ABSTRACT
During long-term operation, low-earth-orbit spacecraft are exposed to a severe environment of electron irradiation and thermal cycle. This affects the electric properties of polyimide, an essential insulation material for spacecraft electrical transmission equipment, particularly the conductivity characteristic. Therefore, this paper investigates the conductivity and its evolution of polyimide after the combination of 20 keV, 8 nA/cm2 electron irradiation, and 243-343 K, 5 K/min thermal cycle in a vacuum environment for 432 h. The results show that the conductivity increases by about 2 orders of magnitude over 432 h, with the threshold field for electric-field-dependent conductivity decreasing. The conductivity growth rate varies, rising during the first 192 h, then increasing in the midelectric field, and decreasing in the high electric field regions. The thermally stimulated depolarization current method demonstrates that increases in γ, ß1, and ß2 trap densities, associated with enhanced motility of end groups, diamines, and dianhydrides after long-chain breaks, lead to higher conductivity and growth rate. Additionally, increases in ß3 and α trap densities, related to increased CâO bonds and free radicals, reduce the threshold field and the conductivity growth rate in the range of 57.0-100.0 kV/mm after 192 h. These findings provide a reference for the performance evaluation and enhancement of spacecraft polyimide materials.
ABSTRACT
Nouns and verbs are fundamental grammatical building blocks of languages. A key question is whether and where the noun-verb division was represented in the brain. Previous studies mainly used univariate analyses to examine this issue. However, the interpretation of activated brain regions in univariate analyses may be confounded with general cognitive processing and/or confounding variables. We addressed these limitations by using partial representation similarity analysis (RSA) of Chinese nouns and verbs with different levels of imageability. Participants were asked to complete the 1-back grammatical class probe (GCP; an explicit measure) and the 1-back word probe (WP; an implicit measure) tasks while undergoing functional magnetic resonance imaging. RSA results showed that the activation pattern in the left posterior middle temporal gyrus (LpMTG) was significantly correlated with the grammatical class representational dissimilarity matrix in the GCP task after eliminating the potential confounding variables. Moreover, the LpMTG did not overlap with the frontal-parietal regions that were activated by verbs vs. nouns or the task effect (CRP vs. WP) in univariate analyses. These results highlight the role of LpMTG in distinguishing nouns from verbs rather than general cognitive processing.
Subject(s)
Brain Mapping , Magnetic Resonance Imaging , Temporal Lobe , Humans , Male , Temporal Lobe/physiology , Temporal Lobe/diagnostic imaging , Female , Magnetic Resonance Imaging/methods , Brain Mapping/methods , Young Adult , Adult , Language , Semantics , Functional Laterality/physiologyABSTRACT
OBJECTIVE: To identify the distinct clusters of social isolation among gynecologic cancer patients and analyze the predictive factors associated with each cluster. METHODS: A total of 463 patients diagnosed with gynecologic cancer were recruited from three tertiary hospitals between November 2021 and March 2023. Using a two-step cluster analysis, participants were categorized into clusters based on social isolation scales. Multinomial logistic regression was then employed to predict factors influencing the identified clusters. RESULTS: Social isolation in gynecologic cancer patients manifested in four distinct clusters: mild social isolation subgroup (13.8%), moderate social isolation subgroup (32.0%), severe isolation subgroup (33.5%), and high social isolation (20.70%). Multivariate logistic regression analysis revealed that cognitive emotional regulation, social support, negative emotions, endometrial cancer, and disease recurrence or metastasis were significant predictive factors for the identified social isolation clusters (P < 0.05). CONCLUSIONS: The study underscored the heterogeneity in the social isolation characteristics of gynecologic cancer patients. Consequently, healthcare professionals should prioritize the identification of potential high-risk groups and devise personalized interventions to prevent and mitigate the occurrence of social isolation.
ABSTRACT
Introduction: This study aims to delineate the etiology and prevalence of isolated pathogens, along with the clinical characteristics of endophthalmitis patients over a 9-year period at hospital in Southwest of China. Additionally, we investigating the metabolic and cellular processes related to environmental factors may offer novel insights into endophthalmitis. Methods: We analyzed data pertaining to endophthalmitis patients treated at the Affiliated Hospital of Yunnan University from 2015 to 2023. According to our clinical data, we conducted an experiment based on transcriptomics and metabolomics analysis to verify whether environmental factors affect behavior of S. epidermidis by culturating S. epidermidis under oxic and microoxic condition. Results: In this study, 2,712 fungi or bacteria strains have been analyzed, gram-positive bacteria constituted 65.08%, with S. epidermidis being the most predominant species (25.55%). Ophthalmic trauma was the primary pathogenic factor for S. epidermidis ocular infections. Regarding fluoroquinolones, S. epidermidis exhibited the higher resistance rate to levofloxacin than moxifloxacin. Moreover, our investigation revealed that S. epidermidis in microoxic environment increase in energy metabolism, amino acid metabolism, and membrane transport. Conclusion: Our findings underscore the significance of S. epidermidis as a crucial pathogen responsible for infectious endophthalmitis. It is crucial to exercise vigilance when considering Levofloxacin as the first-line drug for empiric endophthalmitis treatment. The metabolites alteration observed during the commensal-to-pathogen conversion under microoxic condition serve as a pivotal environmental signal contributing to S. epidermidis metabolism remodeling, toward more pathogenic state.
ABSTRACT
Neurodegenerative diseases (NDs) refer to a group of diseases in which slow, continuous cell death is the main pathogenic event in the nervous system. Most NDs are characterized by cognitive dysfunction or progressive motor dysfunction. Treatments of NDs mainly target alleviating symptoms, and most NDs do not have disease-modifying drugs. The pathogenesis of NDs involves inflammation and apoptosis mediated by mitochondrial dysfunction. Dantrolene, approved by the US Food and Drug Administration, acts as a RyRs antagonist for the treatment of malignant hyperthermia, spasticity, neuroleptic syndrome, ecstasy intoxication and exertional heat stroke with tolerable side effects. Recently, dantrolene has also shown therapeutic effects in some NDs. Its neuroprotective mechanisms include the reduction of excitotoxicity, apoptosis and neuroinflammation. In summary, dantrolene can be considered as a potential therapeutic candidate for NDs.
ABSTRACT
The spatial photonic Ising machine has achieved remarkable advancements in solving combinatorial optimization problems. However, it still remains a huge challenge to flexibly map an arbitrary problem to the Ising model. In this paper, we propose a general spatial photonic Ising machine based on the interaction matrix eigendecomposition method. The arbitrary interaction matrix can be configured in the two-dimensional Fourier transformation based spatial photonic Ising model by using values generated by matrix eigendecomposition. The error in the structural representation of the Hamiltonian decreases substantially with the growing number of eigenvalues utilized to form the Ising machine. In combination with the optimization algorithm, as low as â¼65% of the eigenvalues are required by intensity modulation to guarantee the best probability of optimal solution for a 20-vertex graph Max-cut problem, and this percentage decreases to below â¼20% for near-zero probability. The 4-spin experiments and error analysis demonstrate the Hamiltonian linear mapping and ergodic optimization. Our work provides a viable approach for spatial photonic Ising machines to solve arbitrary combinatorial optimization problems with the help of the multi-dimensional optical property.
ABSTRACT
BACKGROUND: Colon cancer is a common tumor in the gastrointestinal tract with a poor prognosis. According to research reports, ubiquitin-dependent modification systems have been found to play a crucial role in the development and advancement of different types of malignant tumors, including colon cancer. However, further investigation is required to fully understand the mechanism of ubiquitination in colon cancer. METHODS: We collected the RNA expression matrix of the E3 ubiquitin ligase-related genes (E3RGs) from the patients with colon adenocarcinoma (COAD) using The Cancer Genome Atlas program (TCGA). The "limma" package was used to obtain differentially expressed E3RGs between COAD and adjacent normal tissues. Then, univariate COX regression and least absolute shrinkage and selection operator (LASSO) analysis were performed to construct the prognostic signature and nomogram model. Afterward, we used the original copy number variation data of COAD to find potential somatic mutation and employed the "pRRophetic" package to investigate the disparity in the effectiveness of chemotherapy drugs between high and low-risk groups. The RT-qPCR was also implied to detect mRNA expression levels in tumor tissues. RESULTS: A total of 137 differentially expressed E3RG3 were screened and 11 genes (CORO2B, KCTD9, RNF32, BACH2, RBCK1, DPH7, WDR78, UCHL1, TRIM58, WDR72, and ZBTB18) were identified for the construction of prognostic signatures. The Kaplan-Meier curve showed a worse prognosis for patients with high risk both in the training and test cohorts (P = 1.037e-05, P = 5.704e-03), and the area under the curve (AUC) was 0.728 and 0.892 in the training and test cohorts, respectively. Based on the stratified analysis, this 11- E3RGs signature was a novel and attractive prognostic model independent of several clinicopathological parameters (age, sex, stage, TNM) in COAD. The DEGs were subjected to GO and KEGG analysis, which identified pathways associated with cancer progression. These pathways included the cAMP signaling pathway, calcium signaling pathway, Wnt signaling pathway, signaling pathways regulating stem cell pluripotency, and proteoglycans in cancer. Additionally, immune infiltration analysis revealed significant differences in the infiltration of macrophages M0, T cells follicular helper, and plasma cells between the two groups. CONCLUSION: We developed a novel independent risk model consisting of 11 E3RGs and verified the effectiveness of this model in test cohorts, providing important insights into survival prediction in COAD and several promising targets for COAD therapy.
