role of PRDX2 in nonalcoholic steatohepatitis (NASH). METHODS: NASH was induced in wild-type (WT) mice and liver-specific PRDX2 knockout (PRDX2 LKO) mice that were fed a methionine-choline deficient diet (MCD) for 5 weeks. Assessments of PRDX2 LKO's impact on the pathogenesis of NASH include histological analyses, quantitative PCR (q-PCR), western blotting (WB), and RNA sequencing (RNA-Seq). RESULTS: PRDX2 LKO mice exhibited a significant increase in hepatic lipid accumulation and inflammation compared to WT mice after MCD feeding. PRDX2 KO markedly elevated circulating levels of aspartate aminotransferase (AST) and the pro-inflammatory signaling pathways within the liver. There was a notable increase in the activities of signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa B (NF-кB). We also found that PRDX2 KO significantly increased the extent of lipid peroxidation in the liver, most likely owing to the impaired peroxidase activity of PRDX2. Of interest, these findings were observed only in MCD-fed female mice, suggesting the sexual dimorphism of PRDX2 KO in MCD-induced NASH. CONCLUSION: PRDX2 deficiency increases MCD-induced NASH in female mice, suggesting a protective role for PRDX2.
Subject(s)
Choline Deficiency , Non-alcoholic Fatty Liver Disease , Mice , Female , Animals , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Choline/metabolism , Methionine/metabolism , Choline Deficiency/metabolism , Liver/metabolism , Racemethionine/metabolism , Diet , Mice, Knockout , Mice, Inbred C57BLABSTRACT
DNA methylation, an epigenetic regulatory mechanism dictating gene transcription, plays a critical role in the occurrence and development of cancer. However, the molecular underpinnings of LINC00987 methylation in the regulation of lung adenocarcinoma (LUAD) remain elusive. This study investigated LINC00987 expression in LUAD patients through analysis of The Cancer Genome Atlas data sets. Quantitative real-time polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization assays were used to assess LINC00987 expression in LUAD. The bisulfite genomic sequence PCR (BSP) assay was used to determine the methylation levels of the LINC00987 promoter. The interaction between LINC00987 and SND1 was elucidated via immunoprecipitation and RNA pull-down assays. The functional significance of LINC00987 and SND1 in Calu-3 and NCI-H1688 cells was evaluated in vitro through CCK-8, EdU, Transwell, flow cytometry, and vasculogenic mimicry (VM) tube formation assays. LINC00987 expression decreased in LUAD concomitant with hypermethylation of the promoter region, while hypomethylation of the LINC00987 promoter in LUAD tissues correlated with tumor progression. Treatment with 5-Aza-CdR augmented LINC00987 expression and inhibited tumor growth. Mechanistically, LINC00987 overexpression impeded LUAD progression and VM through direct binding with SND1, thereby facilitating its phosphorylation and subsequent degradation. Additionally, overexpression of SND1 counteracted the adverse effects of LINC00987 downregulation on cell proliferation, apoptosis, cell migration, invasion, and VM in LUAD in vitro. In conclusion, this pioneering study focuses on the expression and function of LINC00987 and reveals that hypermethylation of the LINC00987 gene may contribute to LUAD progression. LINC00987 has emerged as a potential tumor suppressor gene in tumorigenesis through its binding with SND1 to facilitate its phosphorylation and subsequent degradation.
Subject(s)
Adenocarcinoma of Lung , Cell Proliferation , DNA Methylation , Disease Progression , Down-Regulation , Gene Expression Regulation, Neoplastic , Lung Neoplasms , RNA, Long Noncoding , Female , Humans , Male , Middle Aged , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/metabolism , Apoptosis , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Endonucleases/genetics , Endonucleases/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Phosphorylation , Promoter Regions, Genetic , RNA, Long Noncoding/geneticsABSTRACT
Metabolic reprogramming induced by Epstein-Barr virus (EBV) often mirrors metabolic changes observed in cancer cells. Accumulating evidence suggests that lytic reactivation is crucial in EBV-associated oncogenesis. The aim of this study was to explore the role of metabolite changes in EBV-associated malignancies and viral life cycle control. We first revealed that EBV (LMP1) accelerates the secretion of the oncometabolite D-2HG, and serum D-2HG level is a potential diagnostic biomarker for NPC. EBV (LMP1)-driven metabolite changes disrupts the homeostasis of global DNA methylation and demethylation, which have a significantly inhibitory effect on active DNA demethylation and 5hmC content. We found that loss of 5hmC indicates a poor prognosis for NPC patients, and that 5hmC modification is a restriction factor of EBV reactivation. We confirmed a novel EBV reactivation inhibitor, α-KG, which inhibits the expression of EBV lytic genes with CpG-containing ZREs and the latent-lytic switch by enhancing 5hmC modification. Our results demonstrate a novel mechanism of which metabolite abnormality driven by EBV controls the viral lytic reactivation through epigenetic modification. This study presents a potential strategy for blocking EBV reactivation, and provides potential targets for the diagnosis and therapy of NPC.
