Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability.

Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 µM) and glucose transporter 9 (GLUT9, IC50 = 18.21 µM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

CCDC92 deficiency ameliorates podocyte lipotoxicity in diabetic kidney disease.

BACKGROUND AND AIMS: Podocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of lipids and lipid-modulating proteins as key determinants of podocyte function in health and kidney disease. CCDC92, a novel member of coiled-coil domain-containing protein family, was indicated relevant to lipid metabolism, coronary heart disease and type 2 diabetes. However, the expression pattern and role of CCDC92 in the kidney is not clear. This study was designed to elucidate the contribution of CCDC92 in the pathogenesis of DKD. METHODS: Sections with a pathological diagnosis of different classes of DKD, including subjects with mild DKD (class II, n = 6), subjects with moderate DKD (class III, n = 6) or subjects with severe DKD (class IV, n = 6), and control samples (n = 12) were detected for the expression level of CCDC92 and lipid accumulation. Two types of diabetic mice model (db/db and HFD/STZ) in podocyte-specific Ccdc92 knockout background were generated to clarify the role of CCDC92 in podocyte lipotoxicity. RESULTS: The level of CCDC92 was increased in renal biopsies sections from patients with DKD, which was correlated with eGFR and lipid accumulation in glomeruli. In animal studies, CCDC92 were also induced in the kidney from two independent diabetic models, especially in podocytes. Podocyte-specific deletion of Ccdc92 ameliorated podocyte injury and ectopic lipid deposition under diabetic condition. Mechanically, CCDC92 promoted podocyte lipotoxicity, at least in part through ABCA1 signaling-mediated lipid homeostasis. CONCLUSION: Our studies demonstrates that CCDC92 acts as a novel regulator of lipid homeostasis to promote podocyte injury in DKD, suggesting that CCDC92 might be a potential biomarker of podocyte injury in DKD, and targeting CCDC92 may be an effective innovative therapeutic strategy for patients with DKD.

Novel process for organic wastewater treatment using aerobic composting technology: Shifting from pollutant removal towards resource recovery.

In this study, an organic wastewater treatment process based on aerobic composting technology was developed in order to explore the transition of wastewater treatment from pollutants removal to resource recovery. The novelty of the process focuses towards the microbial metabolic heat that is often ignored during the composting, and taking advantage of this heat for wastewater evaporation to achieve zero-discharge treatment. Meanwhile, this process can retain the wastewater's nutrients in the composting substrate to realize the recovery of resources. This study determined the optimum condition for the process (initial water content of 50 %, C/N ratio of 25:1, ventilation rate of 3 m3/h), and 69.9 % of the total heat generated by composting was used for wastewater treatment under the condition. The HA/FA ratio of composting substrate increased from 0.07 to 0.53 after wastewater treatment, and the retention ratio of TOC and TN was 52.3 % and 61.7 %, respectively, which proved the high recycling value of the composting products. Thermoduric and thermophilic bacteria accounted for 44.3 % of the community structure at the maturation stage, which played a pivotal role in both pollutant removal and resource recovery.

Exploring the humification process of municipal sludge in hyperthermophilic composting through metagenomic and untargeted metabolomic.

Hyperthermophilic composting (HC) has been widely recognized for the advantage of high treatment efficiency for organic wastes. However, the humification process is still unclear. In this study, the humification process of HC was investigated, compared to conventional composting (CK). The results showed that the highest composting temperature, organic matter degradation rate, and humification index in HC were 92.62 °C, 23.98%, and 1.59, while those in CK were 70.23 °C, 14.49 %, and 1.04, indicating HC accelerated humification process. Moreover, the results of metagenomic and untargeted metabolomic showed that the genes and metabolisms related to carbohydrate, lipid, amino acid, fatty acid, and nucleotide were more abundant in HC. Consequently, the metabolic pathways regarding organic matter degradation and microbial reproduction were enhanced in the high temperature stage of HC, further accelerating the humification reaction in the low temperature stage. This work contributes to the comprehension of the humification mechanism in HC.

Electric heating promotes sludge composting process: Optimization of heating method through machine learning algorithms.