Subject(s)
Colonic Neoplasms , Ubiquitin-Protein Ligases , Humans , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Prognosis , Ubiquitin-Protein Ligases/genetics , Female , Male , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Middle AgedABSTRACT
Gastric cancer (GC) remains a prominent malignancy that poses a significant threat to human well-being worldwide. Despite advancements in chemotherapy and immunotherapy, which have effectively augmented patient survival rates, the mortality rate associated with GC remains distressingly high. This can be attributed to the elevated proliferation and invasive nature exhibited by GC. Our current understanding of the drivers behind GC cell proliferation remains limited. Hence, in order to reveal the molecular biological mechanism behind the swift advancement of GC, we employed single-cell RNA-sequencing (scRNA-seq) to characterize the tumour microenvironment in this study. The scRNA-seq data of 27 patients were acquired from the Gene Expression Omnibus database. Differential gene analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis were employed to investigate 38 samples. The copy number variation level exhibited by GC cells was determined using InferCNV. The CytoTRACE, Monocle and Slingshot analysis were used to discern the cellular stemness and developmental trajectory of GC cells. The CellChat package was utilized for the analysis of intercellular communication crosstalk. Moreover, the findings of the data analysis were validated through cellular functional tests conducted on the AGS cell line and SGC-7901 cell line. Finally, this study constructed a risk scoring model to evaluate the differences of different risk scores in clinical characteristics, immune infiltration, immune checkpoints, functional enrichment, tumour mutation burden and drug sensitivity. Within the microenvironment of GC, we identified the presence of 8 cell subsets, encompassing NK_T cells, B_Plasma cells, epithelial cells, myeloid cells, endothelial cells, mast cells, fibroblasts, pericytes. By delving deeper into the characterization of GC cells, we identified 6 specific tumour cell subtypes: C0 PSCA+ tumour cells, C1 CLDN7+ tumour cells, C2 UBE2C+ tumour cells, C3 MUC6+ tumour cells, C4 CHGA+ tumour cells and C5 MUC2+ tumour cells. Notably, the C2 UBE2C+ tumour cells demonstrated a close association with cell mitosis and the cell cycle, exhibiting robust proliferative capabilities. Our findings were fortified through enrichment analysis, pseudotime analysis and cell communication analysis. Meanwhile, knockdown of the transcription factor CREB3, which is highly active in UBE2C+ tumour cells, significantly impedes the proliferation, migration and invasion of GC cells. And the prognostic score model constructed with CREB3-related genes showcased commendable clinical predictive capacity, thus providing valuable guidance for patients' prognosis and clinical treatment decisions. We have identified a highly proliferative cellular subgroup C2 UBE2C+ tumour cells in GC for the first time. The employment of a risk score model, which is based on genes associated with UBE2C expression, exhibits remarkable proficiency in predicting the prognosis of GC patients. In our investigation, we observed that the knockdown of the transcription factor CREB3 led to a marked reduction in cellular proliferation, migration and invasion in GC cell line models. Implementing a stratified treatment approach guided by this model represents a judicious and promising methodology.