Subject(s)
DNA Methylation , Epstein-Barr Virus Infections , Herpesvirus 4, Human , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Virus Activation , Humans , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/physiology , Nasopharyngeal Carcinoma/virology , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Neoplasms/virology , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Epstein-Barr Virus Infections/virology , Epstein-Barr Virus Infections/complications , Viral Matrix Proteins/metabolism , Viral Matrix Proteins/genetics , Epigenesis, Genetic , Disease ProgressionABSTRACT
BACKGROUND: Because of to the removal of subclassification of papillary renal cell carcinoma (pRCC), the survival prognostification of localized pRCC after surgical treatment became inadequate. Sarcopenia was widely evaluated and proved to be a predictive factor for prognosis in RCC patients. Therefore, we comprehensively investigated the survival prediction of the body composition parameters for localized pRCC. METHODS: Patients pathologically diagnosed with pRCC between February 2012 and February 2022 in our center were enrolled. The body composition parameters, including skeletal muscle index (SMI), subcutaneous adipose tissue (SAT), and perirenal adipose tissue (PRAT), were measured by the images of preoperative computed tomography (CT). The primary outcome was set as progression-free survival (PFS), and the cutoff values of body composition parameters were calculated by using the Youden from receiver operating characteristic curve (ROC) curves. Univariate and multivariate Cox proportional regression analyses were performed to explore independent risk factors for survival prediction. Then, significant factors were used to construct a prognostic nomogram. The performance of the nomogram was evaluated by Harrell's C-index, calibration curves and time-dependent ROC curves. RESULTS: A total of 105 patients were enrolled for analysis. With a median follow-up time of 30.48 months, 25 (23.81%) patients experienced cancer progression. The percentage of sarcopenia was 74.29%. Univariate Cox analysis identified that gender, PRAT, SAT, skeletal muscle (SM), sarcopenia, surgical technique, and tumor diameter were associated with progression. Further multivariate analysis showed that sarcopenia (hazard ratio [HR] 0.15, 95% confidence interval [CI] 0.03-0.66), SAT (HR 6.36, 95% CI 2.39-16.93), PRAT (HR 4.66, 95% CI 1.77-12.27), tumor diameter (HR 0.35, 95% CI 0.14-0.86), and surgical technique (HR 2.85, 95% CI 1.06-7.64) were independent risk factors for cancer progression. Then, a prognostic nomogram based on independent risk factors was constructed and the C-index for progression prediction was 0.831 (95% CI 0.761-0.901), representing a reasonable discrimination, the calibration curves, and the time-dependent ROC curves verified the good performance of the nomogram. CONCLUSIONS: A prognostic nomogram, including sarcopenia, SAT, PRAT, tumor diameter, and surgical technique, was constructed to calculate the probability of progression for localized pRCC patients and needs further external validation for clinical use in the future.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Nomograms , Sarcopenia , Humans , Sarcopenia/pathology , Sarcopenia/diagnostic imaging , Male , Female , Retrospective Studies , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Kidney Neoplasms/mortality , Middle Aged , Carcinoma, Renal Cell/surgery , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/mortality , Survival Rate , Follow-Up Studies , Prognosis , Aged , ROC Curve , Progression-Free Survival , Body Composition , AdultABSTRACT
We theoretically study the second-harmonic generation (SHG) of two-dimensional (2D) materials excited by a Laguerre-Gaussian (LG) beam at normal incidence and provide a method to distinguish SHG induced by the electric dipole (ED) interaction and SHG induced by the electric quadrupole and magnetic dipole (EQ-MD) interaction by their different dependence on the LG beam parameters, including the effective spot area v02 and the order of orbital angular momentum (OAM) m. In an approximation of neglecting reflection and taking a beam radius to infinity, the intensity of the ED induced SHG is proportional to F m/v02 with Fm = 2-2|m|(2|m|)!/(π(|m|!)2), while the EQ-MD induced one is proportional to (4|m|+2)F m/v04. An in-plane isotropic substrate can strongly affect the signal amplitude but slightly change the v0 and m dependence. Our results provide an all-optical way to detect the OAM by SHG, as well as a theoretical basis for studying the EQ-MD induced SHG by the LG beams.
