Modulating Activity Evaluation of Gut Microbiota with Versatile Toluquinol.

Gut microbiota have important implications for health by affecting the metabolism of diet and drugs. However, the specific microbial mediators and their mechanisms in modulating specific key intermediate metabolites from fungal origins still remain largely unclear. Toluquinol, as a key versatile precursor metabolite, is commonly distributed in many fungi, including Penicillium species and their strains for food production. The common 17 gut microbes were cultivated and fed with and without toluquinol. Metabolic analysis revealed that four strains, including the predominant Enterococcus species, could metabolize toluquinol and produce different metabolites. Chemical investigation on large-scale cultures led to isolation of four targeted metabolites and their structures were characterized with NMR, MS, and X-ray diffraction analysis, as four toluquinol derivatives (1-4) through O1/O4-acetyl and C5/C6-methylsulfonyl substitutions, respectively. The four metabolites were first synthesized in living organisms. Further experiments suggested that the rare methylsulfonyl groups in 3-4 were donated from solvent DMSO through Fenton's reaction. Metabolite 1 displayed the strongest inhibitory effect on cancer cells A549, A2780, and G401 with IC50 values at 0.224, 0.204, and 0.597 µM, respectively, while metabolite 3 displayed no effect. Our results suggest that the dominant Enterococcus species could modulate potential precursors of fungal origin and change their biological activity.

[Degradation of SMX with Peracetic Acid Activated by Nano Core-shell Co@NC Catalyst].

Peracetic acid (PAA), as a new oxidant, has attracted increasing attention in the treatment of refractory organic pollution in sewage. In this study, the nano core-shell Co@NC catalyst was prepared via etching and used to activate PAA to degrade sulfamethoxazole (SMX) in sewage. The results indicated that the degradation rate of SMX reached 98%, and its reaction rate constant was 0.80 min-1 under optimal conditions (catalyst dosage=0.02 g·L-1, PAA concentration=0.12 mmol·L-1, pH=7, SMX concentration=10 µmol·L-1). With the increase in PAA concentration and core-shell Co@NC dosage, the degradation efficiency of SMX increased. The study found that the core-shell Co@NC/PAA system had the best degradation effect on SMX under near-neutral conditions (pH 6.0-8.0), and both acidic and alkaline environments were not conducive to SMX degradation. HCO3- and humic acid showed significant inhibition on the degradation of SMX, whereas Cl- showed weak inhibition. In addition, through a free radical quenching experiment and electron paramagnetic resonance (EPR) detection, acetoxy radical (CH3CO2CO3·) were the main active species for the degradation of organic pollutants in the system. Transformation products (TPs) of SMX were analyzed by U-HPLC-Q-Exactive Orbitrap HRMS, and a possible degradation path of SMX was proposed. At the same time, the catalyst recycling experiment showed that the nano core-shell Co@NC catalyst had good stability and reusability.

Arthrocolins Synergizing with Fluconazole Inhibit Fluconazole-Resistant Candida albicans by Increasing Riboflavin Metabolism and Causing Mitochondrial Dysfunction and Autophagy.

Our previous study reported that seminaturally occurring arthrocolins A to C with unprecedented carbon skeletons could restore the antifungal activity of fluconazole against fluconazole-resistant Candida albicans. Here, we showed that arthrocolins synergized with fluconazole, reducing the fluconazole minimum and dramatically augmenting the survivals of 293T human cells and nematode Caenorhabditis elegans infected with fluconazole-resistant C. albicans. Mechanistically, fluconazole can induce fungal membrane permeability to arthrocolins, leading to the intracellular arthrocolins that were critical to the antifungal activity of the combination therapy by inducing abnormal cell membranes and mitochondrial dysfunctions in the fungus. Transcriptomics and reverse transcription-quantitative PCR (qRT-PCR) analysis indicated that the intracellular arthrocolins induced the strongest upregulated genes that were involved in membrane transports while the downregulated genes were responsible for fungal pathogenesis. Moreover, riboflavin metabolism and proteasomes were the most upregulated pathways, which were accompanied by inhibition of protein biosynthesis and increased levels of reactive oxygen species (ROS), lipids, and autophagy. Our results suggested that arthrocolins should be a novel class of synergistic antifungal compounds by inducing mitochondrial dysfunctions in combination with fluconazole and provided a new perspective for the design of new bioactive antifungal compounds with potential pharmacological properties. IMPORTANCE The prevalence of antifungal-resistant Candida albicans, which is a common human fungal pathogen causing life-threatening systemic infections, has become a challenge in the treatment of fungal infections. Arthrocolins are a new type of xanthene obtained from Escherichia coli fed with a key fungal precursor toluquinol. Different from those artificially synthesized xanthenes used as important medications, arthrocolins can synergize with fluconazole against fluconazole-resistant Candida albicans. Fluconazole can induce the fungal permeability of arthrocolins into fungal cells, and then the intracellular arthrocolins exerted detrimental effects on the fungus by inducing fungal mitochondrial dysfunctions, leading to dramatically reduced fungal pathogenicity. Importantly, the combination of arthrocolins and fluconazole are effective against C. albicans in two models, including human cell line 293T and nematode Caenorhabditis elegans. Arthrocolins should be a novel class of antifungal compounds with potential pharmacological properties.

