Metagenomic insights into the abundance and composition of resistance genes in aquatic environments:Influence of stratification and geography

A global survey was performed with 122 aquatic metagenomic DNA datasets (92 lake water and 30 seawater) obtained from the Sequence Read Archive (SRA). Antibiotic resistance genes (ARGs) and metal resistance genes (MRGs) were derived from the dataset sequences via bioinformatic analysis. The relative abundances of ARGs and MRGs in lake samples were in the ranges ND (not detected)-1.34x10(0) and 1.22x10(-3) -1.98x10(-1) copies per 16S rRNA, which were higher than those in seawater samples. Among ARGs, multidrug resistance genes and bacitracin resistance genes had high relative abundances in both lake and sea water samples. Multimetal resistance genes, mercury resistance genes and copper resistance genes had the greatest relative abundance for MRGs. No significant difference was found between epilimnion and hypolimnion in abundance or the Shannon diversity index for ARGs and MRGs. Principal coordinates analysis and permutational multivariate analysis of variance (PERMANOVA) test showed that stratification and geography had significant influence on the composition of ARGs and MRGs in lakes (p < 0.05, PERMANOVA). Coastal seawater samples had significantly greater relative abundance and a higher Shannon index for both ARGs and MRGs than deep ocean and Antarctic seawater samples (p < 0.05, Kruskal-Wallis one-way ANOVA), suggesting that human activity may exert more selective pressure on ARGs and MRGs in coastal areas than those in deep ocean and Antarctic seawater

Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors

Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2,4-disubstituted quinazolines (series 4-7) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b, was discovered with a good balance between high potency (IC50 0.68μM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI50 8.54μM), as well as other human tumor cell lines (GI50<20μM), and a desirable druglike property profile with low logP value (2.54) and high aqueous solubility (95.6μg/mL). Molecular modeling elucidated an expected binding mode of 4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound

Effectiveness Study of Moxibustion on Pain Relief in Primary Dysmenorrhea: Study Protocol of a Randomized Controlled Trial

Dysmenorrhea is a prevalent problem in menstruating women. As a nonpharmacologic and free of relevant side effects intervention, moxibustion is considered as a safe treatment and has long been recommended for dysmenorrhea in China. However, the exact effects of moxibustion in PD have not been fully understood. Therefore we designed this random clinical trial aiming to (1) investigate whether moxibustion is safe and effective for pain relief in primary dysmenorrhea when compared to conventional pain-killers and (2) assess the acceptability and side effects associated with moxibustion. The results of this trial will contribute to a better understanding of the different effects of moxibustion in pain relief in primary dysmenorrhea when compared to conventional pharmacologic pain treatment

Using multi-tissue transcriptome-wide association study to identify candidate susceptibility genes for respiratory infectious diseases

Objective: We explore the candidate susceptibility genes for influenza A virus (IAV), measles, rubella, and mumps and their underlying biological mechanisms.Methods: We downloaded the genome-wide association study summary data of four virus-specific immunoglobulin G (IgG) level data sets (anti-IAV IgG, anti-measles IgG, anti-rubella IgG, and anti-mumps virus IgG levels) and integrated them with reference models of three potential tissues from the Genotype-Tissue Expression (GTEx) project, namely, whole blood, lung, and transformed fibroblast cells, to identify genes whose expression is predicted to be associated with IAV, measles, mumps, and rubella.Results: We identified 19 significant genes (ULK4, AC010132.11, SURF1, NIPAL2, TRAP1, TAF1C, AC000078.5, RP4-639F20.1, RMDN2, ATP1B3, SRSF12, RP11-477D19.2, TFB1M, XXyac-YX65C7_A.2, TAF1C, PCGF2, and BNIP1) associated with IAV at a Bonferroni-corrected threshold of p &lt; 0.05; 14 significant genes (SOAT1, COLGALT2, AC021860.1, HCG11, METTL21B, MRPL10, GSTM4, PAQR6, RP11-617D20.1, SNX8, METTL21B, ANKRD27, CBWD2, and TSFM) associated with measles at a Bonferroni-corrected threshold of p &lt; 0.05; 15 significant genes (MTOR, LAMC1, TRIM38, U91328.21, POLR2J, SCRN2, Smpd4, UBN1, CNTROB, SCRN2, HOXB-AS1, SLC14A1, AC007566.10, AC093668.2, and CPD) associated with mumps at a Bonferroni-corrected threshold of p &lt; 0.05; and 13 significant genes (JAGN1, RRP12, RP11-452K12.7, CASP7, AP3S2, IL17RC, FAM86HP, AMACR, RRP12, PPP2R1B, C11orf1, DLAT, and TMEM117) associated with rubella at a Bonferroni-corrected threshold of p &lt; 0.05.Conclusions: We have identified several candidate genes for IAV, measles, mumps, and rubella in multiple tissues. Our research may further our understanding of the pathogenesis of infectious respiratory diseases

