ABSTRACT
Molecular property prediction faces the challenge of limited labeled data as it necessitates a series of specialized experiments to annotate target molecules. Data augmentation techniques can effectively address the issue of data scarcity. In recent years, Mixup has achieved significant success in traditional domains such as image processing. However, its application in molecular property prediction is relatively limited due to the irregular, non-Euclidean nature of graphs and the fact that minor variations in molecular structures can lead to alterations in their properties. To address these challenges, we propose a novel data augmentation method called Mix-Key tailored for molecular property prediction. Mix-Key aims to capture crucial features of molecular graphs, focusing separately on the molecular scaffolds and functional groups. By generating isomers that are relatively invariant to the scaffolds or functional groups, we effectively preserve the core information of molecules. Additionally, to capture interactive information between the scaffolds and functional groups while ensuring correlation between the original and augmented graphs, we introduce molecular fingerprint similarity and node similarity. Through these steps, Mix-Key determines the mixup ratio between the original graph and two isomers, thus generating more informative augmented molecular graphs. We extensively validate our approach on molecular datasets of different scales with several Graph Neural Network architectures. The results demonstrate that Mix-Key consistently outperforms other data augmentation methods in enhancing molecular property prediction on several datasets.
Subject(s)
Algorithms , Molecular Structure , Computational Biology/methods , SoftwareABSTRACT
In synthetic aperture radar (SAR) signal processing, compared with the raw data of level-0, level-1 SAR images are more readily accessible and available in larger quantities. However, an amount of level-1 images are affected by radio frequency interference (RFI), which typically originates from Linear Frequency Modulation (LFM) signals emitted by ground-based radars. Existing research on interference suppression in level-1 data has primarily focused on two methods: transforming SAR images into simulated echo data for interference suppression, or focusing interference in the frequency domain and applying notching filters to reduce interference energy. However, these methods overlook the effective utilization of the interference parameters or are confined to suppressing only one type of LFM interference at a time. In certain SAR images, multiple types of LFM interference manifest bright radiation artifacts that exhibit varying lengths along the range direction while remaining constant in the azimuth direction. It is necessary to suppress multiple LFM interference on SAR images when original echo data are unavailable. This article proposes a joint sparse recovery algorithm for interference suppression in the SAR image domain. In the SAR image domain, two-dimensional LFM interference typically exhibits differences in parameters such as frequency modulation rate and pulse width in the range direction, while maintaining consistency in the azimuth direction. Based on this observation, this article constructs a series of focusing operators for LFM interference in SAR images. These operators enable the sparse representation of dispersed LFM interference. Subsequently, an optimization model is developed that can effectively suppress multi-LFM interference and reduce image loss with the assistance of a regularization term in the image domain. Simulation experiments conducted in various scenarios validate the superior performance of the proposed method.
ABSTRACT
BACKGROUND: Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases and is the leading cause of pain and disability in the aged population. However, the underlying biological mechanism has not been fully understood. This study aims to reveal the causal effect of circulation metabolites on OA susceptibility. METHODS: A two-sample Mendelian Randomization (MR) analysis was performed to estimate the causality of GDMs on OA. A genome-wide association study (GWAS) of 486 metabolites was used as the exposure, whereas 8 different OA phenotypes, including any-site OA (All OA), knee and/or hip OA (knee/hip OA), knee OA, hip OA, spine OA, finger and/or thumb OA (hand OA), finger OA, thumb OA, were set the outcomes. Inverse-variance weighted (IVW) was used for calculating causal estimates. Methods including weight mode, weight median, MR-egger, and MR-PRESSO were used for the sensitive analysis. Furthermore, metabolic pathway analysis was performed via the web-based Metaconflict 4.0. All statistical analyses were performed in R software. RESULTS: In this MR analysis, a total of 235 causative associations between metabolites and different OA phenotypes were observed. After false discovery rate (FDR) correction and sensitive analysis, 9 robust causative associations between 7 metabolites (e.g., arginine, kynurenine, and isovalerylcarnitine) and 5 OA phenotypes were finally identified. Additionally, eleven significant metabolic pathways in 4 OA phenotypes were identified by metabolic pathway analysis. CONCLUSION: The finding of our study suggested that identified metabolites and metabolic pathways can be considered useful circulating metabolic biomarkers for OA screening and prevention in clinical practice, and can also serve as candidate molecules for future mechanism exploration and drug target selection.