Acetylation of Sesquiterpenyl Epoxy-Cyclohexenoids Regulates Fungal Growth, Stress Resistance, Endocytosis, and Pathogenicity of Nematode-Trapping Fungus Arthrobotrys oligospora via Metabolism and Transcription.

Sesquiterpenyl epoxy-cyclohexenoids (SECs) that depend on a polyketide synthase-terpenoid synthase (PKS-TPS) pathway are widely distributed in plant pathogenic fungi. However, the biosynthesis and function of the acetylated SECs still remained cryptic. Here, we identified that AOL_s00215g 273 (273) was responsible for the acetylation of SECs in Arthrobotrys oligospora via the construction of Δ273, in which the acetylated SECs were absent and major antibacterial nonacetylated SECs accumulated. Mutant Δ273 displayed increased trap formation, and nematicidal and antibacterial activities but decreased fungal growth and soil colonization. Glutamine, a key precursor for NH3 as a trap inducer, was highly accumulated, and biologically active phenylpropanoids and antibiotics were highly enriched in Δ273. The decreased endocytosis and increased autophagosomes, with the most upregulated genes involved in maintaining DNA and transcriptional stability and pathways related to coronavirus disease and exosome, suggested that lack of 273 might result in increased virus infection and the acetylation of SECs played a key role in fungal diverse antagonistic ability.

The Multifaceted Gene 275 Embedded in the PKS-PTS Gene Cluster Was Involved in the Regulation of Arthrobotrisin Biosynthesis, TCA Cycle, and Septa Formation in Nematode-Trapping Fungus Arthrobotrys oligospora.

The predominant nematode-trapping fungus Arthrobotrys oligospora harbors a unique polyketide synthase-prenyltransferase (PKS-PTS) gene cluster AOL_s00215g responsible for the biosynthesis of sesquiterpenyl epoxy-cyclohexenoids (SECs) that are involved in the regulation of fungal growth, adhesive trap formation, antibacterial activity, and soil colonization. However, the function of one rare gene (AOL_s00215g275 (275)) embedded in the cluster has remained cryptic. Here, we constructed two mutants with the disruption of 275 and the overexpression of 275, respectively, and compared their fungal growth, morphology, resistance to chemical stress, nematicidal activity, transcriptomic and metabolic profiles, and infrastructures, together with binding affinity analysis. Both mutants displayed distinct differences in their TCA cycles, SEC biosynthesis, and endocytosis, combined with abnormal mitochondria, vacuoles, septa formation, and decreased nematicidal activity. Our results suggest that gene 275 might function as a separator and as an integrated gene with multiple potential functions related to three distinct genes encoding the retinoic acid induced-1, cortactin, and vacuolar iron transporter 1 proteins in this nematode-trapping fungus. Our unexpected findings provide insight into the intriguing organization and functions of a rare non-biosynthetic gene in a biosynthetic gene cluster.

Visible-Light-Promoted Cross-Coupling Reactions of 4-Alkyl-1,4-dihydropyridines with Thiosulfonate or Selenium Sulfonate: A Unified Approach to Sulfides, Selenides, and Sulfoxides.

