Dopamine promotes Klebsiella quasivariicola proliferation and inflammatory response in the presence of macrophages.

Background: Dopamine, a frequently used therapeutic agent for critically ill patients, has been shown to be implicated in clinical infections recently, however, the precise mechanisms underlying this association remain elusive. Klebsiella quasivariicola, a novel strain belonging to the Klebsiella species, exhibits potential pathogenic attributes. The impact of dopamine on K. quasivariicola infection has aroused our interest. Objective: Considering the contribution of host immune factors during infection, this study aimed to investigate the intricate interactions between K. quasivariicola, dopamine, and macrophages were explored. Methods: RAW264.7 cells and C57/BL6 mice were infected with K. quasivariicola, and the bacterial growth within macrophage, the production of inflammatory cytokines and the pathological changes in mice lungs were detected, in the absence or presence of dopamine. Results: Dopamine inhibited the growth of K. quasivariicola in the medium, but promoted bacterial growth when co-cultured with macrophages. The expression of proinflammatory cytokines increased in RAW 264.7 cells infected with K. quasivariicola, and a significant rise was observed upon the addition of dopamine. The infection of K. quasivariicola in mice induced an inflammatory response and lung injury, which were exacerbated by the administration of dopamine. Conclusions: Our findings suggest that dopamine may be one of the potential risk factors associated with K. quasivariicola infection. This empirical insight provides solid references for clinical precision medicine. Furthermore, an in vitro model of microbes-drugs-host immune cells for inhibitor screening was proposed to more accurately replicate the complex in vivo environment. This fundamental work had contributed to the present understanding of the crosstalk between pathogen, dopamine and host immune cells.

Prediction of Effectiveness and Toxicities of Immune Checkpoint Inhibitors Using Real-World Patient Data.

PURPOSE: Although immune checkpoint inhibitors (ICIs) have improved outcomes in certain patients with cancer, they can also cause life-threatening immunotoxicities. Predicting immunotoxicity risks alongside response could provide a personalized risk-benefit profile, inform therapeutic decision making, and improve clinical trial cohort selection. We aimed to build a machine learning (ML) framework using routine electronic health record (EHR) data to predict hepatitis, colitis, pneumonitis, and 1-year overall survival. METHODS: Real-world EHR data of more than 2,200 patients treated with ICI through December 31, 2018, were used to develop predictive models. Using a prediction time point of ICI initiation, a 1-year prediction time window was applied to create binary labels for the four outcomes for each patient. Feature engineering involved aggregating laboratory measurements over appropriate time windows (60-365 days). Patients were randomly partitioned into training (80%) and test (20%) sets. Random forest classifiers were developed using a rigorous model development framework. RESULTS: The patient cohort had a median age of 63 years and was 61.8% male. Patients predominantly had melanoma (37.8%), lung cancer (27.3%), or genitourinary cancer (16.4%). They were treated with PD-1 (60.4%), PD-L1 (9.0%), and CTLA-4 (19.7%) ICIs. Our models demonstrate reasonably strong performance, with AUCs of 0.739, 0.729, 0.755, and 0.752 for the pneumonitis, hepatitis, colitis, and 1-year overall survival models, respectively. Each model relies on an outcome-specific feature set, though some features are shared among models. CONCLUSION: To our knowledge, this is the first ML solution that assesses individual ICI risk-benefit profiles based predominantly on routine structured EHR data. As such, use of our ML solution will not require additional data collection or documentation in the clinic.

Diosmetin Ameliorates HFD-induced Cognitive Impairments via Inhibiting Metabolic Disorders, Mitochondrial Dysfunction and Neuroinflammation in Male SD Rats.