Uninterrupted CAG repeat drives striatum-selective transcriptionopathy and nuclear pathogenesis in human Huntingtin BAC mice

In Huntington's disease (HD), the uninterrupted CAG repeat length, but not the polyglutamine length, predicts disease onset. However, the underlying pathobiology remains unclear. Here, we developed bacterial artificial chromosome (BAC) transgenic mice expressing human mutant huntingtin (mHTT) with uninterrupted, and somatically unstable, CAG repeats that exhibit progressive disease-related phenotypes. Unlike prior mHTT transgenic models with stable, CAA-interrupted, polyglutamine-encoding repeats, BAC-CAG mice show robust striatum-selective nuclear inclusions and transcriptional dysregulation resembling those in murine huntingtin knockin models and HD patients. Importantly, the striatal transcriptionopathy in HD models is significantly correlated with their uninterrupted CAG repeat length but not polyglutamine length. Finally, among the pathogenic entities originating from mHTT genomic transgenes and only present or enriched in the uninterrupted CAG repeat model, somatic CAG repeat instability and nuclear mHTT aggregation are best correlated with early-onset striatum-selective molecular pathogenesis and locomotor and sleep deficits, while repeat RNA-associated pathologies and repeat-associated non-AUG (RAN) translation may play less selective or late pathogenic roles, respectively

Arsenic and Cadmium Accumulation in Soil as Affected by Continuous Organic Fertilizer Application: Implications for Clean Production

As and Cd in soil can be assimilated and accumulated by vegetables and can be subsequently ingested by humans. Contradictory effects of organic fertilizer application on As and Cd accumulation in soil have been reported in previous studies. An eight-year greenhouse study was conducted on a sandy loam soil in Beijing, China to investigate the effects of organic fertilizer application rate on soil properties, and As and Cd accumulation in soil. The contamination risk of pak choi grown after eight years’ application of organic fertilizer was also evaluated. Soil organic carbon increased 3.0–3.8 times with low, medium and high rates of fertilizer application in 2018 compared to the initial soil. Organic fertilizer application significantly increased soil nutrients and microbial biomass while it mildly affected soil pH. The bioavailability of As/Cd has decreased after eight years’ application of organic fertilizer. Pak choi crop harvested from all three treatments in 2018 did not pose a threat to human health, even for life-time consumption. Soil total As content significantly decreased with organic fertilizer application, mainly due to the lower As content in the applied fertilizer than that in soil. Continuous application of clean organic fertilizer can be adopted to reduce the contamination risk of highly contaminated soil in the soil–plant system

Antibiotics and antibiotic resistance genes in global lakes:A review and meta-analysis

Lakes are an important source of freshwater, containing nearly 90% of the liquid surface fresh water worldwide. Long retention times in lakes mean pollutants from discharges slowly circulate around the lakes and may lead to high ecological risk for ecosystem and human health. In recent decades, antibiotics and antibiotic resistance genes (ARGs) have been regarded as emerging pollutants. The occurrence and distribution of antibiotics and ARGs in global freshwater lakes are summarized to show the pollution level of antibiotics and ARGs and to identify some of the potential risks to ecosystem and human health. Fifty-seven antibiotics were reported at least once in the studied lakes. Our meta-analysis shows that sulfamethoxazole, sulfamerazine, sulfameter, tetracycline, oxytetracycline, erythromycin, and roxithromycin were found at high concentrations in both lake water and lake sediment. There is no significant difference in the concentration of sulfonamides in lake water from China and that from other countries worldwide; however, there was a significant difference in quinolones. Erythromycin had the lowest predicted hazardous concentration for 5% of the species (HC5) and the highest ecological risk in lakes. There was no significant difference in the concentration of sulfonamide resistance genes (sul1 and sul2) in lake water and river water. There is surprisingly limited research on the role of aquatic biota in propagation of ARGs in freshwater lakes. As an environment that is susceptible to cumulative build-up of pollutants, lakes provide an important environment to study the fate of antibiotics and transport of ARGs with a broad range of niches including bacterial community, aquatic plants and animals

Optimization of 4-( N -Cycloamino)phenylquinazolines as a Novel Class of Tubulin-Polymerization Inhibitors Targeting the Colchicine Site

The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a–c and 5a–m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI50 1.9–3.2 nM), significant potency against tubulin assembly (IC50 0.77 μM), and substantial inhibition of colchicine binding (99% at 5 μM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose