ABSTRACT
Hypotrichosis is a genetic disorder characterized by a diffuse and progressive loss of scalp and/or body hair. Nonetheless, the causative genes for several affected individuals remain elusive, and the underlying mechanisms have yet to be fully elucidated. Here, we discovered a dominant variant in a disintegrin and a metalloproteinase domain 17 (ADAM17) gene caused hypotrichosis with woolly hair. Adam17 (p.D647N) knockin mice mimicked the hair abnormality in patients. ADAM17 (p.D647N) mutation led to hair follicle stem cell (HFSC) exhaustion and caused abnormal hair follicles, ultimately resulting in alopecia. Mechanistic studies revealed that ADAM17 binds directly to E3 ubiquitin ligase tripartite motif-containing protein 47 (TRIM47). ADAM17 variant enhanced the association between ADAM17 and TRIM47, leading to an increase in ubiquitination and subsequent degradation of ADAM17 protein. Furthermore, reduced ADAM17 protein expression affected the Notch signaling pathway, impairing the activation, proliferation, and differentiation of HFSCs during hair follicle regeneration. Overexpression of Notch intracellular domain rescued the reduced proliferation ability caused by Adam17 variant in primary fibroblast cells.
Subject(s)
ADAM17 Protein , Alopecia , Hair Follicle , Ubiquitin-Protein Ligases , ADAM17 Protein/metabolism , ADAM17 Protein/genetics , Animals , Alopecia/genetics , Alopecia/metabolism , Alopecia/pathology , Mice , Hair Follicle/metabolism , Hair Follicle/pathology , Humans , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Male , Signal Transduction/genetics , Tripartite Motif Proteins/metabolism , Tripartite Motif Proteins/genetics , Female , Mutation , Gene Knock-In Techniques , Cell Proliferation/genetics , Cell Differentiation/genetics , Proteolysis , Disease Models, Animal , Fibroblasts/metabolism , Receptors, Notch/metabolism , Receptors, Notch/geneticsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Exocarpium Citri Grandis (ECG), the epicarp of C. grandis 'Tomentosa' which is also known as Hua-Ju-Hong in China, has been widely used for thousands of years to treat inflammatory lung disorders such as asthma, and cough as well as dispelling phlegm. However, its underlying pharmacological mechanisms in acute lung injury (ALI) remain unclear. AIM OF THE STUDY: To explore the therapeutic effect of ECG on ALI and reveal the potential mechanisms based on experimental techniques in vivo and in vitro. MATERIALS AND METHODS: Lipopolysaccharides (LPS) induced ALI in mice and induced RAW 264.7 cell inflammatory model were established to investigate the pharmacodynamics of ECG. ELISA kits, commercial kits, Western Blot, qPCR, Hematoxylin and Eosin (H&E) staining, immunohistochemistry, and immunofluorescence technologies were used to evaluate the pharmacological mechanisms of ECG in ameliorating ALI. RESULTS: ECG significantly attenuated pulmonary edema in LPS-stimulated mice and decreased the levels of IL1ß, IL6, and TNF-α in serum and BALF, reduced MDA and iron concentration as well as increased SOD and GSH levels in lung tissues, and also decreased the ROS level in BALF and Lung tissue. Further pharmacological mechanism studies showed that ECG significantly inhibited mRNA expression of inflammatory signaling factors and chemokines, and down-regulated the expression of TLR4, MyD88, NF-κB p65, NF-κB p-p65 (S536), COX2, iNOS, Txnip, NLRP3, ASC, Caspase-1, JAK1, p-JAK1 (Y1022), JAK2, STAT1, p-STAT1 (S727), STAT3, p-STAT3 (Y705), STAT4, p-STAT4 (Y693), and Keap1, and also up-regulated the expression of Trx-1, Nrf2, HO-1, NQO1, GPX4, PCBP1, and SLC40A1. In the LPS-induced RAW264.7 cell inflammatory model, ECG showed similar results to animal experiments. CONCLUSIONS: Our results showed that ECG alleviated ALI by inhibiting TLR4/MyD88/NF-κB p65 and JAK/STAT signaling pathway-mediated inflammatory response, Txnip/NLRP3 signaling pathway-mediated inflammasome activation, and regulating Nrf2/GPX4 axis-mediated ferroptosis. Our findings provide an experimental basis for the application of ECG.
Subject(s)
Acute Lung Injury , Ferroptosis , Inflammasomes , Lipopolysaccharides , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Acute Lung Injury/drug therapy , Acute Lung Injury/chemically induced , Acute Lung Injury/metabolism , Mice , Lipopolysaccharides/toxicity , RAW 264.7 Cells , Ferroptosis/drug effects , Male , Inflammasomes/metabolism , Inflammation/drug therapy , Anti-Inflammatory Agents/pharmacology , Mice, Inbred C57BL , Citrus/chemistry , Signal Transduction/drug effects , Plant Extracts/pharmacology , Lung/drug effects , Lung/pathology , Lung/metabolismABSTRACT
Background: In addition to abnormal liver inflammation, the main symptoms of non-alcoholic steatohepatitis (NASH) are often accompanied by gastrointestinal digestive dysfunction, consistent with the concept of spleen deficiency (SD) in traditional Chinese medicine. As an important metabolic sensor, whether peroxisome proliferator-activated receptor alpha (PPARα) participates in regulating the occurrence and development of NASH with SD (NASH-SD) remains to be explored. Methods: Clinical liver samples were collected for RNA-seq analysis. C57BL/6J mice induced by folium sennae (SE) were used as an SD model. qPCR analysis was conducted to evaluate the inflammation and metabolic levels of mice. PPARα knockout mice (PPARαko) were subjected to SE and methionine-choline-deficient (MCD) diet to establish the NASH-SD model. The phenotype of NASH and the inflammatory indicators were measured using histopathologic analysis and qPCR as well. Results: The abnormal expression of PPARα signaling, coupled with metabolism and inflammation, was found in the results of RNA-seq analysis from clinical samples. SD mice showed a more severe inflammatory response in the liver evidenced by the increases in macrophage biomarkers, inflammatory factors, and fibrotic indicators in the liver. qPCR results also showed differences in PPARα between SD mice and control mice. In PPARαko mice, further evidence was found that the lack of PPARα exacerbated the inflammatory response phenotype as well as the lipid metabolism disorder in NASH-SD mice. Conclusion: The abnormal NR signaling accelerated the vicious cycle between lipotoxicity and inflammatory response in NAFLD with SD. Our results provide new evidence for nuclear receptors as potential therapeutic targets for NAFLD with spleen deficiency.
Subject(s)
Non-alcoholic Fatty Liver Disease , PPAR alpha , Animals , Mice , Inflammation , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , PPAR alpha/metabolism , Spleen/metabolism , Spleen/pathologyABSTRACT
Cutaneous squamous carcinoma is the second most common epithelial malignancy, associated with significant morbidity, mortality, and economic burden. However, the mechanisms underlying cSCC remain poorly understood. In this study, we identified TGM3 as a novel cSCC tumor suppressor that acts via the PI3K-AKT axis. RT-qPCR, IHC and western blotting were employed to assess TGM3 levels. TGM3-overexpression/knockdown cSCC cell lines were utilized to detect TGM3's impact on epithelial differentiation as well as tumor cell proliferation, migration, and invasion in vitro. Additionally, subcutaneous xenograft tumor models were employed to examine the effect of TGM3 knockdown on tumor growth in vivo. Finally, molecular and biochemical approaches were employed to gain insight into the tumor-suppressing mechanisms of TGM3. TGM3 expression was increased in well-differentiated cSCC tumors, whereas it was decreased in poor-differentiated cSCC tumors. Loss of TGM3 is associated with poor differentiation and a high recurrence rate in patients with cSCC. TGM3 exhibited tumor-suppressing activity by regulating cell proliferation, migration, and invasion both in vitro and in vivo. As a novel cSCC tumor differentiation marker, TGM3 expression was positively correlated with cell differentiation. In addition, our results demonstrated an interaction between TGM3 and KRT14 that aids in the degradation of KRT14. TGM3 deficiency disrupts keratinocytes differentiation, and ultimately leads to tumorigenesis. Furthermore, RNA-sequence analysis revealed that loss of TGM3 enhanced EMT via the PI3K-AKT signaling pathway. Deguelin, a PI3K-AKT inhibitor, blocked cSCC tumor growth induced by TGM3 knockdown in vivo. Taken together, TGM3 inhibits cSCC tumor growth via PI3K-AKT signaling, which could also serve as a tumor differentiation marker and a potential therapeutic target for cSCC. Proposed model depicted the mechanism by which TGM3 suppress cSCC development. TGM3 reduces the phosphorylation level of AKT and degrades KRT14. In the epithelial cell layer, TGM3 exhibits a characteristic pattern of increasing expression from bottom to top, while KRT14 and pAKT are the opposite. Loss of TGM3 leads to reduced degradation of KRT14 and activation of pAKT, disrupting keratinocyte differentiation, and eventually resulting in the occurrence of low-differentiated cSCC.
Subject(s)
Carcinoma, Squamous Cell , Skin Neoplasms , Humans , Proto-Oncogene Proteins c-akt/metabolism , Skin Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Keratin-14/genetics , Keratin-14/metabolism , Carcinoma, Squamous Cell/metabolism , Signal Transduction , Cell Proliferation/genetics , Cell Differentiation , Antigens, Differentiation , Transglutaminases/genetics , Transglutaminases/metabolism , Cell Line, TumorABSTRACT
Casting defects in turbine blades can significantly reduce an aero-engine's service life and cause secondary damage to the blades when exposed to harsh environments. Therefore, casting defect detection plays a crucial role in enhancing aircraft performance. Existing defect detection methods face challenges in effectively detecting multi-scale defects and handling imbalanced datasets, leading to unsatisfactory defect detection results. In this work, a novel blade defect detection method is proposed. This method is based on a detection transformer with a multi-scale fusion attention mechanism, considering comprehensive features. Firstly, a novel joint data augmentation (JDA) method is constructed to alleviate the imbalanced dataset issue by effectively increasing the number of sample data. Then, an attention-based channel-adaptive weighting (ACAW) feature enhancement module is established to fully apply complementary information among different feature channels, and further refine feature representations. Consequently, a multi-scale feature fusion (MFF) module is proposed to integrate high-dimensional semantic information and low-level representation features, enhancing multi-scale defect detection precision. Moreover, R-Focal loss is developed in an MFF attention-based DEtection TRansformer (DETR) to further solve the issue of imbalanced datasets and accelerate model convergence using the random hyper-parameters search strategy. An aero-engine turbine blade defect X-ray (ATBDX) image dataset is applied to validate the proposed method. The comparative results demonstrate that this proposed method can effectively integrate multi-scale image features and enhance multi-scale defect detection precision.
ABSTRACT
Oxygen-reduced air flooding (ORAF) can effectively improve oil recovery in low-permeability reservoirs, but oxygen corrosion and CO2 corrosion in downstream gathering pipelines are inevitable due to the existence of oxygen, which limits the popularization and application of ORAF. In this paper, research on the corrosion inhibitor is carried out for the gathering pipeline of an oilfield with ORAF in China. Under the conditions of a simulated onsite gathering pipeline, 6 kinds of anti-CO2 corrosion inhibitors and 6 kinds of antioxygen corrosion inhibitors were selected to evaluate and screen the effects of 20# steel by the dynamic weight loss method. Two antioxygen corrosion inhibitors KY-12 and KY-17 and one anti-CO2 corrosion inhibitor A were selected for the experiment. The corrosion inhibition rates of the three inhibitors reached 83.67, 91.49, and 78.44%, respectively, at a temperature of 40 °C and an inhibitor concentration of 1000 mg/L. Through the experimental evaluation of three primary corrosion inhibitors at different temperatures (25, 40, and 55 °C) and different concentrations (400, 500, 800, 1000, and 2000 mg/L), the KY-17 corrosion inhibitor with the best stability at different temperatures was selected, and the corrosion inhibition effect was the best at different concentrations, with the highest slow release rate reaching 92.7%. This conclusion has a good reference significance for the selection and dosage of corrosion inhibitors for downstream gathering pipelines of the ORAF oilfield.