Currently, accumulating evidence has indicated that overnutrition-associated obesity may result in not only metabolic dysregulations, but also cognitive impairments. This study aimed to investigate the protective effects of Diosmetin, a bioflavonoid compound with multiple biological functions, on cognitive deficits induced by a high fat diet (HFD) and the potential mechanisms. In the present study, oral administration of Diosmetin (25, 50 and 100 mg/kg) for 12 weeks significantly reduced the body weight, restored glucose tolerance and normalized lipid profiles in the serum and liver in HFD-induced obese rats. Diosmetin also significantly ameliorated depression-like behaviors and impaired spatial memory in multiple behavioral tests, including the open field test, elevated plus-maze and Morris water maze, which was in accordance with the decreased pathological changes and neuronal damage in different regions of hippocampus as suggested by H&E and Nissl staining. Notably, our results also indicated that Diosmetin could significantly improve mitochondrial dysfunction induced by HFD through upregulating genes involved in mitochondrial biogenesis and dynamics, increasing mitochondrial ATP levels and inhibiting oxidative stress. Moreover, the levels of key enzymes involved in the TCA cycle were also significantly increased upon Diosmetin treatment. Meanwhile, Diosmetin inhibited HFD-induced microglial overactivation and down-regulated inflammatory cytokines both in the serum and hippocampus. In conclusion, these results indicated that Diosmetin might be a novel nutritional intervention to prevent the occurrence and development of obesity-associated cognitive dysfunction via metabolic regulation and anti-inflammation.

Integrative metagenomic and metabolomic analyses reveal the potential of gut microbiota to exacerbate acute pancreatitis.

Early dysbiosis in the gut microbiota may contribute to the severity of acute pancreatitis (AP), however, a comprehensive understanding of the gut microbiome, potential pathobionts, and host metabolome in individuals with AP remains elusive. Hence, we employed fecal whole-metagenome shotgun sequencing in 82 AP patients and 115 matched healthy controls, complemented by untargeted serum metabolome and lipidome profiling in a subset of participants. Analyses of the gut microbiome in AP patients revealed reduced diversity, disrupted microbial functions, and altered abundance of 77 species, influenced by both etiology and severity. AP-enriched species, mostly potential pathobionts, correlated positively with host liver function and serum lipid indicators. Conversely, many AP-depleted species were short-chain fatty acid producers. Gut microflora changes were accompanied by shifts in the serum metabolome and lipidome. Specifically, certain gut species, like enriched Bilophila wadsworthia and depleted Bifidobacterium spp., appeared to contribute to elevated triglyceride levels in biliary or hyperlipidemic AP patients. Through culturing and whole-genome sequencing of bacterial isolates, we identified virulence factors and clinically relevant antibiotic resistance in patient-derived strains, suggesting a predisposition to opportunistic infections. Finally, our study demonstrated that gavage of specific pathobionts could exacerbate pancreatitis in a caerulein-treated mouse model. In conclusion, our comprehensive analysis sheds light on the gut microbiome and serum metabolome in AP, elucidating the role of pathobionts in disease progression. These insights offer valuable perspectives for etiologic diagnosis, prevention, and intervention in AP and related conditions.

Urine LMs quantitative analysis strategy development and LMs CWP biomarkers discovery.

Coal workers' pneumoconiosis (CWP) is one of the most common inhalation occupational diseases. It is no effective treatment methods. Early diagnosis of CWP could reduce mortality. Lipid mediators (LMs) as key mediators in the generation and resolution of inflammation, are natural biomarkers for diagnosis inflammatory disease, such as CWP. The UHPLC-MRM technique was used to detect LMs in urine. The metabolic network of LMs in CWP and CT group samples was comprehensively analyzed. Screening for major difference compounds between the two groups. Aimed to contribute to the early diagnosis and treatment of CWP. Urinary levels of 13-OxoODE, 9-OxoODE, and 9,10-EpOME were significantly higher in the CWP group compared with the CT group (P < 0.05). In the model group, the area under the receiver operating characteristic (ROC) for 9-OxoODE,13-OxoODE,9,10-EpOME was 84.4%, 73.3%, and 80.9%, respectively. In the validation group, the area under the ROC was 87.0%, 88.8%, and 68.8% for 9-OxoODE,13-OxoODE,9,10-EpOME, respectively. According to the logistic regression model, the area under the ROC was 80.4% in the model group and 86.7% in the validation group. 13-OxoODE,9-OxoODE,9,10-EpOME could be used as biomarkers for early diagnosis. Significant abnormalities of LOX and CYP450 enzyme pathways were seen in CWP organisms. Changes in the CYP450 enzyme pathway may be associated with PAHs.

Cellulase Promotes Mycobacterial Biofilm Dispersal in Response to a Decrease in the Bacterial Metabolite Gamma-Aminobutyric Acid.

Biofilm dispersal contributes to bacterial spread and disease transmission. However, its exact mechanism, especially that in the pathogen Mycobacterium tuberculosis, is unclear. In this study, the cellulase activity of the M. tuberculosis Rv0062 protein was characterized, and its effect on mycobacterial biofilm dispersal was analyzed by observation of the structure and components of Rv0062-treated biofilm in vitro. Meanwhile, the metabolite factors that induced cellulase-related biofilm dispersal were also explored with metabolome analysis and further validations. The results showed that Rv0062 protein had a cellulase activity with a similar optimum pH (6.0) and lower optimum temperature (30 °C) compared to the cellulases from other bacteria. It promoted mycobacterial biofilm dispersal by hydrolyzing cellulose, the main component of extracellular polymeric substrates of mycobacterial biofilm. A metabolome analysis revealed that 107 metabolites were significantly altered at different stages of M. smegmatis biofilm development. Among them, a decrease in gamma-aminobutyric acid (GABA) promoted cellulase-related biofilm dispersal, and this effect was realized with the down-regulation of the bacterial signal molecule c-di-GMP. All these findings suggested that cellulase promotes mycobacterial biofilm dispersal and that this process is closely associated with biofilm metabolite alterations.

Formononetin ameliorates isoproterenol induced cardiac fibrosis through improving mitochondrial dysfunction.

Formononetin, an isoflavone compound, has been extensively researched due to its various biological activities, including a potent protective effect on the cardiovascular system. However, the impact of formononetin on cardiac fibrosis has not been investigated. In this study, C57BL/6 mice were used to establish cardiac fibrosis animal models by subcutaneous injecting of isoproterenol (ISO) and formononetin was orally administrated. The results showed that formononetin reversed ISO-induced heart stiffness revealed by early-to-atrial wave ratio (E/A ratio). Masson staining, western blot, immunohistochemistry and real-time PCR exhibited that the cardiac fibrosis and fibrosis-related proteins (collage III, fibronectin, TGF-ß1, α-SMA, and vimentin) and genes (Col1a1, Col3a1, Acta2 and Tgfb1) induced by ISO were significantly suppressed by formononetin. Furthermore, by combining metabolomics and network pharmacology, we found three important targets (ALDH2, HADH, and MAOB), which are associated with mitochondrial function, were involved in the beneficial effect of formononetin. Further validation revealed that these three genes were more abundance in cardiomyocyte than in cardiac fibroblast. The mRNA expression of ALDH2 and HADH were decreased, while MOAB was increased in cardiomyocyte upon ISO treatment and these phenomena were reversed by formononetin. In addition, we investigated mitochondrial membrane potential and ROS production in cardiomyocytes, the results showed that formononetin effectively improved mitochondrial dysfunction induced by ISO. In summary, we demonstrated that formononetin via regulating the expressions of ALDH2, HADH, and MAOB in cardiomyocyte to improve mitochondrial dysfunction and alleviate ß-adrenergic activation cardiac fibrosis.

Apigenin analogs as α-glucosidase inhibitors with antidiabetic activity.

This study investigated the inhibitory potential of a series of synthesized compounds (L1-L27) on α-glucosidase. Among them, compound L22 showed significant inhibitory effect. Through enzymatic kinetics studies, we demonstrated that L22 acts via a non-competitive inhibition mode with a Ki value of 2.61 µM, highlighting its high affinity for the enzyme. Molecular docking studies revealed the formation of hydrogen bonds between L22 and α-glucosidase and diverse interactions with neighboring amino acid residues. Furthermore, molecular dynamics simulations confirmed the stability of the L22-α-glucosidase complex. In a mouse model of type 2 diabetes, treatment with L22 significantly lowered fasting blood glucose levels, and reduced insulin resistance, suggesting its potential as a therapeutic agent for type 2 diabetes. Furthermore, L22 showed a protective effect against oxidative stress in the liver and alleviated liver and pancreatic abnormalities. These results provide valuable insights into the mechanism of action of L22 and its potential applications to treat type 2 diabetes, and improve liver health.