In this paper, a visible-light-promoted cross-coupling of 4-alkyl-1,4-dihydropyridines with thio-/selenium sulfonates under transition-metal-free conditions is described. This strategy features easily available substrates, mild reaction conditions, high yields, and high chemoselectivity. A novel synthetic route for the construction of a sulfide or selenide Csp3-S or Csp3-Se bond under transition-metal-free conditions without an additive oxidant or base is developed. This method is well extended to the synthesis of a class of thiolated or selenylated glycosides that has not been explored before. Sulfoxides were also successfully chemoselectively observed via a facile variation of the atmosphere under photocatalyzed conditions.

Deficit of long-term memory traces for words in children with cochlear implants.

OBJECTIVE: Language experience can develop long-term memory traces for speech units in the brain, to ensure efficient processing of speech sounds. However, prelingually deafened children lack sufficient auditory input before cochlear implantation. Whether the experience-dependent long-term memory traces exist in prelingually deafened children with cochlear implants (CIs) remains unclear. METHODS: We presented CI and normal hearing (NH) children with Mandarin Chinese spoken disyllables in an oddball paradigm and recorded event-related potentials. Each disyllable was defined as a meaningful word or a meaningless pseudoword by the tonal information in the second syllable. RESULTS: The amplitude of mismatch negativity (MMN) elicited by words was larger than that elicited by pseudowords in NH children. However, this enhancement of the MMN amplitude was not found in CI children. Behavioral results showed later recognition points for words and lower accuracies for speech comprehension in CI children than in NH children. Furthermore, increased theta power for words compared with pseudowords was only found in NH children. CONCLUSIONS: Our findings indicate a deficit of long-term memory traces for words in prelingually deafened children with cochlear implants. SIGNIFICANCE: Early speech input may be crucial to the formation of long-term memory traces for speech units.

ZC4H2 stabilizes RNF220 to pattern ventral spinal cord through modulating Shh/Gli signaling.

ZC4H2 encodes a C4H2 type zinc-finger nuclear factor, the mutation of which has been associated with disorders with various clinical phenotypes in human, including developmental delay, intellectual disability and dystonia. ZC4H2 has been suggested to regulate spinal cord patterning in zebrafish as a co-factor for RNF220, an ubiquitin E3 ligase involved in Gli signaling. Here we showed that ZC4H2 and RNF220 knockout animals phenocopy each other in spinal patterning in both mouse and zebrafish, with mispatterned progenitor and neuronal domains in the ventral spinal cord. We showed evidence that ZC4H2 is required for the stability of RNF220 and also proper Gli ubiquitination and signaling in vivo. Our data provides new insights into the possible etiology of the neurodevelopmental impairments observed in ZC4H2-associated syndromes.

Role of photoresponse of π electrons in light-driven DNA dissociations.

The role of photoresponse of π electrons in light-driven DNA dissociations is theoretically studied. A new model combining the Peyrard-Bishop-Dauxois model and the charge ladder model is first proposed. Then the evolutions of π-electronic states and H-bond stretching in the light-driven DNA dissociations are studied. The results show that light irradiation will induce ultrafast charge redistribution among bases, leading to the precursory insulator-to-metallic transition. This electronic transition will assist DNA to dissociate. Effects of screened Coulomb interactions on dissociation dynamics is emphatically discussed. Finally, it is also found that light-driven DNA dissociation preferentially occurs in the adenine-thymine-rich region rather than the guanine-cytosine-rich region.

NCAPH plays important roles in human colon cancer.

Colon cancer (CC) is one of the major malignancies worldwide, whose pathogenesis is complex and requires the accumulated alteration of multiple genes and signaling pathways. Condensins are multi-protein complexes that play pivotal roles in chromosome assembly and segregation during mitosis, meiosis and even tumorigenesis. Using tissue microarrays by immunohistochemistry and hematoxylin-eosin staining, we found that non-SMC condensin I complex subunit H (NCAPH) in colon cancerous tissues was higher than that in all corresponding adjacent non-cancerous tissues. We then characterized the exact function of the NCAPH in CC. We provided evidences showing that NCAPH is highly expressed in colorectal cancer cell lines comparing with normal human colonic epithelial cells, and identified many NCAPH mutations in CC patients. We found that depletion of NCAPH inhibits CC cell proliferation, migration in vitro and xenograft tumor formation in vivo. Furthermore, NCAPH knockdown promotes cell apoptosis and cell cycle arrest at G2/M phase. Interestingly, the NCAPH high expression in tumor tissues of colon patients had a significantly better prognosis and survival rate than low-expression patients, suggesting that NCAPH high expression promotes colonic cancerous cell proliferation; on the other hand, it may also sensitize these cells responding to chemo- or radio-therapies. Collectively, these findings reveal an important role of NCAPH in CC, indicating that NCAPH could be used as a new therapeutic target in future.