Composting with electric heating has attracted extensive attention for the advantage of high treatment efficiency for sludge. However, there are challenges in investigating how electric heating affects the composting process and how to reduce its energy consumption. This study investigated the effects of different electric heating methods on composting. The highest temperature, water content reduction, organic matter reduction, and weight reduction rate in group B6 (heating in the first and second stages) were 76.00° C, 16.76 %, 4.90 %, and 35.45 %, respectively, indicating that electric heating promoted water evaporation and organic matter degradation. In conclusion, electric heating promoted the sludge composting process and the heating method of group B6 was optimal for composting characteristics. This work contributes to the understanding of the mechanism of electric heating promoting composting process and providing theoretical support for the engineering application of composting with electric heating.

Treatment performance of multistage active biological process (MSABP) reactor for saline sauerkraut wastewater: acclimatization, optimization and improvement.

The wastewater with a high concentration of organics and salt is a major contaminant in the production of sauerkraut. In this study, a multistage active biological process (MSABP) system was constructed to treat sauerkraut wastewater. The key process parameters of the MSABP system were analyzed and optimized by response surface methodology. The optimization results indicated that the most optimal removal efficiencies and removal loading rates of chemical oxygen demand (COD) and NH4+-N were 87.9%, 95.5%, 2.11 kg·m-3·d-1 and 0.12 kg·m-3·d-1, respectively, with hydraulic retention time (HRT) of 2.5 d and pH of 7.3. Meanwhile, this system could also be improved for the further treatment of COD and total nitrogen by effluent recycle and ozone oxidation. The COD and total nitrogen removal efficiencies of the modified MSABP system were 99.9% and 60.2%, respectively. In addition, the modified system could also reduce the potential harm from high concentrations of NO2--N.

Effects of recycling hyper-thermal inoculum by repeated batch cultivation into co-composting of sludge and livestock-poultry manure.

The enrichment and adaptation of hyper-thermal compost-derived thermophilic inoculum by repeated batch cultivation (RBC) was conducted by investigating bacterial community. The effects of recycling hyper-thermal inoculum by RBC into co-composting were investigated through evaluating the influences of temperature, pH, moisture, C/N ratio, transformation of nitrogen, composting maturity, humification levels and scanning electron microscopy (SEM). The results showed that RBC enriched the thermophilic bacterial community and nitrogen fixation bacteria of the compost-derived thermophilic inoculum. Simultaneously, recycling the inoculum into co-composting increased the temperature, nitrate nitrogen (NO3--N) and Germination index (GI), and improved the transformation of nitrogen and humification levels. Conclusively, recycling hyper-thermal inoculum by RBC into co-composting can improve the degradation process.

An efficient anoxic/aerobic/aerobic/anoxic process for domestic sewage treatment: From feasibility to application.

In this paper, the anoxic/aerobic/aerobic/anoxic (AOOA) process was proposed using fixed biofilms in a continuous plug-flow multi-chamber reactor, and no sludge reflux operation was performed during the 190 days of operation. The reactor volume ratio of 1.5:2:1.5:1 (A/O/O/A) with the dissolved oxygen (DO) concentration of 2 mg L-1 in the aerobic zone was the optimal condition for reactor operation. According to the results obtained from the treatment of real domestic sewage, when the hydraulic retention time (HRT) was 6 h, the effluent of the reactor could meet the discharge standard even in cold conditions (13°C). Specifically, the elemental-sulfur-based autotrophic denitrification (ESAD) process contributed the most to the removal of total inorganic nitrogen (TIN) in the reactor. In addition, the use of vibration method was helpful in removing excess sludge from the biofilms of the reactor. Overall, the AOOA process is an efficient and convenient method for treating domestic sewage.

Denitrification Performance in Packed-Bed Reactors Using Novel Carbon-Sulfur-Based Composite Filters for Treatment of Synthetic Wastewater and Anaerobic Ammonia Oxidation Effluent.

To avoid nitrate pollution in water bodies, two low-cost and abundant natural organic carbon sources were added to make up the solid-phase denitrification filters. This study compared four novel solid-phase carbon-sulfur-based composite filters, and their denitrification abilities were investigated in laboratory-scale bioreactors. The filter F4 (mixture of elemental sulfur powder, shell powder, and peanut hull powder with a mass ratio of 6:2.5:1.5) achieved the highest denitrification ability, with an optimal nitrate removal rate (NRR) of 723 ± 14.2 mg NO3 --N⋅L-1⋅d-1 when the hydraulic retention time (HRT) was 1 h. The HRT considerably impacted effluent quality after coupling of anaerobic ammonium oxidation (ANAMMOX) and solid-phase-based mixotrophic denitrification process (SMDP). The concentration of suspended solids (SS) of the ANAMMOX effluent may affect the performance of the coupled system. Autotrophs and heterotrophs were abundant and co-existed in all reactors; over time, the abundance of heterotrophs decreased while that of autotrophs increased. Overall, the SMDP process showed good denitrification performance and reduced the sulfate productivity in effluent compared to the sulfur-based autotrophic denitrification (SAD) process.