Subject(s)
Cell Proliferation , Gene Expression Regulation, Neoplastic , Single-Cell Analysis , Stomach Neoplasms , Tumor Microenvironment , Humans , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Stomach Neoplasms/metabolism , Tumor Microenvironment/genetics , Cell Proliferation/genetics , Single-Cell Analysis/methods , Cell Line, Tumor , Gene Expression Profiling , DNA Copy Number Variations/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Communication/geneticsABSTRACT
Hypoimmunogenicity and the immunosuppressive microenvironment of ovarian cancer severely restrict the capability of immune-mediated tumor killing. Immunogenic cell death (ICD) introduces a theoretical principle for antitumor immunity by increasing antigen exposure and presentation. Despite recent research progress, the currently available ICD inducers are still very limited, and many of them can hardly induce sufficient ICD based on traditional endoplasmic reticulum (ER) stress. Accumulating evidence indicates that inducing mitochondrial stress usually shows a higher efficiency in evoking large-scale ICD than that via ER stress. Inspired by this, herein, a mitochondria-targeted polyprodrug nanoparticle (named Mito-CMPN) serves as a much superior ICD inducer, effectively inducing chemo-photodynamic therapy-caused mitochondrial stress in tumor cells. The rationally designed stimuli-responsive polyprodrugs, which can self-assemble into nanoparticles, were functionalized with rhodamine B for mitochondrial targeting, cisplatin and mitoxantrone (MTO) for synergistic chemo-immunotherapy, and MTO also serves as a photosensitizer for photodynamic immunotherapy. The effectiveness and robustness of Mito-CMPNs in reversing the immunosuppressive microenvironment is verified in both an ovarian cancer subcutaneous model and a high-grade serous ovarian cancer model. Our results support that the induction of abundant ICD by focused mitochondrial stress is a highly effective strategy to improve the therapeutic efficacy of immunosuppressive ovarian cancer.
Subject(s)
Antineoplastic Agents , Mitochondria , Nanoparticles , Ovarian Neoplasms , Photochemotherapy , Photosensitizing Agents , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/immunology , Ovarian Neoplasms/therapy , Mitochondria/drug effects , Photochemotherapy/methods , Animals , Humans , Cell Line, Tumor , Photosensitizing Agents/administration & dosage , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Prodrugs/administration & dosage , Prodrugs/therapeutic use , Prodrugs/pharmacology , Immunogenic Cell Death/drug effects , Mice, Inbred BALB C , Cisplatin/pharmacology , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Immunotherapy/methods , Tumor Microenvironment/drug effectsABSTRACT
Cisplatin (CDDP) is a standard non-small cell lung cancer (NSCLC) chemotherapy, but its efficacy is hampered by resistance, partly due to the Warburg effect. This study investigates how thyroid hormones enhance the Warburg effect, increasing sensitivity to cisplatin in lung cancer. Clinical data from advanced NSCLC patients were analyzed based on thyroid hormone levels, categorizing patients into high and low groups. Cellular experiments involved Control, 10uM CDDP, 10uM CDDP + 0.1uM T3, and 10uM CDDP + 0.1uM T4 categories. Parameters were measured in A549 and PC9 lung cancer cells, including proliferation, apoptosis, mitochondrial membrane potential, ROS production, glycolysis enzyme activity, lactic acid level, and ATP content. Gene and protein expressions were assessed using qPCR and Western Blot. Analysis revealed higher FT3 levels correlated with prolonged progression-free survival before chemotherapy (median PFS: high FT3 group = 12.67 months, low FT3 group = 7.03 months, p = 0.01). Cellular experiments demonstrated that thyroid hormones increase lung cancer cell sensitivity to cisplatin, inhibiting proliferation and enhancing efficacy. The mechanism involves thyroid hormones and cisplatin jointly down-regulating MSI1/AKT/GLUT1 expression, reducing lactic acid and glycolysis. This Warburg effect reversal boosts ATP levels, elevates ROS, and decreases MMP, enhancing cisplatin effectiveness in A549 and PC9 cells. In conclusion, elevated free T3 levels in advanced NSCLC patients correlate with prolonged progression-free survival under cisplatin chemotherapy. Cellular experiments reveal that thyroid hormones enhance lung cancer cell sensitivity to cisplatin by reversing the Warburg effect, providing a mechanistic basis for improved therapeutic outcomes.
