Comprehensive analysis of CYBB as a prognostic marker and therapeutic target in glioma: A bioinformatics approach.

Background: In the central nervous system, glioma is the most common malignant tumor, and patients have a poor prognosis. Identification of novel marker genes and establishment of prognostic models are important for early diagnosis and prognosis determination. Methods: Download glioma data from the CGGA and TCG databases. Application of bioinformatics to analyze the impact of CYBB on the clinicopathological characteristics, immunological features and prognosis of gliomas. Using single-cell sequencing data from 7 glioblastoma patients in the CGGA database, the role of CYBB in the tumor microenvironment was analyzed. In addition, a prognostic model was constructed based on CYBB high and low differentially expressed genes and mitochondrial genes. Results: The expression of CYBB is closely related to various clinical features, immune cell infiltration level, immune checkpoint and survival time of patients. A 10-gene prediction model was constructed based on the differentially expressed genes of low and high CYBB and mitochondria-related genes. Glioma patients with higher risk scores had significantly lower survival probabilities. Receiver operating characteristic curves and nomograms were plotted over time to show the predictive accuracy and predictive value of the 10-gene prognostic model. Conclusions: Our study shows that CYBB is strongly correlated with clinical characteristics features and prognosis of glioma patients, and can be used as a potential therapeutic target. Prognostic models based on CYBB and mitochondrial genes have good performance in predicting prognosis of glioma patients.

Resveratrol ameliorates glioblastoma inflammatory response by reducing NLRP3 inflammasome activation through inhibition of the JAK2/STAT3 pathway.

OBJECTIVES: The aim of this study was to investigate the anti-tumor effect of resveratrol (RSV) on glioblastoma (GBM) and its specific mechanism in improving the inflammatory response of the tumor microenvironment. The tumor microenvironment of GBM is highly neuroinflammatory, inducing tumor immunosuppression. Therefore, ameliorating the inflammatory response is an important focus for anti-tumor research. METHODS: The anti-tumor effect of RSV on GBM was demonstrated through in vitro cellular assays, including CCK-8, EdU, PI staining, Transwell, wound healing assay, and flow cytometry. Potential mechanisms of RSV's anti-GBM effects were identified through network pharmacological analysis. In addition, the relationship of RSV with the JAK2/STAT3 signaling pathway and the inflammasome NLRP3 was verified using Western blot. RESULTS: RSV significantly inhibited cell viability in GBM cell lines LN-229 and U87-MG. Furthermore, it inhibited the proliferation and invasive migration ability of GBM cells, while promoting apoptosis. Network pharmacological analysis revealed a close association between the anti-GBM effects of RSV and the JAK/STAT signaling pathway, as well as inflammatory responses. Western blot analysis confirmed that RSV inhibited the over-activation of the inflammasome NLRP3 through the JAK2/STAT3 signaling pathway. Partial reversal of RSV's inhibition of inflammasome NLRP3 was observed with the addition of the JAK/STAT agonist RO8191. CONCLUSIONS: In vitro, RSV can exert anti-tumor effects on GBM and improve the inflammatory response in the GBM microenvironment by inhibiting the activation of the JAK2/STAT3 signaling pathway. These findings provide new insights into potential therapeutic targets for GBM.

Glucose regulates the HMGB1 signaling pathway through SIRT1 in glioma.

BACKGROUND: Glucose is a fundamental substance for numerous cancers, including glioma. However, its influence on tumor cells regulatory mechanisms remains uncertain. SIRT1 is a regulator of deacetylation and a key player in the progression of malignant tumors. The objective of this study was to examine the role of glucose and SIRT1 in glioma. METHODS: This study investigated the association of SIRT1 expression with clinicopathological features and prognosis in glioma patients using the TCGA database. The Western blotting technique was used to identify the expression of SIRT1 protein in glioma cells. The study also examined the impact of differing glucose concentrations on the biological functions of glioma cells. The study investigated the expression of SIRT1 and HMGB1 signaling pathways in glioma. Additionally, resilience experiments were conducted utilizing SRT1720. RESULTS: SIRT1 is a gene that suppresses tumors and is low expressed in gliomas. Low expression of this gene is strongly linked to a poor prognosis in patients with glioma. High concentrations of glucose can promote the proliferation, migration, and invasion of glioma cells, while also inhibiting apoptosis. The findings of this mechanistic study provide evidence that glucose can down-regulate SIRT1 expression, leading to increased levels of acetylated HMGB1. This in turn promotes the ex-nuclear activation of HMGB1 and associated signaling pathways, ultimately driving glioma malignancy. CONCLUSION: Glucose has the ability to regulate the HMGB1 associated signaling pathway through SIRT1, thus promoting glioma progression. This holds significant research value.