Subject(s)
Osteoarthritis, Hip , Osteoarthritis, Knee , Humans , Genome-Wide Association Study , Mendelian Randomization Analysis , Osteoarthritis, Knee/genetics , Metabolic Networks and Pathways/genetics , Polymorphism, Single NucleotideABSTRACT
Kutzneria is a rare genus of Actinobacteria that harbors a variety of secondary metabolite gene clusters and produces several interesting types of bioactive secondary metabolites. Recent efforts have partially elucidated the biosynthetic pathways of some of these bioactive natural products, suggesting the diversity and specificity of secondary metabolism within this genus. Here, we summarized the chemical structures, biosynthetic pathways, and key metabolic enzymes of the secondary metabolites isolated from Kutzneria strains. In-depth comparative genomic analysis of all six available high-quality Kutzneria genomes revealed that the majority (77%) of the biosynthetic gene cluster families of Kutzneria were untapped and identified homologues of key metabolic enzymes in the putative gene clusters, including cytochrome P450s, halogenases, and flavin-dependent N-hydroxylases. The present study suggests that Kutzneria exhibits great potential to synthesize novel secondary metabolites, encodes a variety of valuable metabolic enzymes, and also provides valuable information for the targeted discovery and biosynthesis of novel natural products from Kutzneria.
Subject(s)
Actinobacteria , Actinomycetales , Biological Products , Secondary Metabolism , Actinobacteria/metabolism , Cytochrome P-450 Enzyme System/metabolism , Multigene Family , Biological Products/metabolism , PhylogenyABSTRACT
BACKGROUND: Functional abdominal pain disorders (FAPDs) are one of the most common gastrointestinal disorders in children. The aim of this study was to investigate the prevalence of FAPDs in children in southern Anhui Province, China and their association with academic stress. METHODS: In this cross-sectional survey, we randomly selected children aged 6-17 years from 11 public schools in southern Anhui Province. FAPDs were diagnosed according to the Rome IV criteria, and a custom-designed questionnaire was used to investigate the association between academic stress and FAPDs in children. RESULTS: A total of 2,344 children aged 6-17 years were enrolled. The mean age was 12.4 ± 3.0 years. Of these children, 335 (14.3%) were diagnosed with FAPDs according to the Rome IV criteria. Among the children with FAPDs, 156 (46.6%) were boys, and 179 (53.4%) were girls. The prevalence was higher in girls than in boys. The most common disorder was irritable bowel syndrome (IBS) (n = 182 (7.8%)). Other types of FAPDs included functional abdominal pain-not otherwise specified (FAPNOS) (n = 70 (3.0%)), functional dyspepsia (FD) (n = 55 (2.3%)), and abdominal migraine (AM) (n = 28 (1.2%)). Academic stress, not meeting parental expectations, poor relationships with parents, and sleep disturbances were independent risk factors for FAPDs in children; academic performance was not associated with the development of FAPDs. CONCLUSION: There was a high prevalence of FAPDs among children in southern Anhui Province, China, and IBS was the most common subtype of functional abdominal pain. Academic stress, rather than academic performance, was associated with FAPDs in children.
Subject(s)
Academic Performance , Irritable Bowel Syndrome , Male , Female , Humans , Child , Adolescent , Cross-Sectional Studies , Abdominal Pain/epidemiology , China/epidemiologyABSTRACT
Lumbar spinal stenosis (LSS), which can lead to irreversible neurologic damage and functional disability, is characterized by hypertrophy and fibrosis in the ligamentum flavum (LF). However, the underlying mechanism is still unclear. In the current study, the effect of Smurf1, a kind of E3 ubiquitin ligase, in promoting the fibrosis and oxidative stress of LF was investigated, and its underlying mechanism was explored. The expression of oxidative stress and fibrosis-related markers was assessed in the tissue of lumbar spinal stenosis (LSS) and lumbar disc herniation (LDH). Next, the expression of the top 10 E3 ubiquitin ligases, obtained from Gene Expression Omnibus (GEO) dataset GSE113212, was assessed in LDH and LSS, and confirmed that Smurf1 expression was markedly upregulated in the LSS group. Furthermore, Smurf1 overexpression promotes the fibrosis and oxidative stress of LF cells. Subsequently, NRF2, an important transcription factor for oxidative stress and fibrosis, was predicted to be a target of Smurf1. Mechanistically, Smurf1 directly interacts with Nrf2 and accelerates Nrf2 ubiquitination and degradation. In conclusion, the current study suggests that Smurf1 facilitated the fibrosis and oxidative stress of LF and induced the development of LSS by promoting Nrf2 ubiquitination and degradation.
Subject(s)
Ligamentum Flavum , Spinal Stenosis , Humans , Spinal Stenosis/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Ligamentum Flavum/metabolism , Ligamentum Flavum/pathology , Fibrosis , Ubiquitination , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Lumbar Vertebrae/metabolism , Hypertrophy/metabolism , Hypertrophy/pathology , Oxidative StressABSTRACT
After being exposed to environmental stimuli during early developmental stages, some organisms may gain or weaken physiological regulating abilities, which would have long-lasting effects on their performance. Environmental hypoxia events can have significant effects on marine organisms, but for breeding programs and other practical applications, it is important to further explore the long-term physiological effects of early hypoxia exposure in economically significant species. In this study, the Pacific abalone Haliotis discus hannai was exposed to moderate hypoxia (â¼4 mg/L) from zygote to trochophora, and the assessments of hypoxia tolerance were conducted on the grow-out stage. The results revealed that juvenile abalones exposed to hypoxia at the early development stages were more hypoxia-tolerant but with slower weight growth, a phenomenon called the trade-off between growth and survival. These phenotypic effects driven by the hypoxia exposure were explained by strong selection of genes involved in signal transduction, autophagy, apoptosis, and hormone regulation. Moreover, long non-coding RNA regulation plays an important role modulating carry-over effects by controlling DNA replication and repair, signal transduction, myocardial activity, and hormone regulation. This study revealed that the ability to create favorable phenotypic differentiation through genetic selection and/or epigenetic regulation is important for the survival and development of aquatic animals in the face of rapidly changing environmental conditions.
Subject(s)
Epigenesis, Genetic , Gastropoda , Animals , Hypoxia/genetics , HormonesABSTRACT
Bacterial secondary metabolites are rich sources of novel drug leads. The diversity of secondary metabolite biosynthetic gene clusters (BGCs) in genome-sequenced bacteria, which will provide crucial information for the efficient discovery of novel natural products, has not been systematically investigated. Here, the distribution and genetic diversity of BGCs in 10 121 prokaryotic genomes (across 68 phyla) were obtained from their PRISM4 outputs using a custom python script. A total of 18 043 BGCs are detected from 5743 genomes with non-ribosomal peptide synthetases (25.4%) and polyketides (15.9%) as the dominant classes of BGCs. Bacterial strains harbouring the largest number of BGCs are revealed and BGC count in strains of some genera vary greatly, suggesting the necessity of individually evaluating the secondary metabolism potential. Additional analysis against 102 strains of discovered bacterial genera with abundant amounts of BGCs confirms that Kutzneria, Kibdelosporangium, Moorea, Saccharothrix, Cystobacter, Archangium, Actinosynnema, Kitasatospora, and Nocardia, may also be important sources of natural products and worthy of priority investigation. Comparative analysis of BGCs within these genera indicates the great diversity and novelty of the BGCs. This study presents an atlas of bacterial secondary metabolite BGCs that provides a lot of key information for the targeted discovery of novel natural products.