Denitrification performance of sulfur-based autotrophic denitrification and biomass­sulfur-based mixotrophic denitrification in solid-phase denitrifying reactors using novel composite filters.

Both the elemental sulfur-based autotrophic denitrification (ESAD) and the biomass­sulfur-based mixotrophic (simultaneous autotrophic and heterotrophic) denitrification processes (BSMD) are efficient methods for removing nitrate from wastewater. However, a comparative analysis of the denitrification capacity of the BSMD and ESAD in the packed bed reactors is still lacking. In this paper, corncob powder was selected as the biomass source to prepare biomass­sulfur-based composite filter (BSCF) for the BSMD process. The denitrification performances of the three identical lab-scale bioreactors packed with varying elemental sulfur-based composite filters (ESCFs) were compared under varying loading conditions, and the optimal ESCF of the ESAD system was 2:1 by weight ratio of sulfur powder to shell powder. In pilot-scale experiments, the results showed that BSCF could decrease the sulfate productivity and gave better denitrification performance than the ESCF with the optimal nitrate removal rate (NRR) of 504 ± 12.3 mg NO3--N·L-1·d-1. In addition, the two-stage flushing strategy (for the removal of aged sludge) can effectively improve the denitrification capacity, while the denitrification will be inhibited when the influent dissolved oxygen concentration was higher than 4.5 mg L-1. Moreover, the heterotrophs and autotrophs were abundant in the reactors. Over time, the abundance of autotrophs increased while that of heterotrophs decreased. Overall, BSCF could be a promising and economic technology to improve the effluent quality.

Simultaneous shortcut nitrification and denitrification in a hybrid membrane aerated biofilms reactor (H-MBfR) for nitrogen removal from low COD/N wastewater.

The residues of nitrogen contaminants due to insufficient organic carbon sources in sewage has always been the main problem faced by wastewater treatment plants in the process of nitrogen removal. In this study, simultaneous shortcut nitrification and denitrification (SND) was achieved in the hybrid membrane aerated biofilm reactor (H-MBfR) for treating low COD/N ratio (∼x223C 4: 1) wastewater. The effects of the aeration pressure and the influent COD/N ratio in H-MBfR were investigated and further optimized by the response surface methodology (RSM). By controlling the dissolved oxygen to achieve SND, the removal efficiencies of NH4+-N, COD and TN of low COD/N ratio wastewater reached maximum values of 95.52%, 96.61% and 72.23%, respectively. Microbial community analysis showed that the influent COD/N ratio had an obvious influence on the microbial community structure. In particular, ammonia oxidizing bacteria (AOB) and denitrifying bacteria had a good commensalism when the COD/N ratio was 4.3. Compared to control reactor, the analysis of membrane bio-fouling showed that H-MBfR has a lower amount of extracellular polymeric substance (EPS) on membrane and a low concentration of MLSS in bulk liquid, which is helpful for the longer-term operation of H-MBfR.

Exploration and verification of the feasibility of the sulfur-based autotrophic denitrification integrated biomass-based heterotrophic denitrification systems for wastewater treatment: From feasibility to application.

The sulfur-based autotrophic denitrification (SAD) and the solid organic carbon-based denitrification processes are both efficient techniques to remove nitrate from wastewater, and the hydrogen ions generated by the SAD process would be consumed in the heterotrophic denitrification process. Therefore, it is possible to improve the denitrification capacity when the solid organic carbon was added into a SAD reactor. In this study, corncob powder and sawdust powder were selected as solid organic carbon sources, and the sulfur-based autotrophic denitrification integrated biomass-based heterotrophic denitrification system was formed (SBD). The laboratory and field experiments showed that SBD could shorten the start-up period, decrease the sulfate productivity, and maintain a good denitrification performance when treated wastewater. According to the field experiment results, when the HRT was 1 h, the effluent total nitrogen (TN) concentration was always lower than 15 mg L-1. In addition, nitrite inhibition was observed when the concentration of nitrite in the reactors reached above 30 mg L-1. The mixture of elemental sulfur powder, shell powder, corncob powder, and sawdust powder with a mass ratio of 6:2:1:1 was the optimal filter for the SBD system, with an average nitrate reduction rate (NAR) of 420 mg NO3-N·L-1·d-1 obtained at the end of the study. During the whole operation, the major autotrophs in the SBD systems were Thermomonas, Ferritrophicum, and Thiobacillus, while the major heterotrophs were Saprospiraceae, Ferruginibacter, Dokdonella, and Simplicispira. Overall, the SBD system was a feasible and practically favorable way to remove nitrate from wastewater.