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BACKGROUND: Cognitive impairment (CI) is a common mental health disorder among older adults, and dietary patterns have an impact on cognitive function. However, no systematic researches have constructed anti-inflammatory diet (AID) and protein-enriched diet (PED) to explore their association with CI among older adults in China. METHODS: The data used in this study were obtained from the 2018 waves of the China Longitudinal Health and Longevity Survey (CLHLS). We construct AID, PED, and calculate scores for CI. We use binary logistic regression to explore the relationship between them, and use restrictive cubic splines to determine whether the relationships are non-linear. Subgroup analysis and sensitivity analysis were used to demonstrate the robustness of the results. RESULTS: A total of 8692 participants (mean age is 83.53 years) were included in the analysis. We found that participants with a higher AID (OR = 0.789, 95% confidence interval: 0.740-0.842, p < 0.001) and PED (OR = 0.910, 95% confidence interval: 0.866-0.956, p < 0.001) score showed lower odds of suffering from CI. Besides, the relationship between the two dietary patterns and CI is linear, and the results of subgroup analysis and sensitivity analysis are also significant. CONCLUSION: Higher intakes of AID and PED are associated with a lower risk of CI among older adults, which has important implications for future prevention and control of CI from a dietary and nutritional perspective.
Subject(s)
Cognitive Dysfunction , Humans , Cognitive Dysfunction/prevention & control , Cognitive Dysfunction/epidemiology , Male , Female , China/epidemiology , Cross-Sectional Studies , Aged, 80 and over , Aged , Dietary Proteins/administration & dosage , Diet , Risk Factors , Longitudinal Studies , CognitionABSTRACT
BACKGROUND: Ovarian cancer (OC) is a major global cause of death among gynecological cancers, with a high mortality rate. Early diagnosis, distinguishing between benign conditions and early malignant OC forms, is vital for successful treatment. This research investigates serum metabolites to find diagnostic biomarkers for early OC identification. METHODS: Metabolomic profiles derived from the serum of 60 patients with benign conditions and 60 patients with malignant OC were examined using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Comparative analysis revealed differential metabolites linked to OC, aiding biomarker identification for early-diagnosis of OC via machine learning features. The predictive ability of these biomarkers was evaluated against the traditional biomarker, cancer antigen 125 (CA125). RESULTS: 84 differential metabolites were identified, including 2-Thiothiazolidine-4-carboxylic acid (TTCA), Methionyl-Cysteine, and Citrulline that could serve as potential biomarkers to identify benign conditions and malignant OC. In the diagnosis of early-stage OC, the area under the curve (AUC) for Citrulline was 0.847 (95 % Confidence Interval (CI): 0.719-0.974), compared to 0.770 (95 % CI: 0.596-0.944) for TTCA, and 0.754 for Methionine-Cysteine (95 % CI: 0.589-0.919). These metabolites demonstrate a superior diagnostic capability relative to CA125, which has an AUC of 0.689 (95 % CI: 0.448-0.931). Among these biomarkers, Citrulline stands out as the most promising. Additionally, in the diagnosis of benign conditions and malignant OC, using logistic regression to combine potential biomarkers with CA125 has an AUC of 0.987 (95 % CI: 0.9708-1) has been proven to be more effective than relying solely on the traditional biomarker CA125 with an AUC of 0.933 (95 % CI: 0.870-0.996). Furthermore, among all the differential metabolites, lipid metabolites dominate, significantly impacting glycerophospholipid metabolism pathway. CONCLUSION: The discovered serum metabolite biomarkers demonstrate excellent diagnostic performance for distinguishing between benign conditions and malignant OC and for early diagnosis of malignant OC.
Subject(s)
Biomarkers, Tumor , Early Detection of Cancer , Metabolomics , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/blood , Ovarian Neoplasms/metabolism , Biomarkers, Tumor/blood , Middle Aged , Adult , Tandem Mass Spectrometry , Aged , Chromatography, High Pressure LiquidABSTRACT
KEY MESSAGE: This study precisely mapped and validated a quantitative trait locus (QTL) located on chromosome 4B for flag leaf angle in wheat. Flag leaf angle (FLANG) is closely related to crop architecture and yield. We previously identified the quantitative trait locus (QTL) QFLANG-4B for FLANG on chromosome 4B, located within a 14-cM interval flanked by the markers Xbarc20 and Xzyh357, using a mapping population of recombinant inbred lines (RILs) derived from a cross between Nongda3331 (ND3331) and Zang1817. In this study, we fine-mapped QFLANG-4B and validated its associated genetic effect. We developed a BC3F3 population using ND3331 as the recurrent parent through marker-assisted selection, as well as near-isogenic lines (NILs) by selfing BC3F3 plants carrying different heterozygous segments for the QFLANG-4B region. We obtained eight recombinant types for QFLANG-4B, narrowing its location down to a 5.3-Mb region. This region contained 76 predicted genes, 7 of which we considered to be likely candidate genes for QFLANG-4B. Marker and phenotypic analyses of individual plants from the secondary mapping populations and their progeny revealed that the FLANG of the ND3331 allele is significantly higher than that of the Zang1817 allele in multiple environments. These results not only provide a basis for the map-based cloning of QFLANG-4B, but also indicate that QFLANG-4B has great potential for marker-assisted selection in wheat breeding programs designed to improve plant architecture and yield.