Subject(s)
Biosynthetic Pathways , Cyanobacteria , Multigene Family , Biosynthetic Pathways/genetics , Cyanobacteria/genetics , Secondary Metabolism/geneticsABSTRACT
BACKGROUND: Acute pancreatitis is a common inflammatory disease. MicroRNAs have been implicated in the pathogenesis of acute pancreatitis. AIMS: The purpose of this study was to investigate the precise roles of miR-193a-5p and miR-320-5p in AP. METHODS: The levels of miR-193a-5p, miR-320-5p and tumor necrosis factor receptor-associated factor 3 were detected by quantitative real-time polymerase chain reaction. Cell apoptosis was determined using flow cytometry. Enzyme-linked immunosorbent assay was performed to measure TNF-α, IL-6, IL-1ß and IL-8 production, amylase activity, and malondialdehyde content. Targeted relationship between miR-193a-5p or miR-320-5p and TRAF3 was confirmed by the dual-luciferase reporter and RNA immunoprecipitation assays. RESULTS: Our data showed that miR-193a-5p and miR-320-5p were down-regulated in acute pancreatitis serum and caerulein-treated AR42J cells. The increased expression of miR-193a-5p or miR-320-5p alleviated caerulein-induced cell injury in AR42J cells. Tumor necrosis factor receptor-associated factor 3 was a direct target of miR-193a-5p and miR-320-5p in AR42J cells. Moreover, miR-193a-5p and miR-320-5p regulated caerulein-induced AR42J cells injury through targeting tumor necrosis factor receptor-associated factor 3. CONCLUSION: The present findings demonstrated that miR-193a-5p and miR-320-5p protected AR42J cells against caerulein-induced cell injury by targeting tumor necrosis factor receptor-associated factor 3, highlighting their roles as potential therapeutic targets for acute pancreatitis treatment.
Subject(s)
MicroRNAs/blood , Pancreatitis/blood , TNF Receptor-Associated Factor 3/metabolism , Adult , Animals , Case-Control Studies , Cell Line , Ceruletide , Female , Humans , Male , MicroRNAs/metabolism , Middle Aged , RatsABSTRACT
BACKGROUND: Growth hormone inducible transmembrane protein (GHITM) is a highly conserved transmembrane protein. This study was conducted to investigate the role of GHITM gene in the apoptosis and growth of the golden apple snail Pomacea canaliculate. RESULTS: The complete cDNA of this gene was cloned using the rapid amplification of cDNA ends (RACE) method and subjected to bioinformatics analysis. The full-length cDNA was 2242 bp, including an open reading frame of 1021 bp that encoded a protein of 342 amino acid residues. The mRNA expression profiles of GHITM gene in different tissues (liver, kidney, gonad and foot) and different growth phases (6-months old and 2-years old) showed that it was expressed in various tissues and different growth phases. Silencing of the GHITM gene by RNAi (RNA interference) experiments revealed that the GHITM gene possibly plays a role in inhibiting apoptosis through detecting the Caspase (Cysteine-requiring Aspartate Protease)-3 activity. In addition, the aperture width and body whorl length of the snail was significantly affected by RNAi, suggesting that this gene plays a significant role in promoting the growth of the organism. CONCLUSIONS: These results demonstrated that the GHITM gene was involved in apoptosis and growth in golden apple snail.