ABSTRACT
BACKGROUND: Accurate microsatellite instability (MSI) testing is essential for identifying gastric cancer (GC) patients eligible for immunotherapy. We aimed to develop and validate a CT-based radiomics signature to predict MSI and immunotherapy outcomes in GC. METHODS: This retrospective multicohort study included a total of 457 GC patients from two independent medical centers in China and The Cancer Imaging Archive (TCIA) databases. The primary cohort (n = 201, center 1, 2017-2022), was used for signature development via Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis. Two independent immunotherapy cohorts, one from center 1 (n = 184, 2018-2021) and another from center 2 (n = 43, 2020-2021), were utilized to assess the signature's association with immunotherapy response and survival. Diagnostic efficiency was evaluated using the area under the receiver operating characteristic curve (AUC), and survival outcomes were analyzed via the Kaplan-Meier method. The TCIA cohort (n = 29) was included to evaluate the immune infiltration landscape of the radiomics signature subgroups using both CT images and mRNA sequencing data. RESULTS: Nine radiomics features were identified for signature development, exhibiting excellent discriminative performance in both the training (AUC: 0.851, 95%CI: 0.782, 0.919) and validation cohorts (AUC: 0.816, 95%CI: 0.706, 0.926). The radscore, calculated using the signature, demonstrated strong predictive abilities for objective response in immunotherapy cohorts (AUC: 0.734, 95%CI: 0.662, 0.806; AUC: 0.724, 95%CI: 0.572, 0.877). Additionally, the radscore showed a significant association with PFS and OS, with GC patients with a low radscore experiencing a significant survival benefit from immunotherapy. Immune infiltration analysis revealed significantly higher levels of CD8 + T cells, activated CD4 + B cells, and TNFRSF18 expression in the low radscore group, while the high radscore group exhibited higher levels of T cells regulatory and HHLA2 expression. CONCLUSION: This study developed a robust radiomics signature with the potential to serve as a non-invasive biomarker for GC's MSI status and immunotherapy response, demonstrating notable links to post-immunotherapy PFS and OS. Additionally, distinct immune profiles were observed between low and high radscore groups, highlighting their potential clinical implications.
Subject(s)
Radiomics , Stomach Neoplasms , Humans , Cohort Studies , Stomach Neoplasms/diagnostic imaging , Stomach Neoplasms/genetics , Stomach Neoplasms/therapy , Retrospective Studies , Microsatellite Instability , Immunotherapy , Tomography, X-Ray Computed , ImmunoglobulinsABSTRACT
The highly sensitive gas sensors used to monitor the decomposition of toxic gases in the dielectric materials of electrical equipment are vital in preventing safety problems arising from corrosion of the equipment. Recently, biphenylene (BPN) has been prepared through surface interpolymer hydrofluorination (HF zipper) reaction, whereas potential gas-sensitive devices based on the BPN monolayer have lacked in-depth investigation. The stable geometries, adsorption energies, interlayer distances, and charge transfers of small molecules of toxic gases (H2S, SO2, SOF2, SO2F2) produced by SF6 chalcogenide molecules of decomposition adsorbed on the original BPN monolayer are systematically researched by using nonequilibrium Green's function methods and density functional theory. The results indicated that all small molecules adsorbed on the BPN monolayer are physisorbed, while the type of adsorption turned from physisorption to chemisorption when BPN carried out adsorption with adsorbing a transition metal atom (TMA). In addition, the characteristics of current-voltage (I-V) curves of H2S and SO2 based on the TMA-BPN gas sensors revealed that the currents in BPN-based gas sensors displayed an obvious anisotropy, and the currents in the zigzag direction are larger than that in the armchair orientation regardless of the molecular adsorption cases. Moreover, the difference of currents for TMA-decorated BPN sensors changed more remarkably before and after the adsorption of H2S and SO2 in the zigzag direction. This work offers insights into the design of gas-sensitive devices through the adsorption of small molecules on the TMA-decorated BPN monolayer.
ABSTRACT
This study aimed to explore the effect of PF in regulating the progression of T1D through regulating gut microbiota and inhibiting TLR4-myD88/TRIF pathway. T1D mouse models were established and received PF treatment through intraperitoneal injection. The glucose, sugar tolerance, the incidence of T1D and H&E staining were detected to verify the effect of PF on T1D. Meanwhile, the changes of gut microbiota and the permeability of intestines in mice were also measured. On parallel, the number and function of immune cells were detected by Flow Cytometry. The expressions of ZO-1, ZO-2 and TLR4-myD88/TRIF pathway related proteins were detected by western blotting. Mice received PF treatment had decreased incidence of T1D and inflammatory infiltration in islet tissues compared with those received PBS treatment. In addition to that, PF treated mice had increased Sutterella species and decreased intestinal permeability, in which the decreased ratio of Th1/Th17 and increased Treg cells were also identified. The expression of TLR4-myD88/TRIF pathway was also suppressed in response to PF treatment. Moreover, further treatment with TLR4 agonist, LPS, could reverse the effect of PF on T1D mice. PF can suppress the TLR4 mediated myD88/TRIF pathway to change the distribution of gut microbiota, so as to protect NOD mice from T1D.