Subject(s)
Chromosome Mapping , Plant Leaves , Quantitative Trait Loci , Triticum , Chromosome Mapping/methods , Chromosomes, Plant/genetics , Genes, Plant , Genetic Linkage , Genetic Markers , Phenotype , Plant Breeding , Plant Leaves/anatomy & histology , Plant Leaves/genetics , Plant Leaves/growth & development , Triticum/genetics , Triticum/growth & development , Triticum/anatomy & histologyABSTRACT
In recent years, 3D fashion design has been relied on for improving attire fashion, design, and presentation with fewer flaws and better visualization. This aids consumers in providing visualized recommendations on modifications, suggestions, and customized attire designs. Considering the influence of automation and intelligent processing in the fashion designing industry, it introduces a Flaw Detection Method in 3D Representation (FDM-3DR) to reduce frequent modifications. The proposed method visualizes the design in three dimensions for its completeness and flawless representation. Based on the consumer recommendation, the lack of design flaws in the representation is identified, and multiple detections are presented. This is required to improve consumer satisfaction and the multi-dimensional projection between flaws and complete attire products. The learning is trained using the fixable representation, and therefore, the previous unsuitable designs are repelled by different recommendations. This improves the design adaptability, recommendation ratio, and representation ratio. Besides, it reduces the recommendation time and flaws.
ABSTRACT
BACKGROUND: Remnant cholesterol (RC) and nonhigh-density lipoprotein cholesterol (nonHDL-C) are key risk factors for atherosclerotic cardiovascular disease (ASCVD), with apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)] also contributing to its residual risk. However, real-world population-based evidence regarding the impact of current clinical LDL-C-centric lipid-lowering therapy (LLT) on achieving RC and nonHDL-C goals, as well as on modifying residual CVD risk factors is limited. METHODS: This prospective observational study enrolled 897 CVD patients from September, 2020 to July, 2021. All participants had previously received low-/moderate-intensity LLT and were discharged with either low-/moderate-intensity LLT or high-intensity LLT. After a median follow-up of 3 months, changes in RC, nonHDL-C, and other biomarkers were assessed. Multivariate logistic regression was performed to analyze the impact of the LLT on goal attainment. RESULTS: Among all patients, 83.50% transitioned to high-intensity LLT from low or moderate. After follow-up, the high-intensity group saw significantly greater reductions in RC (-20.51% vs. -3.90%, P = 0.025), nonHDL-C (-25.12% vs. 0.00%, P < 0.001), apoB (-19.35% vs. -3.17%, P < 0.001), triglycerides (-17.82% vs. -6.62%, P < 0.001), and LDL-C and total cholesterol. Spearman correlation analysis revealed that LDL-C reduction from current LLT was strongly correlated with nonHDL-C reduction (r = 0.87, P < 0.001). Patients who received high-intensity LLT had significant improvements in attainment of RC (from 44.2% to 60.7%, χ² = 39.23, P < 0.001) and nonHDL-C (from 19.4% to 56.9%, χ² = 226.06, P < 0.001) goals. Furthermore, multivariate logistic regression showed that high-intensity LLT was a protective factor for RC [odds ratio (OR) = 0.66; 95% confidence intervals (CI), 0.45-0.97; P = 0.033] and nonHDL-C goal attainment (OR = 0.51; 95% CI, 0.34-0.75; P < 0.001), without a significant increase of adverse reactions. CONCLUSION: Current levels of clinically prescribed LDL-C-centric treatment can reduce RC and other lipid-related residual risk factors, but high-intensity LLT is better at achieving nonHDL-C and RC goals than low-/moderate-intensity LLT, with a good safety profile. More targeted RC treatments are still needed to reduce residual lipid risk further.