Subject(s)
Apoptosis/genetics , Membrane Proteins/genetics , Open Reading Frames/genetics , Snails/genetics , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , DNA, Complementary/genetics , Gene Expression Profiling/methods , Membrane Proteins/classification , Membrane Proteins/metabolism , Phylogeny , RNA Interference , Snails/growth & development , Snails/metabolismABSTRACT
High-performance dielectric nanomaterials have received increasing attention due to their important applications in the field of energy storage. Among various dielectric materials, polymer nanocomposite is one of the most promising candidates. However, the problems of environmental pollution caused by polymer-based dielectric materials have been extensively studied in recent years, which need to be solved urgently, leading to the search for new biodegradable dielectric materials. Herein, we report composite materials based on biodegradable and renewable chitin and molybdenum disulfide (MoS2) nanosheets for the first time. The MoS2 nanosheets were first fabricated by glycerol/urea system and then KOH/urea aqueous solution was used to directly dissolve chitin at low temperature together with the dispersion of the MoS2 nanosheets in a simple green process. The two-dimensional MoS2 nanosheets possess high polarization strength, and a large specific surface area can enhance the interfacial polarization with chitin; meanwhile, it can serve as a charge breakdown barrier to hinder the propagation of electrical tree branches. The results also show that the dielectric constant and breakdown strength of the chitin/MoS2 nanocomposites were increased, while the dielectric loss remained low. When the MoS2 content was 5 wt %, the charge and discharge efficiencies of the composite film were more than 80%, and the breakdown strength also reached 350 MV m-1, thus resulting in a high discharge energy density of 4.91 J cm-3, which was more than twice of the neat chitin (2.17 J cm-3). Furthermore, the nanocomposite films exhibited good thermal stability. Therefore, these chitin-based nanocomposite films are promising as high-performance biomass-based dielectric capacitors.
Subject(s)
Molybdenum , Nanocomposites , Chitin , Electricity , PolymersABSTRACT
Antibiotic resistance genes (ARGs) are considered to be a type of emerging contaminant; their interaction with biochar (BC) could affect their dissemination and fate in the environment. Although adsorption of ARGs onto bulk-BC has been reported, the interaction with nanosized BC (nano-BC) is largely unknown. In this study, the interactions of a model extracellular DNA (eDNA, calf thymus DNA) and two typical ARGs (ampC and ermB) extracted from a natural river with bulk- and nano-BCs from two pyrolysis temperatures (400 and 700 °C) were investigated. Only adsorption was observed on bulk-BCs, while not only adsorption but also fragmentation of these eDNA molecules was found to occur on nano-BCs. Also, their replication was greatly inhibited by nano-BCs. The electron paramagnetic resonance results indicated that hydroxyl radicals produced from persistent free radicals (PFRs) on nano-BCs played a major role in the damage of eDNA. Moreover, the direct contact with nonradical reacting sites and PFRs on nano-BCs also contributed to the decay of eDNA. Comparatively, PFRs in bulk-BCs were difficult to be reached by eDNA because of steric hindrance and played a negligible role in destroying eDNA. These findings highlight the importance of the size effect in evaluating the reactivity and related environmental risks of PFRs on BC and improve our understanding on the interaction between ARGs and BC.
Subject(s)
Anti-Bacterial Agents , Charcoal , Adsorption , Drug Resistance, Microbial/geneticsABSTRACT
The black-and-white traits on shells and mantle edges of the Pacific oyster, Crassostrea gigas, are inheritable and correlated, and black shells (melanin pigmentation) are usually found in the Pacific oysters. Based on differentially expressed genes from RNA-Seq and physiological characteristics, in this study, Black-shelled Pacific oysters (BSO) and White-shelled Pacific oysters (WSO) were selected to determine the molecular differences between oysters with obviously different melanin content. The differences in the process of immune recognition and modulation indicated that BSO may be more sensitive to the immune substances. There might have different modulation mode of apoptosis and phagocytosis between BSO and WSO, and caspase-3 might have played a key role in the apoptotic process of BSO. Different oxidation-related pathways were enriched in both BSO and WSO, suggesting the different response strategies of BSO and WSO to oxidative stress. The physiological evidences showed that, compared with WSO, in BSO, the tyrosinase content, the caspase-3 activity and the suppression of hydroxyl radical increased, and the reactive oxygen species concentration decreased. Therefore, immune-related molecular and physiological differences were found between BSO and WSO.