ABSTRACT
OBJECTIVE: To determine the clinical markers based on cognitive and motor profiles in predicting phenoconverion and phenotype in isolated rapid eye movement sleep behavior disorder (iRBD). METHODS: 45 iRBD patients and 25 healthy controls were included in the follow-up study. All participates received comprehensive evaluations of cognitive, motor and autonomic function at baseline. Positive phenoconversion were identified according to standard diagnostic criteria during follow-up. RESULTS: 21 iRBD patients displayed phenoconversion in a mean follow-up of 2.9 ± 1.6 years, with 14 presenting motor phenotype and 7 cognitive phenotype. In iRBD, visuospatial, memory, attention-executive function, information processing speed, and motor function predicted phenoconversion, with the combination of Trail Making Test (TMT) and Alternate-tap Test (ATT) performing best (sensitivity = 95.0 %, specificity = 75.0 %); attention-executive function, information processing speed, and motor function predicted motor phenotype conversion, with the combination of TMT and ATT performing best (sensitivity = 100 %, specificity = 66.7 %); visuospatial, memory, and attention-executive function predicted cognitive phenotype conversion, with TMT performing best (sensitivity = 83.3 %, specificity = 91.7 %). Furthermore, individuals with lower z-scores of TMT, Symbol Digit Modalities Test, and ATT than the established cutoff values in iRBD exhibited a significantly higher risk for phenoconversion at follow-up (HR = 2.98, 9.53, 11.68; respectively). CONCLUSIONS: In iRBD, the attention-executive and motor function served as optimum combined markers in predicting phenoconversion and motor phenotype, whereas the attention-executive function performed best in predicting cognitive phenotype. Poor attention-executive function, information processing speed and motor function in iRBD independently increased the risk of phenoconversion.
Subject(s)
REM Sleep Behavior Disorder , Humans , Follow-Up Studies , Executive Function , Cognition , PhenotypeABSTRACT
is missing (Quiz).
Subject(s)
Dermatitis, Atopic , Hyperpigmentation , Aged , Humans , PatientsABSTRACT
In order to investigate the corrosion behavior of N80 steel in production wellbores of oxygen-reduced air drive, the main corrosion control factors are analyzed based on gray relational analysis. Taking reservoir simulation results as indoor simulation parameters, the corrosion behavior in different production periods is studied by the dynamic weight loss method combined with metallographic microscopy, XRD, 3D morphology, and other related characterizations. The results show that oxygen content is most sensitive to the corrosion of production wellbores. The corrosion rate increases significantly under oxygen-containing conditions, and the corrosion rate at an oxygen content of 3% (0.3 MPa) is about 5 times higher than that without oxygen. At the initial stage of oil displacement, the corrosion is CO2-dominated localized corrosion, and the corrosion products are mainly compact FeCO3. With the prolongation of gas injection time, the wellbore is in a CO2/O2 balanced environment, the corrosion changes into a combined action of the two, and the corrosion products are FeCO3 and loose porous Fe2O3. After continuous gas injection for 3 years, the production wellbore is in a high O2 and low CO2 environment, the dense FeCO3 is destroyed, the corrosion pit develops horizontally, and the corrosion changes to O2-dominated comprehensive corrosion.
