Abstract
Motivation
Most genetic variants implicated in complex diseases by genome-wide association studies (GWAS) are non-coding, making it challenging to understand the causative genes involved in ...disease. Integrating external information such as quantitative trait locus (QTL) mapping of molecular traits (e.g. expression, methylation) is a powerful approach to identify the subset of GWAS signals explained by regulatory effects. In particular, expression QTLs (eQTLs) help pinpoint the responsible gene among the GWAS regions that harbor many genes, while methylation QTLs (mQTLs) help identify the epigenetic mechanisms that impact gene expression which in turn affect disease risk. In this work, we propose multiple-trait-coloc (moloc), a Bayesian statistical framework that integrates GWAS summary data with multiple molecular QTL data to identify regulatory effects at GWAS risk loci.
Results
We applied moloc to schizophrenia (SCZ) and eQTL/mQTL data derived from human brain tissue and identified 52 candidate genes that influence SCZ through methylation. Our method can be applied to any GWAS and relevant functional data to help prioritize disease associated genes.
Availability and implementation: moloc is available for download as an R package (https://github.com/clagiamba/moloc). We also developed a web site to visualize the biological findings (icahn.mssm.edu/moloc). The browser allows searches by gene, methylation probe and scenario of interest.
Supplementary information
Supplementary data are available at Bioinformatics online.
Abstract
There is abundant evidence suggesting that the right ventrolateral prefrontal cortex (rVLPFC) plays an important role in down-regulating the emotional response to social exclusion. However, ...a causal relationship between rVLPFC function and explicit emotional regulation is not clear in the context of social exclusion. This study employed anodal transcranial direct current stimulation (tDCS) to activate rVLPFC while participants used emotional regulation to reappraise pictures of social exclusion. Forty-four participants were randomly assigned to an active tDCS group or a sham group. Both groups viewed social exclusion images under two conditions: in the no-reappraisal condition, participants were instructed to passively view social exclusion images; in the reappraisal condition, they reappraised the images to down-regulate negative emotional responses. Compared to sham stimulation, anodal tDCS over the rVLPFC resulted in less negative emotion ratings, and produced significantly smaller pupil diameter in the reappraisal, compared to no-reappraisal block. The tDCS also led to longer fixation durations to rejectees and shorter fixation durations to rejecters. Taken together, these findings suggest a causal role for rVLPFC in down-regulation of negative emotions produced by social exclusion. This study has implications for clinical interventions targeting emotional regulation deficits.
Benefits and risks of antimicrobial drugs, used in food-producing animals, continue to be complex and controversial issues. This review comprehensively presents the benefits of antimicrobials drugs ...regarding control of animal diseases, protection of public health, enhancement of animal production, improvement of environment, and effects of the drugs on biogas production and public health associated with antimicrobial resistance. The positive and negative impacts, due to ban issue of antimicrobial agents used in food-producing animals, are also included in the discussion. As a double-edged sword, use of these drugs in food-animals persists as a great challenge.
Quinolones are widely used broad-spectrum antibacterials with incomplete elucidated mechanism of action. Here, molecular basis for the antibacterial action of quinolones, from target to network, is ...fully discussed and updated. Quinolones trap DNA gyrase or topoisomerase IV to form reversible drug-enzyme-DNA cleavage complexes, resulting in bacteriostasis. Cell death arises from chromosome fragmentation in protein synthesis-dependent or -independent pathways according to distinguished quinolone structures. In the former pathway, irreversible oxidative DNA damage caused by reactive oxygen species kills bacteria eventually. Toxin–antitoxin mazEF is triggered as an additional lethal action. Bacteria survive and develop resistance by SOS and other stress responses. Enlarged knowledges of quinolone actions and bacterial response will provide new targets for drug design and approaches to prevent bacterial resistance.
Display omitted Quinolone action network: the primary target, cell death pathway and bacterial response.
► The history of discovering the primary targets of quinolones is described in details. ► The latest crystal structures of quinolone-type IIA topoisomerase–DNA complexes are updated. ► The network and pathway of quinolone action are proposed. ► The bacterial responses to quinolone stress are reviewed.
The inflammatory response has a complex pathogenesis; thus, it is a critical contributor to the development and complication of many diseases. Zhishi and Zhiqiao are famous Citrus herbal medicines ...that are rich in bioactive phenolic constituents with multiple anti-inflammatory activities.
Establishment of a multi-component-target-pathway network strategy to investigate the usage of Zhishi and Zhiqiao on inflammatory diseases can provide a reference for mechanisms of traditional Chinese medicine (TCM).
A multi-component-target-pathway network strategy was constructed to elucidate the various antiinflammatory effects of Zhishi and Zhiqiao by integrating multi-constituent determination, network pharmacology, molecular mechanisms in cells and integrated metabolomics in animals.