Subject(s)
Apoptosis/physiology , Crassostrea/immunology , Melanins/physiology , Phagocytosis/physiology , Animals , Crassostrea/genetics , Melanins/immunologyABSTRACT
Black carbon nanoparticles (nano-BC) are one of the most active components in pyrogenic carbonaceous matter and involved in many biogeochemical processes. This study investigated heteroaggregation of nano-BC with goethite (a model of natural mineral colloids) and the configuration effect of heteroaggregates on phenanthrene (PHE) sorption. Nano-BC could significantly enhance the dispersion of goethite via heteroaggregation when its concentration was higher than the critical concentration ( Cc). The Cc was dependent on the surface potential of nano-BC, which was directly measured for the first time in this study. Configuration and stability of the heteroaggregates were regulated by BC-goethite mass ratio and solution pH. At pH 5.3, oppositely charged goethite and nano-BC interacted with each other through electrostatic attraction and the configuration of heteroaggregates was dependent on BC-goethite mass ratio. At pH 7.4, where both goethite and nano-BC were negatively charged, they heteroaggregated with each other mainly through H-bonding and Lewis acid-base mechanisms, and the configuration of heteroaggregates was independent of BC-goethite mass ratio. For PHE sorption, small-sized heteroaggregates were more favorable than large ones due to the higher content of active sorption sites. Interestingly, at a higher concentration of PHE, we found that the solute molecules could probably penetrate into and/or alter the configuration of heteroaggregates and enhance its sorption capacity for PHE. These findings are useful for understanding the effect of nano-BC on colloidal stability and organic compound sorption of minerals.
Subject(s)
Nanoparticles , Phenanthrenes , Adsorption , Carbon , Colloids , Iron Compounds , MineralsABSTRACT
OBJECTIVE: To investigate the effects of down-regulation of PTTG1 expression on the proliferation, invasiveness and apoptosis of androgen-independent human prostate cancer LNCaP-AI cells and their sensitivity to androgen antagonists. METHODS: Human prostate cancer LNCaP-AI cells were transfected with siRNA targeting the PTTG1 gene using the Lipofectamine 2000 transfection reagent. The proliferation, invasiveness and apoptosis of the cells were detected by MTT, Transwell assay and flow cytometry, respectively. The protein expressions of PTTG1, p-Akt, and p-ERK were determined by Western blot and the mRNA expression of PTTG1 measured by agarose gel electrophoresis. RESULTS: The siRNA expression vector markedly down-regulated the expression of PTTG1, which effectively suppressed the proliferation of the LNCaP-AI cells, with the inhibition rates of (19.47 ± 2.12), (24.01 ± 2.13) and (48.02 ± 2.22)% at 24, 48 and 72 hours, respectively, after transfection, with statistically significant differences among the three groups (P <0.05). The number of the cells passing through the polycarbonate film was remarkably decreased at 24, 48 and 72 hours (74.67 ± 9.85, 56.44 ± 8.66 and 37.33 ± 6.14) as compared with the baseline (111.11 ± 13.47) (P <0.01), while the apoptosis rate of the cells was significantly increased at 24, 48 and 72 hours (18.32 ± 0.94), (19.94 ± 1.30) and (21.73 ± 1.88)% in comparison with the baseline (ï¼»2.17 ± 0.49ï¼½%)ï¼ (P <0.05). PTTG1 siRNA combined with androgen antagonist flumatide exhibited even more significant effects in inhibiting the proliferation and promoting the apoptosis of the LNCaP-AI cells than either used alone, and in a flumatide dose-dependent manner. The inhibition and apoptosis rates of the LNCaP-AI cells treated with 50 nmol/L flumatide were (27.13 ± 3.52) and (3.94 ± 0.48)%, and those treated with siRNA + 50 nmol/L flumatide were (67.51 ± 5.13) and (19.93 ± 1.72)%, respectively, both with statistically significant differences between the two groups (P <0.05). The inhibition and apoptosis rates of the cells treated with 100 nmol/L flumatide were (43.72 ± 3.90) and (5.33 ± 0.66)%, and those treated with siRNA + 100 nmol/L flumatide were (73.19 ± 4.78) and (23.43 ± 1.76)%, respectively, both with statistically significant differences between the two groups (P <0.05). CONCLUSIONS: The siRNA expression vector can down-regulate the expression of PTTG1, which can inhibit the proliferation and invasiveness of LNCaP-AI cells, promote their apoptosis, and increase their sensibility to androgen antagonists. Suppressing the expression of PTTG1 may enhance the effect of androgen-deprivation therapy on advanced prostate cancer.