ABSTRACT
Purpose: To evaluate the correlation between sleep microstructure, autonomic nervous system activity, and neuropsychological characteristics in chronic insomnia (CI) patients with obstructive sleep apnea (OSA). Patients and Methods: Forty-five CI-OSA patients, forty-six CI patients and twenty-two matched healthy control subjects (HCs) were enrolled. CI-OSA patients were then divided into two groups: mild OSA and moderate-to-severe OSA. All participants completed neuropsychological tests, which included the Hamilton Depression and Anxiety Scales (HAMD and HAMA), the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), the Epworth Sleepiness Scale (ESS), and the Mini-mental State Examination (MMSE). The autonomic nervous system activity and sleep microstructure were examined by the PSM-100A. Results: The CI-OSA patients exhibited higher scores on the PSQI, ESS, ISI, HAMA, and HAMD than HCs and CI patients (all p < 0.01). The CI-OSA patients had a lower proportion of stable sleep, REM sleep and a higher proportion of unstable sleep ratio (all p < 0.01) than HCs and CI patients (all p < 0.01). The CI-OSA patients had higher ratios of LF and LF/HF, and lower ratios of HF and Pnn50% (all p < 0.01) than HCs and CI patients (all p < 0.01). Compared to CI-mild OSA patients, the CI-moderate-to-severe OSA patients presented with a higher ESS scores, higher ratios of LF and LF/HF, and lower ratios of HF (all p < 0.05). In CI-OSA patients, higher HAMD scores were correlated with decreased MMSE scores (r=-0.678, p < 0.01). A higher LF ratio was correlated with higher HAMD and HAMA scores (r=0.321, p=0.031, r =0.449, p =0.002), and a higher HF ratio was correlated with lower HAMD and HAMA scores (r=-0.321, P =0.031, r =-0.449, p =0.002). Conclusion: OSA exacerbates the abnormalities of sleep microstructure and the autonomic nervous dysfunction in CI patients. Dysfunction of the autonomic nervous system could contribute to mood deterioration in CI with OSA patients.
ABSTRACT
Following the publication of the above paper, a concerned reader drew to the authors' attention that, in Fig. 4C on p. 8, the 'Invasion, miR675inhibitor' data panel appeared to contain an overlapping section with the 'Invasion, miR675inhibitor + pcDNA3.1H19' data panel for the SCL1 cell line, such that the data were likely to have been derived from the same original source, even though they were intended to show the results from differently performed experiments. After having examined the original data, the authors also realized that the 'InhibitorNC' and 'miR675inhibitor' data panels showing the migration assay experiments for the A431 cell line in the same figure part had also inadvertently been derived from the same original source. After having been granted permission from the Editor of Oncology Reports to repeat the experiments shown in Fig. 4C, the revised version of Fig. 4, incorporating the new data for Fig. 4C, is shown on the next page. Note that these errors did not affect the overall conclusions reported in the study, and the repeated experiment yielded similar results to those obtained originally. The authors are grateful to the Editor for allowing them the opportunity to publish this corrigendum, and all the authors agree with the publication of this; furthermore, they apologize for any inconvenience caused to the readership of the Journal. [Oncology Reports 45: 39, 2021; DOI: 10.3892/or.2021.7990].
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In this paper, the interacting characteristics of febuxostat (FBST), an inhibitor of xanthine oxidase for treating gout patients with hyperuricemia with calf thymus DNA (ctDNA) was investigated through multi-spectroscopic methodologies combined with theoretical calculation for understanding the interacting mode on ctDNA, affinity with ctDNA, interacting forces, as well as the alteration in the conformation of ctDNA after interacting FBST The experimental results demonstrated that interacting FBST with ctDNA formed 1:1 complex, the association constant was 913 M-1 at 298 K, suggesting the affinity of FBST on ctDNA was very weak, the interacting mode of FBST on ctDNA was groove binding, and it inserted into the minor groove with rich A-T region of ctDNA. Based on the results of the thermodynamic analysis and theoretical calculation, it can be inferred that the dominated interacting forces between FBST and ctDNA were van der Waals forces and hydrogen bond. And, interacting FBST with ctDNA was a spontaneous, enthalpy-driven, and exothermic process because of ΔG0 < 0, ΔH0 < 0, and |ΔH0| > T|ΔS0|. The results of the circular dichroism (CD) measurements indicated the conformation of ctDNA was weakly disturbed after interacting with FBST but still maintained B-conform. The studied results offer significant insight into further clarifying whether it has genotoxicity.
