CoMFA Directed Molecular Design for Significantly Improving Fungicidal Activity of Novel [1,2,4]-Triazolo-[3,4-b][1,3,4]-thiadizoles.

Target based molecular design via the aid of computation is one of the most efficient methods in the discovery of novel pesticides. Here, a combination of the comparative molecular field analysis (CoMFA) and molecular docking was applied for discovery of potent fungicidal [1,2,4]-triazolo-[3,4-b][1,3,4]-thiadiazoles. Bioassay results indicated that the synthesized target compounds 3a, 3b, and 3c exhibited good activity against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Fusarium graminearum, Physalospora piricola, Rhizoctonia solani, and Sclerotinia sclerotiorum with an EC50 value falling between 0.64 and 16.10 µg/mL. Specially, 3c displayed excellent fungicidal activity against C. arachidicola and R. solani, which was 5 times more potent than the lead YZK-C22. The enzymatic inhibition assay and fluorescence quenching analysis with R. solani pyruvate kinase (RsPK) showed a weaker binding affinity between RsPK and 3a, 3b, or 3c. Transcriptomic analyses showed that 3c exerted its fungicidal activity by disrupting steroid biosynthesis and ribosome biogenesis in eukaryotes. These findings support that 3c is a promising fungicide candidate, and a fine modification from a lead may lead to a totally different mode of action.

Ontology characterization, enrichment analysis, and similarity calculation-based evaluation of disease-syndrome-formula associations by applying SoFDA.

Clinical symptom-based diagnosis and therapy play a crucial role in personalized medicine and drug discovery. The syndromes, distinctive groups of clinical symptoms summarized by traditional Chinese medicine (TCM) theories and clinical experiences, are used as the core diagnostic criteria and therapeutic guidance in TCM. However, there is still a lack of standardized data, information, and intrinsic molecular basis to help TCM syndromes better classify diseases and guide tailored medications. To address this problem, we built the first integrated web platform, SoFDA (http://www.tcmip.cn/Syndrome/front/), with a curated ontology of 319 TCM syndromes, 8045 diseases, and 1359 TCM herbal formulas and their relationships with genes, diseases, and formulas. This platform proposed an association measurement by calculating Jaccard/Cosine similarities between TCM syndromes and their related biomedical entities with case and control validations. On this basis, the SoFDA platform enables biomedical and pharmaceutical scientists to rank and filter the most promising associations for disease diagnosis and tailored interventions. Conversely, the targeted gene sets and symptom sets can also be associated with TCM syndromes, formulas, and diseases for function illustration. Notably, SoFDA explores the multi-way associations among diseases, TCM syndromes, symptom genes, herbal formulas, drug targets, and pathways in heterogeneous biomedical networks with lots of customization. The protocol here implements all the analyses above using the SoFDA platform. Collectively, SoFDA may provide insights into the biological basis of disease-specific TCM syndromes and the underlying molecular mechanisms, as well as a tailored treatment for single or multiple symptoms within a syndrome.

Changes of phosphorus species during (hydro) thermal treatments of iron-rich sludge and their solubilization mediated by a phosphate solubilizing microorganism.

This study systematically evaluated phosphorus (P) solubilization from pyrochar and hydrochar derived from both raw sludge and iron-rich sludge. The data indicated, that an increase in thermal treatment temperature and the presence of iron promoted the accumulation of P in both pyrochar (derived at 300, 500, and 800 °C) and hydrochar (derived at 100, 200, and 280 °C). After incubating pyrochar and hydrochar with a phosphate solubilizing microorganism (PSM) (Pseudomonas aeruginosa) for 30 days, PSM significantly promoted the solubilization of P in pyrochar and hydrochar synthesized at low temperatures rather than those at high temperatures, with a 59 % increase for the pyrolysis of raw sludge at 300 °C than that pyrolyzed at 800 °C and a 62 % increase for the hydrothermal treatment of raw sludge at 100 °C than that treated at 280 °C. And the phenomena were more obvious on the char samples derived from iron-rich sludge. The mass balance of different P species in the solid and liquid phases indicated that after incubating with PSM for 30 days, NaOH-P was the main P solubilized from the solid phase of pyrochar and HCl-P was the main P solubilized from the solid phase of hydrochar. Considering P availability to plants, the preliminary economic analysis indicated that the hydrothermal treatment of iron-rich sludge at 100 °C showed the highest economic benefits for P recovery, with the net cost of 28.79 USD/ton wet sludge. This study was useful in giving novel insights into the reuse of char samples as P fertilizer, and also suggested the importance of Pseudomonas aeruginosa and other bacteria in sludge application, particularly in terms of P solubilization.