Subject(s)
Cholesterol, LDL , Cholesterol , Lipoprotein(a) , Triglycerides , Humans , Male , Female , Middle Aged , Prospective Studies , Aged , Triglycerides/blood , Risk Factors , Cholesterol, LDL/blood , Lipoprotein(a)/blood , Cholesterol/blood , Hypolipidemic Agents/therapeutic use , Apolipoproteins B/blood , Cardiovascular Diseases/prevention & control , Cholesterol, HDL/blood , Biomarkers/bloodABSTRACT
Background: DHEA is a steroid hormone produced by the gonads, adrenal cortex, brain, and gastrointestinal tract. While the anti-obesity, anti-atherosclerosis, anti-cancer, and memory-enhancing effects of DHEA have been substantiated through cell experiments, animal studies, and human trials, the precise mechanisms underlying these effects remain unclear. Altered mitochondrial dynamics can lead to mitochondrial dysfunction, which is closely related to many human diseases, especially cancer and aging. This study was to investigate whether DHEA inhibits lung adenocarcinoma through the mitochondrial pathway and its molecular mechanism. Methods: Through animal experiments and cell experiments, the effect of DHEA on tumor inhibition was determined. The correlation between FASTKD2 expression and DHEA was analyzed by Western blot, Reverse transcription-quantitative PCR, Immunohistochemistry, and TCGA database. Results: In this study, DHEA supplementation in the diet can inhibit the tumor size of mice, and the effect of adding DHEA one week before the experiment is the best. DHEA limits the glycolysis process by inhibiting G6PDH activity, increases the accumulation of reactive oxygen species, and initiates apoptosis in the mitochondrial pathway of cancer cells. Conclusion: DHEA suppresses mitochondrial fission and promotes mitochondrial fusion by downregulating the expression of FASTKD2, thereby inhibiting tumor growth and prolonging the overall survival of lung adenocarcinoma patients, which also provides a new target for the prevention and treatment of lung adenocarcinoma.
ABSTRACT
Purpose: In recent years, due to the increasingly prominent role of voice behavior in leader decision-making and organizational performance, such behavior has become a central topic for scholars. A majority of studies explore the "uphold" effects of multiple leader behavior toward the voice behavior; nonetheless, our study revealed the "undo" effect --- leader hypocrisy on voice behavior. Drawing on social cognitive theory, we investigated the relationship between leader hypocrisy and voice behavior, examined the mediating effects of cognition-based trust and affect-based trust, and the moderating effect of moral identity. Patients and Methods: We conducted a three-wave survey in a large Chinese corporation to test the hypothesized model. We collected 562 employees to participate in this survey. Results: The results show that leader hypocrisy negatively impacts employees' cognition-based and affect-based trust, and both types of trust mediate the relationship between leader hypocrisy and voice behavior, respectively. In the meantime, moral identity manifested the negative effect of leader hypocrisy on cognition-based and affect-based trust. Conclusion: Our research not only enriches the related research on leader hypocrisy and voice behavior but also uncovers the underlying mechanism through which leader hypocrisy affects voice behavior and the boundary conditions of this effect. Meanwhile, our research provides a theoretical reference for increasing employees' voice behavior and promoting the healthy development of enterprises.
ABSTRACT
Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.
Subject(s)
Apelin Receptors , Cardiovascular Agents , Drug Design , Apelin Receptors/agonists , Apelin Receptors/chemistry , Apelin Receptors/ultrastructure , Cryoelectron Microscopy , GTP-Binding Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal Transduction , Humans , Cardiovascular Agents/chemistryABSTRACT
BACKGROUND: The value of SyMRI-derived parameters from lumbar marrow for predicting early treatment response and optimizing the risk stratification of the Revised International Staging System (R-ISS) in participants with multiple myeloma (MM) is unknown. METHODS: We prospectively enrolled participants with newly diagnosed MM before treatment. The SyMRI of lumbar marrow was used to calculate T1, T2, and PD values and the clinical features were collected. All participants were divided into good response (≥VGPR) and poor response (Subject(s)
Multiple Myeloma
, Humans
, Male
, Female
, Prognosis
, Multiple Myeloma/diagnostic imaging
, Multiple Myeloma/pathology
, Bone Marrow/diagnostic imaging
, Bone Marrow/pathology
, Pilot Projects
, Neoplasm Staging
, Magnetic Resonance Imaging
, Retrospective Studies