Subject(s)
Febuxostat , Xanthine Oxidase , Circular Dichroism , DNA/chemistry , Febuxostat/pharmacology , Humans , Molecular Docking Simulation , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , ThermodynamicsABSTRACT
Sleep deprivation negatively influences cognition, however, the regulatory mechanisms to counteract this effect have not been identified. IGF-1 has been shown to be anti-inflammatory and neuroprotective in CNS injury models. In this study, we determined the impact of IGF-1 on brain injury and inflammation while modeling sleep deprivation. We found that IGF-1 was downregulated in human peripheral blood and in mice subjected to sleep deprivation for 5 days, with reduced activation of the downstream PI3K/AKT/GSK-3ß pathway in mice brains. In addition, we found reduced levels of the anti-apoptosis enzyme Bcl-2 and increased levels of pro-apoptosis enzyme Caspase-9 expression, together with increased pro-inflammatory factors. The administration of IGF-1 after sleep deprivation induced activation of the PI3K/AKT/GSK-3ß pathway, reversed changes in Bcl-2, Caspase-9, and pro-inflammatory factors, and alleviated cognitive impairment. Notably, IGF-1 also induced activation of the PI3K/AKT/GSK-3ß pathway, and displayed anti-apoptosis and anti-inflammatory properties under normal sleep conditions,while IGF-1 did not improve the cognition under normal sleep conditions. These results suggest that the IGF-1/PI3K/AKT/GSK-3ß pathway is involved in the regulation of cognitive function after sleep deprivation through modulation of apoptosis and inflammatory response. IGF-1 could be a viable therapeutic target, though further investigation is required to better understand its role in sleep deprivation.
Subject(s)
Cognitive Dysfunction , Phosphatidylinositol 3-Kinases , Animals , Apoptosis , Cognition , Cognitive Dysfunction/etiology , Glycogen Synthase Kinase 3 beta , Insulin-Like Growth Factor I/pharmacology , Mice , Neuroinflammatory Diseases , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Sleep Deprivation/complicationsABSTRACT
OBJECTIVE: To investigate the positive impact of e-aid cognitive behavioural therapy on the sleep quality, anxiety, and depression of nurses on site during the COVID-19 pandemic. METHODS: Nurses on site at the Tianjin Medical University General Hospital Airport Site experiencing insomnia, anxiety and depression during the COVID-19 prevention and control period, from February 2020 to April 2021, were selected and divided into either an e-aid cognitive behavioural therapy (eCBT-I) group or a control group using a randomized grouping method. The eCBT-I group was given standard eCBT-I for 6 weeks; the control group did not get any intervention. The Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) were used to evaluate the sleep quality of the subjects. The Generalized Anxiety Disorder 7-item (GAD-7) and the Patient Health Questionnaire (PHQ-9) were used to assess the subjects' anxiety and depression. Changes in sleep quality, anxiety and depression before and after treatment were compared between the two groups. RESULTS: Of 118 nurses randomized, the PSQI and ISI scores within the eCBT-I group (n=60) were significantly lower after treatment (5.9 ± 3.9, 6.7 ± 4.5) than before treatment (10.4 ± 3.5, 12.4 ± 4.7) (p <0.05). Compared to the scores of the control group (n=58) (9.1 ± 3.9, 10.6 ± 4.1), the PSQI and ISI scores in the eCBT-I group (5.9 ± 3.9, 6.7 ± 4.5) were lower after treatment (p <0.05). The GAD-7 and PHQ-9 scores in the eCBT-I group were all lower after treatment (3.7±3.4, 4.2±4.1) than before treatment (6.7±4.9, 7.7±5.1) (p <0.05). Compared with subjects in the control group (7.1±5.6, 7.3±5.1), subjects in the eCBT-I group (3.7±3.4, 4.2±4.1) had lower scores on the GAD-7 and PHQ-9 scales after treatment (p <0.05). CONCLUSION: eCBT-I improved the sleep quality of frontline nurses during the COVID-19 prevention and control period and relieved anxiety and depression.