Deciphering the impacts of composition of extracellular polymeric substances on sludge dewaterability: An often overlooked role of amino acids.

An investigation was conducted for waste activated sludge pretreated by different methods (e.g., ultrasonic, thermal, ozone, and acid/alkaline) in order to establish correlations between amino acids and parameters related to sludge dewaterability (e.g., capillary suction time (CST), specific resistance to filtration (SRF), proteins (PN) and polysaccharides (PS) in different fractions of extracellular polymeric substances (EPS), zeta potential, and particle sizes). The results indicated that glycine, serine, and threonine were the key identified amino acids correlated with parameters related to sludge dewaterability. To be exemplified, glycine showed positive correlations with the normalized CST (regression coefficient (R) = 0.72, p < 0.05), the normalized SRF (R = 0.74, p < 0.05), PN in soluble EPS (R = 0.89, p < 0.05), PS in soluble EPS (R = 0.56, p < 0.05), tryptophan-like PN in soluble EPS (R = 0.60, p < 0.05), and tryptophan-like PN in loosely-bound EPS (R = 0.58, p < 0.05). After adding extra glycine, serine, and threonine into sludge samples, sludge dewaterability was deteriorated. The hydrophilic functional groups of CO and C-OH were found to be more predominant in sludge with the presence of these amino acids. The Lewis acid-base interaction predominated in determining the net attraction among sludge flocs. Moreover, the presence of glycine, serine, and threonine resulted in high repulsive hydrophilic interaction, which deteriorated sludge dewaterability. This study emphasized the importance of amino acids in sludge dewatering and amino acids might be incorporated into parameters reflecting sludge dewaterability.

Add-On Chinese Medicine for Coronavirus Disease 2019 (ACCORD): A Retrospective Cohort Study of Hospital Registries.

Chinese medicine (CM) was extensively used to treat COVID-19 in China. We aimed to evaluate the real-world effectiveness of add-on semi-individualized CM during the outbreak. A retrospective cohort of 1788 adult confirmed COVID-19 patients were recruited from 2235 consecutive linked records retrieved from five hospitals in Wuhan during 15 January to 13 March 2020. The mortality of add-on semi-individualized CM users and non-users was compared by inverse probability weighted hazard ratio (HR) and by propensity score matching. Change of biomarkers was compared between groups, and the frequency of CMs used was analyzed. Subgroup analysis was performed to stratify disease severity and dose of CM exposure. The crude mortality was 3.8% in the semi-individualized CM user group and 17.0% among the non-users. Add-on CM was associated with a mortality reduction of 58% (HR = 0.42, 95% CI: 0.23 to 0.77, [Formula: see text] = 0.005) among all COVID-19 cases and 66% (HR = 0.34, 95% CI: 0.15 to 0.76, [Formula: see text] = 0.009) among severe/critical COVID-19 cases demonstrating dose-dependent response, after inversely weighted with propensity score. The result was robust in various stratified, weighted, matched, adjusted and sensitivity analyses. Severe/critical patients that received add-on CM had a trend of stabilized D-dimer level after 3-7 days of admission when compared to baseline. Immunomodulating and anti-asthmatic CMs were most used. Add-on semi-individualized CM was associated with significantly reduced mortality, especially among severe/critical cases. Chinese medicine could be considered as an add-on regimen for trial use.

Improvement of sludge dewaterability by ammonium sulfate and the potential reuse of sludge as nitrogen fertilizer.