Mycobacterium tuberculosis Rv1987 protein attenuates inflammatory response and consequently alters microbiota in mouse lung.

Introduction: Healthy lung microbiota plays an important role in preventing Mycobacterium tuberculosis (Mtb) infections by activating immune cells and stimulating production of T-helper cell type 1 cytokines. The dynamic stability of lung microbiota relies mostly on lung homeostasis. In our previous studies, we found that Mtb virulence factor, Rv1987 protein, can mediate host immune response and enhance mycobacterial survival in host lung. However, the alteration of lung microbiota and the contribution of lung microbiota dysbiosis to mycobacterial evasion in this process are not clear so far. Methods: M. smegmatis which does not contain the ortholog of Rv1987 protein was selected as a model strain to study the effects of Rv1987 on host lung microbiota. The lung microbiota, immune state and metabolites of mice infected by M. smegmatis overexpressing Rv1987 protein (MS1987) were detected and analyzed. Results: The results showed that Rv1987 inhibited inflammatory response in mouse lung and anaerobic bacteria and Proteobacteria, Bacteroidota, Actinobacteriota and Acidobacteriota bacteria were enriched in the lung tissues correspondingly. The immune alterations and microbiota dysbiosis affected host metabolic profiles, and some of significantly altered bacteria in MS1987-infected mouse lung, such as Delftia acidovorans, Ralstonia pickettii and Escherichia coli, led to anti-inflammatory responses in mouse lung. The secretory metabolites of these altered bacteria also influenced mycobacterial growth and biofilm formation directly. Conclusion: All these results suggested that Rv1987 can attenuate inflammatory response and alter microbiota in the lung, which in turn facilitates mycobacterial survival in the host.

Rapid ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of three characteristic urinary saccharide metabolites in patients with glycogen storage diseases (type â b and â ¡).

Urinary 1,5-anhydroglucitol (1, 5-AG), 6-α-D-glucopyranosyl-maltotriose (Glc4) and maltotetraose (M4) are important biomarkers for glycogen storage disease (types Ib and Ⅱ). This study aimed to develop and validate an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to detect these three urinary saccharide metabolites. Urine samples were diluted and then analyzed. Chromatographic separation was performed on an Acquity™ UPLC Amide column (2.1 × 100 mm, 1.7 µm) with gradient elution. The quantitation of analytes was achieved on a 5500 Qtrap mass spectrometer using negative multiple reaction monitoring (MRM) mode. The calibration curves for all analytes were linear over the range of 0.500 to 100 µg/mL with a correlation coefficient, R2 ≥ 0.999. The percent relative standard deviations (RSD%) were ≤12.8%, and the percent relative errors (RE%) were in the range of -11.7%-11.0%. The relative matrix effects of all analytes were between 87.2% and 104% with RSD% < 3.10% across three concentrations. The developed analytical method was simple, accurate, and reliable for rapid and simultaneous analysis of these three urinary saccharide metabolites. It was applied to healthy volunteers and patients. To our knowledge, it was the first validated assay for urinary maltotetraose quantification. This work provides support for exploring the potential of maltotetraose as a biomarker for Pompe disease.

Comparative study of the plasma pharmacokinetics and tissue residues of trimethoprim in silky fowls and 817 broilers after single oral administration.