Subject(s)
COVID-19 , Cognitive Behavioral Therapy , Sleep Initiation and Maintenance Disorders , Humans , Pandemics , Sleep Initiation and Maintenance Disorders/therapy , Sleep Quality , Cognitive Behavioral Therapy/methods , Anxiety/therapy , Anxiety/psychologyABSTRACT
Background: Recent studies have identified that transglutaminases (TGMs) are involved in a widespread epigenetic modification in tumorigenesis. However, it remains unclear how transglutaminase 3 (TGM3) affects in pan-cancer. The present study aimed to explore the clinical and prognostic function of TGM3 in pan-cancer as well as to explore the relationship of TGM3 expression with clinical stage, survival rate, prognosis condition, immune infiltration and mutation indicators. Methods: The relevant data of tumors were obtained from The Cancer Genome Atlas (TCGA), TARGET, Cancer Cell Line Encyclopedia (CCLE) and Genotype-Tissue Expression (GTEx) databases. According to the Human Protein Atlas (HPA) and TIMER databases, we evaluated the protein expression levels of TGM3 in different organs and tissues as well as their association with immune cell infiltration and immunotherapeutic response in pan-cancers. Expression differences between normal and tumor tissues as well as survival and prognosis situation, clinical data characteristics, tumor mutational burden (TMB), microsatellite instability (MSI), and RNA methylation were also assessed. Oncogenic analyses were also evaluated by GSEA. Results: Compared to normal tissues, some tumor tissues had a lower expression level of TGM3, while other tumor tissues had a high expression level of TGM3. Further studies showed that high TGM3 expression had a certain risk impact on pan-cancer as high TGM3 expression levels were detrimental to the survival of several cancers, except for pancreatic cancer (PAAD). High expression level of TGM3 was also related to higher clinical stages in most cancers. The expression level of TGM3 was significantly negatively correlated with the expression of immune infiltration-related cells, including B cells, CD8+ T cells, CD4+ T cells, neutrophils, macrophages and dendritic cells (DCs). Furthermore, in most cancer types, TGM3 was inversely correlated with TMB, MSI, and methylation, suggesting that TGM3 expression can be used to assess potential therapeutic response, especially immune-related targeted therapy. GSEA analysis elucidated the biological and molecular function of TGM3 in various cancer types. Taken together, these bioinformatic analyses identified TGM3 as an important biomarker for clinical tumor prognosis and evaluation of treatment efficacy. Conclusion: We comprehensively analyzed the clinical characteristics, tumor stages, immune infiltration, methylation level, gene mutation, functional enrichment analysis and immunotherapeutic value of TGM3 in pan-cancer, providing implications for the function of TGM3 and its role in clinical treatment.
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The treatment of recessive dystrophic epidermolysis bullosa (RDEB) remains challenging. Elevated IgE levels have previously been reported in several RDEB patients. In this prospective, single-centre, open intervention study, elevated IgE levels were seen in 11 out of 12 patients with intense pruritus, and the patients with elevated IgE levels received anti-IgE therapy every 4 weeks for at least three cycles. Compared with the baseline, 10 patients with RDEB had good clinical outcomes with enhanced wound healing, a reduction in Birmingham (epidermolysis bullosa) EB severity score by 15%, a reduction in affected body surface area by 23.3%, amelioration of skin inflammation, and an increase in type VII collagen deposition by 13.1-fold. All the patients had a good tolerance to anti-IgE therapy. Furthermore, patients with higher IgE levels tended to have higher disease severity and more favorable clinical outcomes. Our report also suggested the potential role of IgE in the pathogenesis of inflammatory conditions associated with RDEB. (ChiCTR1900021437).