A novel method to enhance sludge dewaterability with ammonium sulfate ((NH4)2SO4) was proposed, and the potential reuse of dewatered sludge cake and filtrate as nitrogen fertilizers was evaluated. Compared with raw sludge, 87.91% reduction of capillary suction time (CST) and 88.02% reduction of specific resistance to filtration (SRF) after adding 80% (m/m) (NH4)2SO4 were achieved, with 38.49% of protein precipitated simultaneously. The (NH4)2SO4 dose destroyed cell membrane, resulting in the release of intracellular water by converting bound water into free water, thus enhancing sludge dewaterability. In the solid phase, the content of protein-N increased, and larger protein aggregates were formed. The (NH4)2SO4 dose destroyed the hydration shell, making proteins to exhibit hydrophobic interactions, and to be aggregated, and precipitated from the liquid phase. When incubated Pennisetum alopecuroides L. with the dewatered sludge cake and filtrate after dewatering and conditioning with (NH4)2SO4, the germination rate of grass seed and shoot lengths both increased while compared with those incubated with dewatered sludge cake and filtrate of the raw sludge. This study might provide insights into sustainable sludge treatment by integrating sludge dewatering and the potential reuse of dewatered sludge cake and filtrate as nitrogen fertilizer via treatment with (NH4)2SO4.

Phosphorus recovery from the liquid phase of anaerobic digestate using biochar derived from iron-rich sludge: A potential phosphorus fertilizer.

A novel technique for phosphorus recovery from the liquid phase of anaerobic digestate was developed using biochar derived from iron-rich sludge (dewatered sludge conditioned with Fenton's reagent). The biochar pyrolyzed from iron-rich sludge at a low temperature of 300 °C (referred to as Fe-300 biochar) showed a better phosphorus (P) adsorption capacity (most of orthophosphate and pyrophosphate) than biochars pyrolyzed at other higher temperatures of 500-900 °C, with the maximum P adsorption capacity of up to 1.843 mg g-1 for the liquid phase of anaerobic digestate. Adsorption isotherms study indicated that 70% P was precipitated through chemical reaction with Fe elements, i.e., Fe(II) and Fe(III) existed on the surface of the Fe-300 biochar, and other 30% was through surface physical adsorption as simulated by a dual Langmuir-Langmuir model using the potassium dihydrogen orthophosphate (KH2PO4) as a model solution. The seed germination rate was increased up to 92% with the addition of Fe-300 biochar after adsorbing most of P, compared with 66% without the addition of biochar. Moreover, P adsorbed by the chemical reaction in form of iron hydrogen phosphate can be solubilized by a phosphate-solubilizing microorganism of Pseudomonas aeruginosa, with the total solubilized P amount of 3.045 mg g-1 at the end of an incubation of 20 days. This study indicated that the iron-rich sludge-derived biochar could be used as a novel and beneficial functional material for P recovery from the liquid phase of anaerobic digestate. The recovered P with biochar can be re-utilized in garden soil as an efficient P-fertilizer, thus increasing the added values of both the liquid phase of anaerobic digestate and the iron-rich sludge.

Profiling of amino acids and their interactions with proteinaceous compounds for sewage sludge dewatering by Fenton oxidation treatment.

During advanced oxidation treatment for enhancing sludge dewaterability, the peptide chains of protein can be decomposed into amino acids. Protein exhibits a great impact on sewage sludge dewaterability. However, the role of amino acids in sludge dewatering remains unclear. In this study, among the 23 types of amino acids investigated, tryptophane (Trp) and lysine (Lys) were identified as the key amino acids affecting sludge dewaterability during Fenton oxidation treatment. The content of lysine showed positive correlations with capillary suction time (CST), specific resistance to filtration (SRF), and bound water content, and the concentrations of total protein, low molecular weight protein, amines and amides, and 3-turn helix of proteinaceous compounds in bound extracellular polymeric substances (EPS), while the content of tryptophane showed negative correlations with the above parameters. The amino acids may be sourced from damage of the membrane and ribosomal proteins by hydroxyl radicals, and the peptide bonds connected with tryptophane were more inclined to be decomposed than other amino acids. Particularly, more amino acids of tryptophane can result in more hydrophobic interaction, and less necessary energy barrier for aggregation of particles. As such, regulating protein degradation towards production of tryptophane may be related with enhanced sludge dewaterability by Fenton oxidation treatment.