The critical roles of propanethiol oxidoreductase and sulfide-quinone oxidoreductase in the propanethiol catabolism pathway in Pseudomonas putida S-1.

Propanethiol (PT) is a hazardous pollutant that poses risks to both the environment and human well-being. Pseudomonas putida S-1 has been identified as a microorganism capable of utilizing PT as its sole carbon source. However, the metabolic pathway responsible for PT degradation in P. putida S-1 has remained poorly understood, impeding its optimization and practical application. In this study, we investigated the catabolic network involved in PT desulfurization with P. putida S-1 and identified key gene modules crucial to this process. Notably, propanethiol oxidoreductase (PTO) catalyzes the initial degradation of PT, a pivotal step for P. putida S-1's survival on PT. PTO facilitates the oxidation of PT, resulting H2S, H2O2, and propionaldehyde (PA). Catalase-peroxidase catalyzes the conversion of H2O2 to oxygen and water, while PA undergoes gradual conversion to Succinyl-CoA, which is subsequently utilized in the tricarboxylic acid cycle. H2S is digested in a comprehensive desulfurization network where sulfide-quinone oxidoreductase (SQOR) predominantly converts it to sulfane sulfur. The transcriptome analysis suggests that sulfur can be finally converted to sulfite or sulfate and exported out of the cell. The PT degradation capacity of P. putida S-1 was enhanced by increasing the transcription level of PTO and SQOR genes in vivo.IMPORTANCEThis work investigated the PT catabolism pathway in Pseudomonas putida S-1, a microorganism capable of utilizing PT as the sole carbon source. Critical genes that control the initiation of PT degradation were identified and characterized, such as pto and sqor. By increasing the transcription level of pto and sqor genes in vivo, we have successfully enhanced the PT degradation efficiency and growth rate of P. putida S-1. This work does not only reveal a unique PT degradation pathway but also highlights the potential of enhancing the microbial desulfurization process in the bioremediation of thiol-contaminated environment.

Efficient Exploration of Chemical Compound Space Using Active Learning for Prediction of Thermodynamic Properties of Alkane Molecules.

We introduce an exploratory active learning (AL) algorithm using Gaussian process regression and marginalized graph kernel (GPR-MGK) to sample chemical compound space (CCS) at minimal cost. Targeting 251,728 enumerated alkane molecules with 4-19 carbon atoms, we applied the AL algorithm to select a diverse and representative set of molecules and then conducted high-throughput molecular simulations on these selected molecules. To demonstrate the power of the AL algorithm, we built directed message-passing neural networks (D-MPNN) using simulation data as the training set to predict liquid densities, heat capacities, and vaporization enthalpies of the CCS. Validations show that D-MPNN models built on the smallest training set considered in this work, which consists of 313 molecules or 0.124% of the original CCS, predict the properties with R2 > 0.99 against the computational data and R2 > 0.94 against the experimental data. The advantage of the presented AL algorithm is that the predicted uncertainty of GPR depends on only the molecular structures, which renders it compatible with high-throughput data generation.

Regulation of low-density lipoprotein on lipid metabolism in macrophages of large yellow croaker (Larimichthys crocea).

Low-density lipoprotein (LDL) is the main carrier of cholesterol transport in plasma, which participates in regulating lipid homeostasis. Studies in mammals have shown that high levels of LDL in plasma absorbed by macrophages trigger the formation of lipid-rich foam cells, leading to the development of atherosclerotic plaques. Although lipid-rich atherosclerosis-like lesions have been discovered in the aorta of several fish species, the physiological function of LDL in fish macrophages remains poorly understood. In the present study, LDL was isolated from the plasma of large yellow croaker (Larimichthys crocea), and mass spectrometry analysis identified two truncated forms of apolipoprotein B100 in the LDL protein profile. Transcriptomic analysis of LDL-stimulated macrophages revealed that differentially expressed genes (DEGs) were enriched in various pathways related to lipid metabolism, as confirmed by the fact that LDL increased total cholesterol and cholesteryl esters content. Meanwhile, the gene and protein expression levels of perilipin2 (PLIN2), a DEG enriched in the PPAR signaling pathway, were upregulated in response to LDL stimulation. Importantly, knocking down plin2 significantly attenuates LDL-induced cholesterol accumulation and promotes cholesterol efflux. Furthermore, the transcription factor PPARγ, which is upregulated in response to LDL stimulation, can enhance the promoter activity of plin2. In conclusion, this study suggests that LDL may upregulate plin2 expression through PPARγ, resulting in cholesterol accumulation in fish macrophages. This study will facilitate the investigation of the function of LDL in regulating lipid homeostasis in macrophages and shed light on the evolutionary origin of LDL metabolism in vertebrates.