Based on the quantitatively determined global and characteristic chemical profiles of Zhishi and Zhiqiao, the component-target-pathway network was predicted by network pharmacology coupled with text mining and docking. The potential antiinflammatory mechanism of the various components in Zhishi and Zhiqiao were verified using LPS-induced inflammatory responses in RAW 264.7 cells. The different metabolic regulating effects of Zhishi and Zhiqiao against an LPS-induced inflammation model were investigated using a plasma metabolomics strategy.
The molecular mechanism of Zhishi mainly suppressed the MAPK signaling pathway, whereas Zhiqiao emphasized the PPAR-AKT signaling pathways simultaneously to block the inflammatory process. Meanwhile, Zhishi and Zhiqiao both exhibited an anti-inflammatory effect by inhibiting the NF-κB signaling pathway to reduce the production of inflammatory mediators. In the metabolomics study, Zhishi and Zhiqiao exhibited variant corrections of the disordered metabolic pathways through amino acid metabolism, glycometabolism and lipid metabolism.
All of these results indicate that Zhishi and Zhiqiao, in a diversified mixture, exert their anti-inflammatory effect through variant pathways. These findings can assist in developing the use of Zhishi and Zhiqiao for inflammatory diseases.
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Antibiotics-induced changes in intestinal flora (dysbiosis) may have various effects on the host. Dysbiosis is associated with numerous metabolites including bile acids, which are produced in the ...liver from cholesterol and metabolized in the gut by intestinal microbiota. Total phenolic extracts of
L. (TPE-CA) are rich in dietary flavanones and their glycosyl derivatives, including flavones, flavonols, polymethoxyflavones and coumarins, which exert positive health effects on the microbiota. The aim of this study is to elucidate the interplays between the intestinal microbiota and bile acids metabolism attributed to antibiotics. Mice were exposed to broad-spectrum antibiotics, such as ampicillin, streptomycin and clindamycin, for 14 days. This exposure resulted in reduced bacterial diversity and richness, and destroyed intestinal permeability. The homeostasis of bile acids was also affected. Subsequent TPE-CA administration, counteracted most of the dysbiosis, and reshaped intestinal permeability, these effects occurred
upregulation of zonula occludens 1 and occludin associated proteins and downregulation of serum endotoxin compared to the antibiotics group. TPE-CA maintained the homeostasis of bile acids
modulation of the liver-gut axis related farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15) pathway and FXR-targeted protein. Our findings indicated that TPE-CA exerted a protective effect on the restoration of intestinal microbiota composition, reshaped barrier integrity and maintained bile acid homeostasis
the liver-gut axis with antibiotics-induced dysbiosis.
Pyrrolizidine alkaloids (PA) induced hepatic sinusoidal obstruction syndrome (HSOS) occurred worldwide and the mortality rate remained high because there were no specific therapies. Defibrotide was ...effective for HSOS following hematopoietic stem cell transplantation. But the pathogenesis of the two types of HSOS were not equivalent. The purpose of this study was to see if defibrotide was also effective in PA induced rat HSOS.
First we improved rat HSOS model by using higher dose (230 mg/kg) of monocrotaline (a kind of PA) as the dose of median lethal dose. So drug effectiveness could be assessed by survival time. Next, male SD rats were divided into 5 groups. They were control group, model group, low dose low molecular weight heparin (LMWH) treatment group, high dose LMWH treatment group and defibrotide treatment group. Rats' survival time, liver function, white blood cell count and cytokines were compared among the groups. The DeLeve score was used to assess the severity of liver pathology.
The model group exhibited typical liver pathology of HSOS, such as hepatic sinus dilation, congestion, endothelial injury of central lobular vein, coagulative necrosis of hepatocytes and fibrin deposition in the subendothelial. The pathologic characteristics indicated that the model was built up successfully. The survival rate was significantly higher in defibrotide group (81.8%) than model group (43.7%), while the survival rates were similar in the two LMWH groups (62.5% and 75%) and model group. The survival time only be prolonged by defibrotide (P=0.028) but not LMWH (P>0.05). DeLeve score was improved most in the defibrotide group than the two LMWH groups (both P<0.01). Changes in DeLeve score, liver function, plasma level of tumor necrosis factor α and plasminogen activator inhibitor-1 exhibited the same trends.
Defibrotide could improve the outcome of monocrotaline-induced rat HSOS indicating that defibrotide might be a better choice than LMWH in clinical practice.
► Using auto solid-phase extraction by carboxylic acid cartridges. ► Using hydrophilic interaction chromatography column to separate. ► A rapid method for quantitative determination of 15 ...aminoglycosides. ► The method reduced the analysis time and improved the extraction efficiency.