Subject(s)
Androgen Antagonists/pharmacology , Apoptosis , Cell Proliferation , Down-Regulation , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , RNA, Small Interfering/metabolism , Securin/metabolism , Cell Line, Tumor , Humans , Male , Neoplasm Invasiveness , Prostatic Neoplasms/drug therapy , Securin/genetics , Time Factors , TransfectionABSTRACT
OBJECTIVE: To explore the expression of pituitary tumor transforming gene 1 (PTTG1) during the transformation of prostate cancer from androgen-dependent (ADPC) to androgen-independent (AIPC). METHODS: We established an AIPC cell model LNCaP-AI by culturing the androgen-dependent LNCaP cell line in the hormone-deprived medium for over 3 months. The cell model was verified and the PTTG1 expression in the LNCaP cells was detected by Western blot and RT-PCR during hormone deprivation. RESULTS: The AIPC cell model LNCaP-AI was successfully established. The PTTG1 expression was gradually increased in the LNCaP cells with the prolonged time of hormone deprivation and the expressions of matrix metalloproteinases MMP-2 and -9 were elevated at the same time. CONCLUSIONS: The expression of PTTG1 is increased gradually in AIPC, which may be a target of gene therapy for advanced prostate cancer.
Subject(s)
Gene Expression Regulation, Neoplastic , Prostatic Neoplasms/genetics , Securin/genetics , Blotting, Western , Cell Line, Tumor , Humans , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Neoplasms, Hormone-Dependent , Prostatic Neoplasms/enzymologyABSTRACT
In this work, the solid solution product of [Nb][C] in the Nb-microalloyed steels with various carbon contents in the range of 0.20~1.80 wt.% was investigated by means of the extraction phase analysis method. The results showed that the Nb content in austenite tended to first decrease and then increase with the increase of carbon content in the steels. A unified solid solution product of [Nb][C] in austenite at different temperatures was obtained according to the results of the experimental steels. The Nb content in austenite of the experimental steels with high carbon contents was lower than that calculated by Ohtani's equation. The existence of NbC precipitates in the case and the core of the specimens carburized at 930 °C and 980 °C were verified by transmission electron microscopy (TEM) observations. The pinning effect of NbC precipitates on austenite grain growth was calculated according to the size and amount of NbC precipitates in the carburized case and the core of the carburized specimens. The calculated results of prior austenite grain sizes were in good agreement with the experimental results, which indicated that the unified solid solution product of [Nb][C] in Nb-microalloyed steels with various carbon contents was applicable for the low-pressure carburizing process.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The dried aerial parts of Veronica linariifolia subsp. dilatata (Nakai & Kitag.) D.Y.Hong named Shui Man Jing (SMJ) is a traditional Chinese medicine with a long history of clinical use in the treatment of chronic bronchitis and coughing up blood, however, its role on acute lung injury (ALI) has not been revealed yet. AIM OF THE STUDY: To assess the efficiency of SMJ on ALI and to investigate whether it inhibited endothelial barrier dysfunction by regulating the EGFR/Akt/ZO-1 pathway to alleviate ALI in vivo and in vitro based on the result of network pharmacology. MATERIALS AND METHODS: An in vivo model of ALI was established using inhalation of atomized lipopolysaccharide (LPS), and the effects of SMJ on ALI were evaluated through histopathological examination and inflammatory cytokines, lung histology and edema, vascular and alveolar barrier disruption. Network pharmacology was applied to predict the mechanism of SMJ in the treatment of ALI. The crucial targets were validated by RT-PCR, Western Blotting, molecular docking, immunohistochemistry and immunofluorescence methods in vivo and in virto. RESULTS: Administration of SMJ protected mice against LPS-induced ALI, including ameliorating the histological alterations in the lung tissues, and decreasing lung edema, protein content of bronchoalveolar lavage fluid, infiltration of inflammatory cell and secretion of cytokines. SMJ exerted protective effects in ALI by inhibiting endothelial barrier dysfunction in mice and bEnd.3 cell. SMJ relieved endothelial barrier dysfunction induced by LPS through upregulating the EGFR expression. SMJ also increased the phosphorylation of Akt, and ZO-1 expression both in vivo and in vitro. CONCLUSION: SMJ attenuates vascular endothelial barrier dysfunction for LPS-induced ALI via EGFR/Akt/ZO-1 pathway, and is a promising novel therapeutic candidate for ALI.
Subject(s)
Acute Lung Injury , Lipopolysaccharides , Humans , Male , Mice , Animals , Lipopolysaccharides/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Molecular Docking Simulation , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Lung , Endothelial Cells , Cytokines/metabolism , Edema/metabolism , ErbB Receptors/metabolismABSTRACT
Despite recent progress in Graph Neural Networks (GNNs), explaining predictions made by GNNs remains a challenging and nascent problem. The leading method mainly considers the local explanations, i.e., important subgraph structure and node features, to interpret why a GNN model makes the prediction for a single instance, e.g. a node or a graph. As a result, the explanation generated is painstakingly customized at the instance level. The unique explanation interpreting each instance independently is not sufficient to provide a global understanding of the learned GNN model, leading to the lack of generalizability and hindering it from being used in the inductive setting. Besides, training the explanation model explaining for each instance is time-consuming for large-scale real-life datasets. In this study, we address these key challenges and propose PGExplainer, a parameterized explainer for GNNs. PGExplainer adopts a deep neural network to parameterize the generation process of explanations, which renders PGExplainer a natural approach to multi-instance explanations. Compared to the existing work, PGExplainer has better generalization ability and can be utilized in an inductive setting without training the model for new instances. Thus, PGExplainer is much more efficient than the leading method with significant speed-up. In addition, the explanation networks can also be utilized as a regularizer to improve the generalization power of existing GNNs when jointly trained with downstream tasks. Experiments on both synthetic and real-life datasets show highly competitive performance with up to 24.7% relative improvement in AUC on explaining graph classification over the leading baseline.
ABSTRACT
Atopic dermatitis is a chronic relapsing skin disease characterized by recurrent, pruritic, localized eczema, while PDE4 inhibitors have been reported to be effective as antiatopic dermatitis agents. 3',4-O-dimethylcedrusin (DCN) is a natural dihydrobenzofuran neolignan isolated from Magnolia biondii with moderate potency against PDE4 (IC50 = 3.26 ± 0.28 µM) and a binding mode similar to that of apremilast, an approved PDE4 inhibitor for the treatment of psoriasis. The structure-based optimization of DCN led to the identification of 7b-1 that showed high inhibitory potency on PDE4 (IC50 = 0.17 ± 0.02 µM), good anti-TNF-α activity (EC50 = 0.19 ± 0.10 µM), remarkable selectivity profile, and good skin permeability. The topical treatment of 7b-1 resulted in the significant benefits of pharmacological intervention in a DNCB-induced atopic dermatitis-like mice model, demonstrating its potential for the development of novel antiatopic dermatitis agents.