Subject(s)
Antibodies, Anti-Idiotypic/therapeutic use , Epidermolysis Bullosa Dystrophica/drug therapy , Adolescent , Adult , Antibodies, Anti-Idiotypic/administration & dosage , Antibodies, Anti-Idiotypic/adverse effects , Autoimmunity , Biopsy , Child , Collagen Type VII/immunology , Disease Management , Disease Susceptibility/immunology , Epidermolysis Bullosa Dystrophica/diagnosis , Epidermolysis Bullosa Dystrophica/etiology , Humans , Immunoglobulin E/blood , Immunoglobulin E/immunology , Middle Aged , Severity of Illness Index , Skin/immunology , Skin/metabolism , Skin/pathology , Treatment Outcome , Wound Healing , Young AdultABSTRACT
The binding behavior of ritonavir (RTV), a HIV/AIDS protease inhibitor, with ct-DNA was characterized through multiple testing technologies and theoretical calculation. The findings revealed that the RTV-DNA complex was formed through the noncovalent interaction mainly including conventional hydrogen bonds and carbon hydrogen bonds as well as hydrophobic interactions (pi-alkyl interactions). The stoichiometry and binding constant of the RTV-DNA complex were 1:1 and 1.87 × 103 M-1 at 298 K, respectively, indicating that RTV has moderate affinity with ct-DNA. The findings confirmed that RTV binds to the minor groove of DNA. The outcomes of CD experiments showed that the binding with RTV changed the conformation of DNA slightly. However, the conformation of RTV had obvious changes after binding to DNA, meaning that the flexibility of RTV molecule played an important role in stabilizing the RTV-DNA complex. Meanwhile, the results of DFT calculation revealed that the RTV and DNA interaction caused the changes in the frontier molecular orbitals, dipole moment and atomic charge distribution of RTV, altering the chemical properties of RTV when it bound to DNA. Communicated by Ramaswamy H. Sarma.
Subject(s)
HIV Protease Inhibitors , Ritonavir , Circular Dichroism , DNA/chemistry , HIV Protease Inhibitors/chemistry , Molecular Docking Simulation , Ritonavir/chemistry , Spectrometry, Fluorescence , ThermodynamicsABSTRACT
OBJECTIVES: To assess the correlation of cognitive function with sleep stability and depressive-anxious symptoms in insomnia patients. METHODS: Twenty-two insomnia patients with cognitive impairment (insomnia-CI), 21 insomnia patients with normal cognition (insomnia-CN), and 15 matched healthy control subjects (HCs) were enrolled and completed neuropsychological tests, the Hamilton Depression and Anxiety Scales (HAMD and HAMA), the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index (PSQI),the Insomnia Severity Index (ISI), and the cardiopulmonary coupling (CPC) examination. Ratios of high-frequency coupling (HFC), low-frequency coupling (LFC), and very low-frequency coupling (VLFC) measured by CPC analysis represent stable sleep, unstable sleep, and wake/rapid eye movement (REM) sleep, respectively. RESULTS: The HAMD, HAMA, PSQI, and ISI scores were higher in the insomnia-CN patients than in the HCs (all p < .01). However, no differences were found in the HFC, LFC, and VLFC ratio between the HCs and insomnia-CN groups. Compared with the insomnia-CN patients, insomnia-CI patients exhibited higher scores on the HAMD, HAMA (all p < .01), and PSQI (p < .05), performed worse on the Auditory Verbal Learning Test, Trial Making Test B, and Stroop Test B (all p < .01), had a lower HFC ratio, and had a higher LFC ratio in the CPC analysis (all p < .01). Furthermore, in the insomnia patients, poorer cognition was correlated with a decreased HFC ratio and an increased VLFC ratio (r = .356, p = .019; r = -.339, p =.026, respectively) and increased HAMD and HAMA scores (r = -.507, p < .001; r = -.561, p < .001, respectively); a higher VLFC ratio was correlated with an increased ISI score (r = .346, p = .023). CONCLUSIONS: Cognitive deterioration in insomnia patients was associated with a decreased stable sleep ratio, an increased wake/REM sleep ratio and more severe symptoms of depression and anxiety. CPC analysis can reflect the severity of insomnia.