An automated method has been developed for the simultaneous quantification of 15 aminoglycosides in muscle, liver (pigs, chicken and cattle), kidney (pigs and cattle), cow milk, and hen eggs by liquid chromatography tandem mass spectrometry. Homogenized samples were extracted by monopotassium phosphate buffer (including ethylene diamine tetraacetic acid), and cleaned up with auto solid-phase extraction by carboxylic acid cartridges. The analytes were separated by a specialized column for aminoglycosides, and eluted with trifluoroacetic acid and acetonitrile. The decision limits (CCα) of apramycin, gentamycin, tobramycin, paromomycin, hygromycin, neomycin, kanamycin, sisomicin, netilmicin, ribostamycin, kasugamycin, amikacin, streptomycin, dihydrostreptomycin and spectinomycin were ranged from 8.1 to 11.8μg/kg and detection capabilities (CCβ) from 16.4 to 21.8μg/kg. High correlation coefficients (r2>0.99) of calibration curves for the analytes were obtained within linear from 20 to 1000μg/kg. Reasonable recoveries (71–108%) were demonstrated with excellent relative standard deviation (RSD). This method is simple pretreatment, rapid determination and high sensitivity, which can be used in the determination of multi-aminoglycosides in complex samples.
Veterinary antibiotics are widely used in animal agriculture. Owing to its good absorption in the gastrointestinal tract, strong tissue permeability, and long biological half-life, doxycycline (DOX) ...is widely used to treat bacterial infections; however, this use can pose an environmental risk. The adsorption/desorption and degradation of DOX in three agricultural soils were investigated. DOX rapidly adsorbed to the soils, with an adsorption equilibrium time of 12 h for the three soils. The Freundlich equation was used to fit the adsorption and desorption of DOX in soils. A high Freundlich affinity coefficient (KF) was obtained from Freundlich isotherms, indicating strong sorption of DOX to agricultural soils and weak mobility to aquatic environment. Soil organic matter, the clay ratio and the cation exchange capacity were significantly positively correlated with KF (P < 0.05). The half-life (DT50) of DOX degradation in the soils ranged from 2.51 to 25.52 d. Soil microorganisms, soil moisture, temperature, the initial concentration, illumination and soil texture all significantly affected the degradation of DOX in soil (P < 0.05). When 8% (w/w) manure was added, DOX degradation was significantly accelerated (P < 0.05). Biotic and abiotic factors affected the degradation of DOX in soils. These results indicated that soil properties and environmental conditions greatly affected the fate and transport of DOX into agricultural soils.
•The adsorption and degradation of DOX in soil were studied in agricultural soils.•Adsorption of DOX was stronger in soil with a high organic matter and clay ratio.•The migration risk of DOX from soil to aquatic environment was low.•Biotic and abiotic factors affected the degradation of DOX in agricultural soils.
Cephalosporins are one of the most widely used antibiotics. When cephalosporins are discharged into the environment, they not only induce the production of antibiotic resistant genes (ARGs) and ...antibiotic resistant bacteria (ARBs) but also cause toxic effects on animals and plants. Due to their complicated environmental behavior and lack of relevant data, the environmental behavior remains unclear. In this study, the adsorption-desorption and degradation characteristics of the third-generation cephalosporin drug ceftiofur (CEF) were investigated in three agricultural soils (sandy loam, loam and clay). According to the relevant parameters of the Freundlich adsorption isotherm (the Kf range was 57.63–122.44 μg1–1/n L1/n kg−1), CEF was adsorbed moderately in the soils and had the potential to migrate into groundwater. CEF exhibited low persistence in the soils and faster degradation than other antibiotics, such as tetracyclines and fluoroquinolones. The degradation half-lives (DT50) of CEF in soils ranged from 0.76 days to 4.31 days. Adding feces, increasing the water content, providing light and increasing the temperature significantly accelerated the degradation of CEF in soils. The DT50 values of CEF in soils were significantly prolonged when the soils were sterilized, indicating that both physical degradation and biodegradation played important roles in the degradation of CEF in soils. The DT50 values of CEF in soils were significantly prolonged at high concentrations, indicating that the degradability of CEF in soils was affected by the initial concentration. No significant differences were observed in the DT50 values for the different soil types (p > 0.05). This study provides useful information about the environmental behavior of CEF and improves the environmental risk assessment of CEF.
●This is the first report of the adsorption-desorption characteristics of CEF in soil.●CEF has the risk of polluting groundwater in low clay and organic carbon content soils.●The degradation of CEF in soil is fast, both biodegradation and physical degradation play an important role.●The ecotoxicity of low concentration CEF in environment is worth further study.
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