Glycerol monolaurate improved intestinal barrier, antioxidant capacity, inflammatory response and microbiota dysbiosis in large yellow croaker (Larimichthys crocea) fed with high soybean oil diets.

Glycerol monolaurate (GML) is a potential candidate for regulating metabolic syndrome and inflammatory response. However, the role of GML in modulating intestinal health in fish has not been well determined. In this study, a 70-d feeding trial was conducted to evaluate the effect of GML on intestinal barrier, antioxidant capacity, inflammatory response and microbiota community of large yellow croaker (13.05 ± 0.09 g) fed with high level soybean oil (SO) diets. Two basic diets with fish oil (FO) or SO were formulated. Based on the SO group diet, three different levels of GML 0.02% (SO0.02), 0.04% (SO0.04) and 0.08% (SO0.08) were supplemented respectively. Results showed that intestinal villus height and perimeter ratio were increased in SO0.04 treatment compared with the SO group. The mRNA expressions of intestinal physical barrier-related gene odc and claudin-11 were significantly up-regulated in different addition of GML treatments compared with the SO group. Fish fed SO diet with 0.04% GML addition showed higher activities of acid phosphatase and lysozyme compared with the SO group. The content of malonaldehyde was significantly decreased and activities of catalase and superoxide dismutase were significantly increased in 0.02% and 0.04% GML groups compared with those in the SO group. The mRNA transcriptional levels of inflammatory response-related genes (il-1ß, il-6, tnf-α and cox-2) in 0.04% GML treatment were notably lower than those in the SO group. Meanwhile, sequencing analysis of bacterial 16S rRNA V4-V5 region showed that GML addition changed gut microbiota structure and increased alpha diversity of large yellow croaker fed diets with a high level of SO. The correlation analysis results indicated that the change of intestinal microbiota relative abundance strongly correlated with intestinal health indexes. In conclusion, these results demonstrated that 0.02%-0.04% GML addition could improve intestinal morphology, physical barrier, antioxidant capacity, inflammatory response and microbiota dysbiosis of large yellow croaker fed diets with a high percentage of SO.

Interpretable Molecular Property Predictions Using Marginalized Graph Kernels.

Marginalized graph kernels have shown competitive performance in molecular machine learning tasks but currently lack measures of interpretability, which are important to improve trust in the models, detect biases, and inform molecular optimization campaigns. We here conceive and implement two interpretability measures for Gaussian process regression using a marginalized graph kernel (GPR-MGK) to quantify (1) the contribution of specific training data to the prediction and (2) the contribution of specific nodes of the graph to the prediction. We demonstrate the applicability of these interpretability measures for molecular property prediction. We compare GPR-MGK to graph neural networks on four logic and two real-world toxicology data sets and find that the atomic attribution of GPR-MGK generally outperforms the atomic attribution of graph neural networks. We also perform a detailed molecular attribution analysis using the FreeSolv data set, showing how molecules in the training set influence machine learning predictions and why Morgan fingerprints perform poorly on this data set. This is the first systematic examination of the interpretability of GPR-MGK and thereby is an important step in the further maturation of marginalized graph kernel methods for interpretable molecular predictions.

[Advances in genomics of multi-drug resistant Stenotrophomonas].

Stenotrophomonas species are non-fermentative Gram-negative bacteria that are widely distributed in environment and are highly resistant to numerous antibiotics. Thus, Stenotrophomonas serves as a reservoir of genes encoding antimicrobial resistance (AMR). The detection rate of Stenotrophomonas is rapidly increasing alongside their strengthening intrinsic ability to tolerate a variety of clinical antibiotics. This review illustrated the current genomics advances of antibiotic resistant Stenotrophomonas, highlighting the importance of precise identification and sequence editing. In addition, AMR diversity and transferability have been assessed by the developed bioinformatics tools. However, the working models of AMR in Stenotrophomonas are cryptic and urgently required to be determined. Comparative genomics is envisioned to facilitate the prevention and control of AMR, as well as to gain insights into bacterial adaptability and drug development.

Effects of supplemental octanoate on hepatic lipid metabolism, serum biochemical indexes, antioxidant capacity and inflammation-related genes expression of large yellow croaker (Larimichthys crocea) fed with high soybean oil diet.

Dietary high soybean oil (SO) levels might cause hepatic lipid deposition, induce oxidative stress and inflammatory response in aquatic animals, while octanoate (OCT) is beneficial to metabolism and health in mammals. However, the effect of OCT has been studied rarely in aquatic animals. In this study, a 10-week feeding trial was conducted to investigate the effect of supplemental OCT on hepatic lipid metabolism, serum biochemical indexes, antioxidant capacity and inflammatory response of large yellow croaker (Larimichthys crocea) fed with high SO levels diet. The negative control diet contained 7% fish oil (FO), while the positive control diet contained 7% SO. The other four experimental diets were supplemented with 0.7, 2.1, 6.3 and 18.9 g/kg sodium octanoate (OCT) based on the positive control diet. Results showed that OCT supplementation effectively reduced the hepatic crude lipid, triglyceride (TG), total cholesterol (TC) and non-esterified free fatty acids contents, and alleviated lipid accumulation caused by the SO diet. Meanwhile, OCT supplementation decreased the serum TG, TC, alanine transaminase, aspartate transaminase and low-density lipoprotein cholesterol levels, increased the serum high-density lipoprotein cholesterol level, improved the serum lipid profiles and alleviated hepatic injury. Furthermore, with the supplementation of OCT, the mRNA expression of genes related to lipogenesis (acc1, scd1, fas, srebp1, dgat1 and cebpα) and fatty acid (FA) transport (fabp3, fatp and cd36) were down-regulated, while the mRNA expression of genes related to lipolysis (atgl, hsl and lpl) and FA ß-oxidation (cpt1 and mcad) were up-regulated. Besides that, dietary OCT increased the total antioxidant capacity, activities of peroxidase, catalase and superoxide dismutase and the content of reduced glutathione, decreased the content of 8-hydroxy-deoxyguanosine and malondialdehyde and relieved hepatic oxidative stress. Supplementation of 0.7 and 2.1 g/kg OCT down-regulated the mRNA expression of genes related to pro-inflammatory cytokines (tnfα, il1ß and ifnγ), and suppressed hepatic inflammatory response. In conclusion, supplementation with 0.7-2.1 g/kg OCT could reduce hepatic lipid accumulation, relieve oxidative stress and regulate inflammatory response in large yellow croaker fed the diet with high SO levels, providing a new way to alleviate the hepatic fat deposition in aquatic animals.

Integrative Analysis of Fruit Quality and Anthocyanin Accumulation of Plum cv. 'Cuihongli' (Prunus salicina Lindl.) and Its Bud Mutation.

Fruit color is one of the quality indicators to judge the freshness of a plum. The coloring process of plum skin is valuable for research due to the high nutritional quality of anthocyanins found in plums. 'Cuihongli' (CHL) and its precocious mutant variety 'Cuihongli Red' (CHR) were used to analyze the changes of fruit quality and anthocyanin biosynthesis during plum development. The results showed that, during the development of the two plums, the total soluble solid and soluble sugar contents were highest at the mature stage, as the titratable acid trended gradually downward as the fruits of the two cultivars matured, and the CHR fruit showed higher sugar content and lower acid content. In addition, the skin of CHR turned red in color earlier than CHL. Compared with CHL, the skin of CHR had higher anthocyanin concentrations, higher activities of phenylalanine ammonia-lyase (PAL), chalcone isomerase (CHI), dihydroflavonol-4-reductase (DFR), and UDPglucose: flavonoid-3-O-glucosyltransferase (UFGT), and higher transcript levels of genes associated with anthocyanin production. In the flesh of the two cultivars, no anthocyanin content was detected. Taken together, these results suggest that the mutation exerted a major effect on anthocyanin accumulation via modification of the level of transcription; thus, CHR advances the ripening period of 'Cuihongli' plum and improves the fruit quality.

Impact of dietary sucralose and sucrose-sweetened water intake on lipid and glucose metabolism in male mice.

AIMS: Overconsumption of sugar-sweetened beverages (SSBs) is associated with an increased risk of metabolic disorders, including obesity and diabetes. However, accumulating evidence also suggests the potential negative impact of consuming nonnutritive sweeteners (NNSs) on weight and glycaemic control. The metabolic effects of sucralose, the most widely used NNS, remain controversial. This study aimed to compare the impact of intake of dietary sucralose (acceptable daily intake dose, ADI dose) and sucrose-sweetened water (at the same sweetness level) on lipid and glucose metabolism in male mice. MATERIALS AND METHODS: Sucralose (0.1 mg/mL) or sucrose (60 mg/mL) was added to the drinking water of 8-week-old male C57BL/6 mice for 16 weeks, followed by oral glucose and intraperitoneal insulin tolerance tests, and measurements of bone mineral density, plasma lipids, and hormones. After the mice were sacrificed, the duodenum and ileum were used for examination of sweet taste receptors (STRs) and glucose transporters. RESULTS: A significant increase in fat mass was observed in the sucrose group of mice after 16 weeks of sweetened water drinking. Sucrose consumption also led to increased levels of plasma LDL, insulin, lipid deposition in the liver, and increased glucose intolerance in mice. Compared with the sucrose group, mice consuming sucralose showed much lower fat accumulation, hyperlipidaemia, liver steatosis, and glucose intolerance. In addition, the daily dose of sucralose only had a moderate effect on T1R2/3 in the intestine, without affecting glucose transporters and plasma insulin levels. CONCLUSION: Compared with mice consuming sucrose-sweetened water, daily drinking of sucralose within the ADI dose had a much lower impact on glucose and lipid homeostasis.

Effects of dietary lysolecithin on growth performance, serum biochemical indexes, antioxidant capacity, lipid metabolism and inflammation-related genes expression of juvenile large yellow croaker (Larimichthys crocea).

A 70-day feeding trial was conducted to investigate effects of dietary lysolecithin on growth performance, serum biochemical indexes, antioxidant capacity, lipid metabolism and inflammation-related genes expression of juvenile large yellow croaker (Larimichthys crocea) with initial weight of 6.04 ± 0.08 g. A formulated diet containing approximately 42% crude protein and 12.5% crude lipid was used as the control diet (CON). The other three experimental diets were formulated with supplementation of 0.2%, 0.4% and 0.6% lysolecithin based on the control diet, respectively. Results showed that weight gain rate (WGR) and specific growth rate (SGR) significantly increased in fish fed diets with lysolecithin compared with those in the control diet (P < 0.05). Fish fed diets with 0.4% and 0.6% lysolecithin had notably higher lipid content in muscle than that in the control diet (P < 0.05). When fish were fed diets with lysolecithin, serum high-density lipoprotein cholesterol (HDL-c) content was notably higher than that in the control diet (P < 0.05), while fish fed the diet with 0.6% lysolecithin had a significant lower serum low-density lipoprotein cholesterol (LDL-c) content than that in the control diet (P < 0.05). Meanwhile, serum aspartate transaminase (AST) and alanine transaminase (ALT) activities in fish fed diets with lysolecithin were remarkably lower than those in the control diet (P < 0.05). With the increase of dietary lysolecithin from 0.2% to 0.6%, mRNA expression of stearoyl-coenzyme A desaturase 1 (scd1), diacylglycerol acyltransferase 2 (dgat2) and sterol-regulatory element binding protein 1 (srebp1) showed decreasing trends. Furthermore, mRNA expression of carnitine palmitoyl transferase 1 (cpt1) and lipoprotein lipase (lpl) among each dietary lysolecithin treatment were significantly higher than those in the control diet (P < 0.05). In terms of inflammation, mRNA expression of tumor necrosis factor α (tnf-α) and interleukin-1 ß (il-1ß) were significantly down-regulated in fish fed diets with lysolecithin compared with those in the control diet (P < 0.05), while the mRNA expression of interleukin-10 (il-10) was significantly higher than that in the control diet (P < 0.05). In conclusion, dietary lysolecithin could promote the growth performance, improve hepatic lipid metabolism and regulate inflammation response in juvenile large yellow croaker, and the optimal supplement level of lysolecithin was approximately 0.4% in this study.

Octanoate Alleviates Dietary Soybean Oil-Induced Intestinal Physical Barrier Damage, Oxidative Stress, Inflammatory Response and Microbial Dysbiosis in Large Yellow Croaker (Larimichthys Crocea).