A comparative study was performed to investigate the differences in plasma pharmacokinetics (PKs) and tissue residues of trimethoprim (TMP) between silky fowls and 817 broilers. The 2 breeds of chickens received compound sulfadiazine suspension by gavage at 20 mg/kg (measured as TMP). Blood and tissue samples were collected at predetermined time points. The concentrations of TMP in plasma and tissue samples were determined by a validated high-performance liquid chromatography (HPLC) method. The plasma concentration-time data were subjected to noncompartment analysis by WinNonlin program (Pharsight Co., Mountain View, CA). The mean plasma concentrations of TMP in silky fowls were significantly lower than those in 817 broilers at all time-points. Significant differences were also observed between silky fowls and 817 broilers in maximum concentration (Cmax), area under the curve from time 0 to 24 h (AUC0 â†’ 24 h), apparent volume of distribution (Vd), and total body clearance (ClB). Silky fowls had significantly higher muscle TMP concentrations and longer tissue residual time than 817 broilers. The tissue concentration of TMP followed the order of leg muscle > breast muscle > liver, which was obviously different from that of 817 broilers. The half-lives of TMP in the leg muscle, breast muscle, and liver of silky fowls were 31.42, 10.78, and 0.38 d, respectively. The current withdrawal time (WDT) was not sufficient to prevent violative residues of TMP in the edible tissues of silky fowls, and a WDT much longer than 8 d might be required.

Development of a rapid simultaneous assay of two urinary tetrasaccharide metabolites using differential ion mobility and tandem mass spectrometry and its application to patients with glycogen storage disease (type Ib and II).

Glucose tetrasaccharide (Glc4) and maltotetraose (M4) are important biomarkers for Pompe disease and other glycogen storage diseases (GSDs). With the development of new treatments for GSDs, more specific and sensitive bioanalytical methods are needed to determine biomarkers. In recent years, differential mobility spectrometry (DMS) has become an effective analytical technique with high selectivity and specificity. This study aimed to develop an efficient analytical method for the two urinary tetrasaccharide metabolites using DMS and apply it to patients with GSDs (type Ib and II). Urine samples were directly diluted and injected into liquid chromatography-differential mobility spectrometry tandem mass spectrometry (LC-DMS-MS/MS). Chromatographic separation was performed on an Acquity™ UPLC BEH Amide column (2.1 × 50 mm, 1.7 µm) with a short gradient elution of 2.6 min. DMS-MS/MS was used to detect two urinary tetrasaccharide metabolites in a negative multiple reaction monitoring mode with isopropanol as a modifier. A total of 20 urine samples from 6 healthy volunteers and 10 patients with GSDs (type Ib and II) were collected for analysis. The method was linear over a concentration range of 0.5~100.0 µg/mL for each urinary tetrasaccharide (r≥0.99). The intra- and inter-day precision RSD% were less than 14.3%, and the accuracy RE% were in the range of -14.3~13.4%. The relative matrix effect was between 86.6 and 114.3%. No carryover or interference was observed. Patients with GSDs (type Ib and II) had significantly higher median urinary Glc4 (P=0.001) and M4 (P=0.012) excretion than healthy subjects. The developed method was simple, rapid, sensitive, and specific. It was successfully applied to healthy volunteers and patients with GSDs (type Ib and II). DMS technology greatly improved analysis efficiency and provided high sensitivity and specificity.

Mycobacterium tuberculosis Rv1324 Protein Contributes to Mycobacterial Persistence and Causes Pathological Lung Injury in Mice by Inducing Ferroptosis.

Mycobacterium tuberculosis (Mtb) is the pathogenic agent of tuberculosis (TB). Intracellular survival plays a central role in the pathogenesis of Mtb, a process that depends on an array of virulence factors for Mtb to colonize and proliferate within a host. Reactive nitrogen and oxygen species (RNS and ROS) are among the most effective antimycobacterial molecules generated by the host during infection. However, Mtb has evolved a number of proteins and enzymes to detoxify ROS and RNS. Secretory protein Rv1324, as a possible thioredoxin, might also have oxidoreductase activity against ROS and RNS during Mtb infection, and it is a potential virulence factor of Mtb. In this study, we investigated the biochemical properties of Mtb Rv1324 and its role in mycobacterial survival and virulence. The results showed that the Rv1324 protein had antioxidant activity and increased the survival of M. smegmatis that was exposed to ROS and RNS. In addition, Rv1324 enhanced the colonization ability of M. smegmatis in the lungs of mice. Further, mice infected with M. smegmatis harboring Rv1324 exhibited pathological injury and inflammation in the lung, which was mediated by ferroptosis. In summary, this study advances our understanding of the mechanisms of mycobacterial survival and pathogenesis, and it reveals a novel target for TB treatment. IMPORTANCE The intracellular survival of M. tuberculosis (Mtb) plays a crucial role in its pathogenesis, which depends on various Mtb oxidoreductases that are resistant to reactive oxygen and nitrogen species (ROS and RNS) that are generated by the host during Mtb infection. Secretory protein Rv1324 is a potential virulence factor of Mtb and is a possible thioredoxin that has oxidoreductase activity against ROS and RNS during Mtb infection. We investigated the biochemical properties of Mtb Rv1324 and its role in mycobacterial survival and virulence. It was confirmed that the Rv1324 protein had antioxidant activity and an increased mycobacterial resistance to ROS and RNS. In addition, Rv1324 enhanced mycobacterial persistence and induced pathological injury and inflammation in the lungs of mice by activating ferroptosis. This study advances our understanding of the mechanisms of mycobacterial survival and pathogenesis, and it reveals a novel target for TB treatment.