Investigation on emission control of NOx precursors and phosphorus reclamation during pyrolysis of ferric sludge.

In this study, a method to reduce the emission of NOx precursors (e.g., hydrogen cyanide (HCN) and ammonia (NH3)) while simultaneously reclaim more plant-available P was proposed through pyrolyzing ferric sludge (sludge conditioned by Fenton's reagents) rather than raw sludge. The nitrogen and phosphorus transformation at different pyrolysis temperatures was investigated. The results indicated that in comparison with the pyrolysis of raw sludge, the remaining iron compounds in ferric sludge can fix char-N in more stable forms (e.g., appearance of pyrrole-N at 900 °C). The secondary cracking of amine-N compounds in tar-N (e.g., 81.67% increase of amine-N at 900 °C) can be inhibited. Hence, more amine-N was remained and less heterocyclic-N and nitrile-N compounds were generated in tarN. Less generation of NH3-N and HCN-N was also observed in NOx precursors (e.g., 5.46% decrease of NH3-N and 6.91% decrease of HCN-N at 900 °C). Moreover, the results of X-ray diffractometry, liquid 31P nuclear magnetic resonance spectroscopic, X-ray photoelectron spectroscopic, and chemical analyses collectively indicated that iron present in ferric sludge also favored reclamation of more plant-available P. In comparison with the pyrolysis of raw sludge, an increase in the total phosphorus pool was noted (18.06-36.26 versus 15.54-30.59 mg g-1 dry solids). A decrease in mobility with the predominant P as sodium hydroxide (NaOH)-P, and an increase in plant-available P can be also obtained. This study indicated that pyrolysis of ferric sludge was a feasible way to simultaneously reduce emission of NOx precursors, reclaim plant-available P, and reuse ferric sludge.

Effects of red mud on emission control of NOx precursors during sludge pyrolysis: A protein model compound study.

The nitrogen-containing gases pyrolyzed from sewage sludge can be converted into NOx compounds, which would cause severe environmental pollution. This study developed a new strategy to reduce the emission of NOx precursors such as ammonia (NH3) and hydrogen cyanide (HCN) using red mud. The highest reduction efficiencies (15.10% for NH3 and 24.72% for HCN) were achieved at 900 °C while compared with those pyrolyzed from raw sludge without the addition of red mud. The transformation and distribution of nitrogenous compounds in three-phase pyrolysates were studied at 400-800 °C for pyrolysis process of a model soybean protein compound. The nitrogenous compounds, i.e., amine-N, heterocyclic-N, and nitrile-N, were identified as the three main intermediates related with the production of NOx precursors. Ferric oxide (Fe2O3) and calcium oxide (CaO) presented in red mud were identified as the driving force which facilitated nitrogen stabilization in char (e.g., at 800 °C, 21.63% increase of char-N after addition of Fe2O3, and 41.54% increase of char-N after addition of CaO). These metal oxides possibly reacted with protein-N to form FexN and CaCxNy, inhibited the secondary cracking of amine-N compounds in tar (e.g., at 800 °C, 2.33% increase of amine-N after addition of Fe2O3, and 0.38% increase of amine-N after addition of CaO), and reduced the production of nitrile-N (e.g., at 800 °C, 30.41% reduction of nitrile-N after addition of Fe2O3, and 27.40% reduction of nitrile-N after addition of CaO) and heterocyclic-N compounds (e.g., at 800 °C, 21.60% reduction of heterocyclic-N after addition of Fe2O3, and 13.98% reduction of heterocyclic-N after addition of CaO). Hence, the emission of NH3 and HCN in gas phase can be controlled. Moreover, Fe2O3 showed better capability in controlling the emission of NOx precursors than CaO (higher reduction of NH3-N and higher reduction of HCN-N). These results indicate that red mud is an efficient catalyst to reduce emission of NOx precursors through controlling intermediates at 400-800 °C.