Octanoate is a type of classical medium-chain fatty acids, which is widely used to treat neurological and metabolic syndrome. However, the specific role of octanoate in repairing intestinal health impairment is currently unknown. Therefore, we investigated whether dietary octanoate repaired the intestinal damage induced by surplus soybean oil in Larimichthys crocea. In this study, dietary octanoate alleviated abnormal morphology of the intestine and enhanced expression of ZO-1 and ZO-2 to improve intestinal physical barrier. Further, dietary octanoate increased antioxidant enzymic activities and decreased the level of ROS to alleviate the intestinal oxidative stress. Dietary octanoate also attenuated the expression of proinflammatory cytokines and the polarity of macrophage to reduce the intestinal inflammatory response. Moreover, the result of intestinal microbial 16S rRNA sequence showed that dietary octanoate repaired the intestinal mucosal microbial dysbiosis, and increased the relative abundance of Lactobacillus. Dietary octanoate supplementation also increased the level of acetic acid in intestinal content and serum through increasing the abundance of acetate-producing strains. Overall, in Larimichthys crocea, dietary octanoate might alleviated oxidative stress, inflammatory response and microbial dysbiosis to repair the intestinal damage induced by surplus soybean oil. This work provides vital insights into the underlying mechanisms and treatment strategies for intestinal damage in vertebrates.

Replacement of Dietary Fishmeal Protein with Degossypolized Cottonseed Protein on Growth Performance, Nonspecific Immune Response, Antioxidant Capacity, and Target of Rapamycin Pathway of Juvenile Large Yellow Croaker (Larimichthys crocea).

A 70-day feeding experiment was carried out to assess the replacement of dietary fishmeal (FM) protein with degossypolized cottonseed protein (DCP) on large yellow croaker (Larimichthys crocea) with initial body weight (13.09 ± 0.50 g). Five isonitrogenous and isolipidic diets replaced fishmeal protein with 0%, 20%, 40%, 60%, and 80% DCP were formulated and named as FM (the control group), DCP20, DCP40, DCP60, and DCP80, respectively. Results displayed that weight gain rate (WGR) and specific growth rate (SGR) in the DCP20 group (263.91% and 1.85% d-1) were significantly increased compared with the control group (194.79% and 1.54% d-1) (P < 0.05). Furthermore, fish fed the diet with 20% DCP significantly increased the activity of hepatic superoxide dismutase (SOD) compared with the control group (P < 0.05). Meanwhile, the content of hepatic malondialdehyde (MDA) in the DCP20, DCP40, and DCP80 groups was significantly lower than that in the control group (P < 0.05). The activity of intestinal trypsin in the DCP20 group was significantly degraded compared with that in the control group (P < 0.05). The transcription of hepatic proinflammatory cytokine genes (interleukin-6 (il-6); tumor necrosis factor-α (tnf-α); and interferon-γ (ifn-γ)) in the DCP20 and DCP40 groups was significantly upregulated compared with that in the control group (P < 0.05). As to the target of rapamycin (TOR) pathway, the transcription of hepatic target of rapamycin (tor) and ribosomal protein (s6) was significantly up-regulated, while the transcription of hepatic eukaryotic translation initiation factor 4E binding protein 1 (4e-bp1) gene was significantly downregulated in the DCP group compared with the control group (P < 0.05). In summary, based on the broken line regression model analysis of WGR and SGR against dietary DCP replacement levels, the optimal replacement level was recommended to be 8.12% and 9.37% for large yellow croaker, respectively. These results revealed that FM protein replaced with 20% DCP could promote digestive enzyme activities and antioxidant capacity and further activate immune response and the TOR pathway so that growth performance of juvenile large yellow croaker was improved.

A Comparative Study of Marginalized Graph Kernel and Message-Passing Neural Network.

This work proposes a state-of-the-art hybrid kernel to calculate molecular similarity. Combined with Gaussian process models, the performance of the hybrid kernel in predicting molecular properties is comparable to that of the directed message-passing neural network (D-MPNN). The hybrid kernel consists of a marginalized graph kernel (MGK) and a radial basis function (RBF) kernel that operate on molecular graphs and global molecular features, respectively. Bayesian optimization was used to obtain the optimal hyperparameters for both models. The comparisons are performed on 11 publicly available data sets. Our results show that their performances are similar, their prediction errors are correlated, and the ensemble predictions of the two models perform better than either of them. Through principal component analysis, we found that the molecular embeddings of the hybrid kernel and the D-MPNN are also similar. The advantage of D-MPNN lies in the computational efficiency and scalability of large-scale data, while the advantage of the graph kernel models lies in the accurate uncertainty quantification.

Graphical Gaussian process regression model for aqueous solvation free energy prediction of organic molecules in redox flow batteries.

The solvation free energy of organic molecules is a critical parameter in determining emergent properties such as solubility, liquid-phase equilibrium constants, pKa and redox potentials in an organic redox flow battery. In this work, we present a machine learning (ML) model that can learn and predict the aqueous solvation free energy of an organic molecule using the Gaussian process regression method based on a new molecular graph kernel. To investigate the performance of the ML model for electrostatic interaction, the nonpolar interaction contribution of the solvent and the conformational entropy of the solute in the solvation free energy, three data sets with implicit or explicit water solvent models, and contribution of the conformational entropy of the solute are tested. We demonstrate that our ML model can predict the solvation free energy of molecules at chemical accuracy with a mean absolute error of less than 1 kcal mol-1 for subsets of the QM9 dataset and the Freesolv database. To solve the general data scarcity problem for a graph-based ML model, we propose a dimension reduction algorithm based on the distance between molecular graphs, which can be used to examine the diversity of the molecular data set. It provides a promising way to build a minimum training set to improve prediction for certain test sets where the space of molecular structures is predetermined.

Comparative insights into multiple drug resistance determinants in Stenotrophomonas maltophilia MER1.

OBJECTIVES: Multidrug-resistant (MDR) Stenotrophomonas maltophilia strain MER1 was isolated from hospital wastewater in Shandong Province, China. This study aimed to determine the genetic determinants related to its striking MDR phenotype. METHODS: Antimicrobial susceptibility testing of strain MER1 was performed by disk diffusion on Mueller-Hinton agar plates, and MICs were interpreted according to Clinical and Laboratory Standards Institute breakpoints. The genome of MER1 was sequenced and assembled using PacBio RS II and BGISEQ-500 platforms. Antimicrobial resistance determinants together with other transferability or adaptability determinants were identified by comparative genomics. Phylogenetic and contextual assays for these elements were conducted to assess the risk of spread of MER1. RESULTS: Antimicrobial susceptibility testing revealed that strain MER1 is resistant to nine different antibiotics, including ampicillin, meropenem, amikacin, erythromycin, vancomycin, tetracycline, tigecycline, colistin and ceftazidime. Several genes were identified encoding efflux pumps and drug-inactivating agents, accounting for resistance to the above antibiotics, including meropenem, tigecycline and colistin regarded as last-line therapies for infections caused by MDR Gram-negative bacteria. MER1 co-harbours two non-mobile mcr homologues. A novel genomic region of variability was demonstrated to confer bacterial robustness and adaptability upon strain MER1. CONCLUSION: Collective efforts revealed the MDR properties and potential genetic determinants of S. maltophilia MER1 isolated from hospital wastewater. Comparative genomic analysis of S. maltophilia MER1 may provide insights into the prevention and treatment of antimicrobial-resistant infections. Our findings raise concern that the MDR genes in the reservoir of S. maltophilia may further spread into various ecological niches or medically high-risk pathogens.

Smooth Muscle Overexpression of PGC1α Attenuates Atherosclerosis in Rabbits.

[Figure: see text].

Predicting Single-Substance Phase Diagrams: A Kernel Approach on Graph Representations of Molecules.

This work presents a Gaussian process regression (GPR) model on top of a novel graph representation of chemical molecules that predicts thermodynamic properties of pure substances in single, double, and triple phases. A transferable molecular graph representation is proposed as the input for a marginalized graph kernel, which is the major component of the covariance function in our GPR models. Radial basis function kernels of temperature and pressure are also incorporated into the covariance function when necessary. We predicted three types of representative properties of pure substances in single, double, and triple phases, i.e., critical temperature, vapor-liquid equilibrium (VLE) density, and pressure-temperature density. The accuracy of the models is nearly identical to the precision of the experimental measurements. Moreover, the reliability of our predictions can be quantified on a per-sample basis using the posterior uncertainty of the GPR model. We compare our model against Morgan fingerprints and a graph neural network to further demonstrate the advantage of the proposed method.