Optimization and evaluation of viral metagenomic amplification and sequencing procedures toward a genome-level resolution of the human fecal DNA virome.

INTRODUCTION: Viruses in the human gut have been linked to health and disease. Deciphering the gut virome is dependent on metagenomic sequencing of the virus-like particles (VLPs) purified from the fecal specimens. A major limitation of conventional viral metagenomic sequencing is the low recoverability of viral genomes from the metagenomic dataset. OBJECTIVES: To develop an optimal method for viral amplification and metagenomic sequencing for maximizing the recovery of viral genomes. METHODS: We performed parallel virus enrichment and DNA extraction to generate âˆ¼ 30 viral DNA samples from each of 5 fresh fecal specimens and conducted the experiments including 1) optimizing the cycle number for high-fidelity enzyme-based PCR amplification, 2) evaluating the reproducibility of the optimally whole viral metagenomic experimental process, 3) evaluating the reliability of multiple displacement amplification (MDA), 4) testing the capability of long-read sequencing for improving viral metagenomic assembly, and 5) comparing the differences between viral metagenomic and bulk metagenomic approaches. RESULTS: Our results revealed that the optimal cycle number for PCR amplification is 15. We verified the reliability of MDA and the effectiveness of long-read sequencing. Based on our optimized results, we generated 151 high-quality viruses using the dataset combined from short-read and long-read sequencing. Genomic analysis of these viruses found that most (60.3%) of them were previously unknown and showed a remarkable diversity of viral functions, especially the existence of 206 viral auxiliary metabolic genes. Finally, we uncovered significant differences in the efficiency and coverage of viral identification between viral metagenomic and bulk metagenomic approaches. CONCLUSIONS: Our study demonstrates the potential of optimized experiment and sequencing strategies in uncovering viral genomes from fecal specimens, which will facilitate future research about the genome-level characterization of complex viral communities.

Meta-analysis of fecal viromes demonstrates high diagnostic potential of the gut viral signatures for colorectal cancer and adenoma risk assessment.

INTRODUCTION: Viruses have been reported as inducers of tumorigenesis. Little studies have explored the impact of the gut virome on the progression of colorectal cancer. However, there is still a problem with the repeatability of viral signatures across multiple cohorts. OBJECTIVES: The present study aimed to reveal the repeatable gut vial signatures of colorectal cancer and adenoma patients and decipher the potential of viral markers in disease risk assessment for diagnosis. METHODS: 1,282 available fecal metagenomes from 9 published studies for colorectal cancer and adenoma were collected. A gut viral catalog was constructed via a reference-independent approach. Viral signatures were identified by cross-cohort meta-analysis and used to build predictive models based on machine learning algorithms. New fecal samples were collected to validate the generalization of predictive models. RESULTS: The gut viral composition of colorectal cancer patients was drastically altered compared with healthy, as evidenced by changes in some Siphoviridae and Myoviridae viruses and enrichment of Microviridae, whereas the virome variation in adenoma patients was relatively low. Cross-cohort meta-analysis identified 405 differential viruses for colorectal cancer, including several phages of Porphyromonas, Fusobacterium, and Hungatella that were enriched in patients and some control-enriched Ruminococcaceae phages. In 9 discovery cohorts, the optimal risk assessment model obtained an average cross-cohort area under the curve of 0.830 for discriminating colorectal cancer patients from controls. This model also showed consistently high accuracy in 2 independent validation cohorts (optimal area under the curve, 0.906). Gut virome analysis of adenoma patients identified 88 differential viruses and achieved an optimal area under the curve of 0.772 for discriminating patients from controls. CONCLUSION: Our findings demonstrate the gut virome characteristics in colorectal cancer and adenoma and highlight gut virus-bacterial synergy in the progression of colorectal cancer. The gut viral signatures may be new targets for colorectal cancer treatment. In addition, high repeatability and predictive power of the prediction models suggest the potential of gut viral biomarkers in non-invasive diagnostic tests of colorectal cancer and adenoma.

A review of gas-phase chemical mechanisms commonly used in atmospheric chemistry modelling.

The atmospheric chemical mechanism is an essential component of airshed models used for investigating the chemical behaviors and impacts of species. Since the first tropospheric chemical mechanism was proposed in the 1960s, various mechanisms including Master Chemical Mechanism (MCM), Carbon Bond Mechanism (CBM), Statewide Air Pollution Research Center (SAPRC) and Regional Atmospheric Chemistry Mechanism (RACM) have been developed for different research purposes. This work summarizes the development and applications of these mechanisms, introduces their compositions and lumping methods, and compares the ways the mechanisms treat radicals with box model simulations. CBM can reproduce urban pollution events with relatively low cost compared to SAPRC and RACM, whereas the chemical behaviors of radicals and the photochemical production of ozone are described in detail in RACM. The photolysis rates of some oxygenated compounds are low in SAPRC07, which may result in underestimation of radical levels. As an explicit chemical mechanism, MCM describes the chemical processes of primary pollutants and their oxidation products in detail. MCM can be used to investigate certain chemical processes; however, due to its large size, it is rarely used in regional model simulations. A box model case study showed that the chemical behavior of OH and HO2 radicals and the production of ozone were well described by all mechanisms. CBM and SAPRC underestimated the radical levels for different chemical treatments, leading to low ozone production values in both cases. MCM and RACM are widely used in box model studies, while CBM and SAPRC are often selected in regional simulations.

Dysbiotic Oral and Gut Viromes in Untreated and Treated Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is influenced by oral and gut bacteria; however, much less is known about the relationship between oral or gut viromes and RA. Here, we performed whole-oral- and whole-gut-virome analyses based on shotgun sequencing of 497 samples. A comparative analysis of the oral and gut viromes in healthy controls and untreated and treated RA patients was performed, and system interaction networks among viruses, bacteria, and RA-associated clinical indices were constructed to address the potential relationship between the virome and RA by principal-coordinate analysis, distance-based redundancy analysis, permutational multivariate analysis, Spearman correlation coefficient analysis, and random-forest model analysis. The results showed that the viromes could be profiled in dental plaque, saliva, and fecal samples, among which saliva had the highest within-sample diversity. Importantly, significantly different diversities and compositions of the oral (i.e., dental plaque and saliva) viromes were observed not only between RA patients and healthy controls but also between untreated and treated RA patients, yet there were relatively minor differences in the gut viromes. Furthermore, to understand how these viruses affected the bacteriome, a virus-bacterium interaction network was constructed from dental plaque, saliva, and fecal samples of RA patients. Additionally, some RA-associated oral taxa, including Lactococcus phage (vOTU70), Bacteroides vulgatus, Lactococcus lactis, Escherichia coli, and Neisseria elongata, were correlated with the RA-related clinical indices. Whole-virome analysis illustrated the potential role of the oral and gut viromes in affecting our body either directly or via bacteria, which characterized neglected and new candidates contributing to the development of RA. IMPORTANCE Our results demonstrated community variation among dental plaque, saliva, and fecal viromes. In oral and gut samples from untreated and treated RA patients, the perturbance of viral composition and the correlation network of microbes and RA-associated clinical indices might be involved in the pathogenicity of RA. The findings in this study expand the knowledge of the potential role of oral and gut viral communities in the development of RA and may contribute to research on correlations between viruses and other diseases.