[Pollution Assessment and Spatial Distribution Characteristics of Heavy Metals in Soils of Coal Mining Area in Longkou City].

The present paper takes the coal mining area of Longkou City as the research area. Thirty-six topsoil (0-20 cm) samples were collected and the contents of 5 kinds of heavy metals were determined, including Cd, As, Ni, Ph, Cr. Geo-statistics analysis was used to analyze the spatial distribution of heavy metals. Principal component analysis (PCA) was used to explore the pollution sources of heavy metals and the degree of heavy metals pollution was evaluated by weighted average comprehensive pollution evaluation method. The results showed that enrichment phenomenon was significant for the 5 kinds of heavy metals. Taking secondary standard of National Environment Quality Standard for Soil as the background value, their exceed standard rates were 72.22%, 100%, 100%, 91.67%, 100%, respectively. Average contents of heavy metals in the soil samples were all over the national standard level two and were 1.53, 11.86, 2.40, 1.31, 4.09 times of the background value. In addition, the average contents were much higher than the background value of the topsoil in the eastern part of Shandong Province and were 9.85, 39.98, 8.85, 4.29, 12.71 times of the background value. According to the semivariogram model, we obtained the nugget-effects of 5 kinds of heavy metals and their values were in the order of As (0.644) > Cd (0.627) > Cr (0.538) > Ni (0.411) > Pb (0.294), all belonging to moderate spatial correlation. On the whole, the central part of the Sangyuan Coal Mine and its surrounding areas were the most seriously polluted, while the pollution of heavy metals in the east and west of the study area was relatively light. Principal component analysis suggested that the enrichment of Cd, As, Ni, Cr was due to irrigation of wastewater, the discharge of industry and enterprise, and the industrial activity. Automobile exhaust and coal combustion were the main pollution sources of Pb. The single-factor assessment of heavy metals pollution showed that the degree of different heavy metals pollution was in the order of As > Cr > Ni > Cd > Pb. Simultaneously, comprehensive pollution evaluation showed that the degree of heavy metals pollution in the study area was very serious, with comprehensive pollution index ranging from 2.17 to 4.66, among which, the numbers of moderate and heavy pollution samples were 10 and 26, respectively. Areas with heavy pollution were mainly distributed in the Sangyuan Coal Mine, Beizao Coal Mine, Liuhai Coal Mine; and the areas with moderate pollution covered Wali Coal Mine, Liangjia Coal Mine, and other regions. The results of this paper will provide data reference and theoretical support for the study of ecological risk assessment in the study area.

[Soil Enzyme Activities and Their Relationships to Environmental Factors in a Typical Oasis in the Upper Reaches of the Tarim River].

The intensity and direction of soil biochemical process can be reflected by soil enzyme. The relationship between enzyme activity of soil and environmental factors is deeply studied in this paper, which can contribute to explore the soil ecological process and to provide scientific evidence for scientific regulation of soil system. Soil samples from new cropland, ten-years cropland, thirty-years cropland, orchard, plantation, natural forest, grassland, saline land and desert in the upper reaches of the Tarim River were collected. The relationships between soil enzyme activities and environmental factors were analyzed by traditional statistics and redundancy analysis ( RDA) . The results showed that soil enzyme activities in this area were low, with the average of enzyme properties as follows: catalase, urease, invertase and alkaline phosphatase, with activity of 4. 27 mL . g -1, 0. 34 mg . g -1, 2. 08 mL . g -1 and 0. 08 mg . g -1, respectively. According to the RDA results, the total nitrogen, organic matter, available potassium, soil moisture and total salt were significantly correlated with enzyme activity while a relatively significant correlationship between bulk density and enzyme activity was found. There was no significant correlationship between available potassium/pH and enzyme activity. The importance of environmental factors to soil enzyme activities could be arranged as total nitrogen > organic matter > available potassium > soil moisture > total salt > bulk density > available potassium > pH.