GlmU inhibitor from the roots of Euphorbia ebracteolata as an anti-tuberculosis agent.

At present, the emerging drug-resistance of Mycobacterium tuberculosis (M. tb) against existing frontline drugs has prompted the development of novel anti-tuberculosis agents based on new targets. Activity of the bifunctional enzyme, glucosamine-1-phosphate acetyltransferase activity and N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) is essential for biosynthesis of the mycobacterium cell wall components and has been proposed as a potential drug target for therapeutic interventions. On the basis of the high-throughput screening of the GlmU AT inhibitor, an extract of Euphorbia ehracteolata displayed a significant inhibitory effect among 49 tested herbal medicines. Using the bioassay-guided separation, an aromatic diterpenoid ebractenoid F was identified as a GlmU AT inhibitor (IC50: 4.608 µg mL-1). Inhibition kinetics showed that ebractenoid F acted as a competitive inhibitor for substrate acetyl-CoA and an uncompetitive inhibitor for substrate GlcN-1-P. Ala434 was deduced to be the key active residue for the interaction between ebractenoid F and GlmU. Furthermore, ebractenoid F displayed an anti-mycobacterial effect against M. tb H37Ra with a minimal inhibitory concentration (MIC) of 12.5 µg mL-1 along with an inhibitory effect on the formation of biofilm and a synergistic effect with isoniazid against M. tb H37Ra. Above all, a GlmU inhibitor was identified from E. ehracteolata and is proposed to be a potential therapeutic anti-tumberculosis agent.

The effective components of herbal medicines used for prevention and control of fish diseases.

The increasing demand for fish consumption has promoted the rapid development of fish aquaculture. With the continuous expansion of culture scale and the deterioration of culture environment, various diseases have broken out frequently, leading to huge economic losses to fish farming. Antibiotics and chemicals are common options to prevent and control of fish diseases, but their use is now restricted or even banned due to serious problems such as drug residues, pathogen resistance, and environmental pollution. Herbs and their extracts have increasingly become promising supplements and alternatives, because of their effectiveness, safety, environmental friendliness and less drug resistance. The application of herbal medicines in prevention and control of fish diseases is mainly attributed to the powerful immune enhancement, antioxidation or direct anti-pathogenic efficacies of their effective components, including mainly polyphenols, polysaccharides, saponins, flavonoids, alkaloids, and essential oils. Recently these herbal active ingredients have been extensively studied for their efficacies in prevention and control of viral, bacterial, parasitic, and fungal diseases in fish. In the present paper, we comprehensively summarize the research progress of the active ingredients of herbal medicines used for prevention and control of fish diseases, especially of their action mechanisms, and highlight the potential application of the herbal medicines in fish aquaculture.

Protein O-mannosyltransferase Rv1002c contributes to low cell permeability, biofilm formation in vitro, and mycobacterial survival in mice.

Mycobacterium tuberculosis (M. tuberculosis) Rv1002c encodes the protein O-mannosyltransferase (PMT), which catalyzes the transfer of mannose to serine or threonine residues of proteins. We explored the function of PMT in vitro and in vivo. Rv1002c protein was heterogeneously overexpressed in nonpathogenic Mycobacterium smegmatis (named as MS_Rv1002c). A series of trials including mass spectrometry, transmission electron microscope, biofilm formation and antibiotics susceptibility were performed to explore the function of PMT on bacterial survival in vitro. Mouse experiments were carried out to evaluate the virulence of PMT in vivo. PMT decreased the cell envelope permeability and promoted microbial biofilm formation. PMT enhanced the mycobacterial survival in vivo and inhibited the release of pro-inflammatory cytokines in serum. The function might be associated with an increased abundance of some mannoproteins in culture filtrate (CF). PMT is likely to be involved in mycobacterial survival both in vivo and in vitro due to increasing the mannoproteins abundance in CF.