Performance of HABR + MSABP system for the treatment of dairy wastewater and analyses of microbial community structure and low excess sludge production.

The potential of the system, a hybrid anaerobic baffled reactor (HABR) coupled with a multi-stage active biological process (MSABP) reactor, for simulated dairy wastewater at various temperature, hydraulic retention time (HRT), and pH was investigated. Percentage removals of chemical oxygen demand (COD) and NH4+ were optimized using response surface methodology. Under optimized conditions (temperature, 33 °C; HRT, 24 h; pH, 7.35), the removal efficiencies of COD and NH4+ were 99.89% and 97.83%, respectively. Miseq sequencing analysis exhibited that the anaerobic segment of the system was dominated by fermentation and acetogenic bacteria, and in the aerobic segment, microorganisms involved in the nitrogen cycle were significantly enriched. Meanwhile, it could be found that the excess sludge production of the process was much lower than that of other bio-processes. The average excess sludge production rate was 0.025-0.05 g SS/g COD removed under different organic loadings.

A novel coupling process with partial nitritation-anammox and short-cut sulfur autotrophic denitrification in a single reactor for the treatment of high ammonium-containing wastewater.

In this study, a novel coupling process with partial nitritation-anaerobic ammonium oxidation (anammox) (PNA) and sulfur autotrophic denitrification (SAD) was studied using an upflow biofilm reactor with mechanical vibration. At a lower dissolved oxygen (DO) concentration (0.40 ±â€¯0.20 mg L-1), ammonia could be efficiently removed from synthetic wastewater by the coupling system with a total nitrogen removal efficiency (NRE) of 98% and an influent NH4+-N concentration of 600 mg L-1. In this system, the nitrate, which was produced during the anammox reaction, could be timely reduced by the SAD reaction. Compared with the conventional PNA and SAD processes, coupling the PNA and SAD processes in a single reactor prevented nitrite accumulation in the SAD reaction and reduced the total sulfate production by 59%. The high-throughput sequencing analysis supported that the SAD bacteria (Thiobacillus) and anammox bacteria (Candidatus Kuenenia) could coexist on the elemental sulfur stone. Additionally, sulfur consumption and sulfate production were increased under a high DO concentration. The sulfate production/nitrate reduction ratio and changing profile of the substrate suggested that the short-cut SAD process mainly occurred in this coupling system. Otherwise, batch experiments also suggested that the nitrite removal rate in the anammox process was 34.5 times higher than that in the SAD process. The outcomes of these experiments revealed that most of the nitrite, as an intermediate product in the SAD reaction, served as an electron acceptor for the anammox reaction. A stoichiometric calculation of this coupling process indicated that the novel reaction scheme with a high NRE was successfully achieved. Under an ideal short-cut SAD process, almost 55% of the sulfur consumption could be reduced in this coupling system. The coupling system provides a new perspective for nitrogen removal in a single reactor and further promotes anammox and SAD performance in wastewater treatment processes.

Effects of vibration on anammox-enriched biofilm in a high-loaded upflow reactor.

An upflow biofilm reactor was operated for 211 days to investigate the effects of vibration on anammox treatment performance. With vibration, the highest nitrogen removal rates (20 kg-N·m-3·d-1) were obtained on day 180. Since the vibration could directly applied on the biofilm, it could release the dinitrogen gas accumulated in the biofilm timely and reduce the internal mass transfer resistance sharply. The specific anammox activity increased by more than 3 times with a higher vibration intensity. Meanwhile, the unique random motion caused by mechanical vibration promotes the production of extracellular proteins. Moreover, the VSS reached 20.97 g·L-1 which was 1.6 times higher than the control reactor. Such enrichment method resulted in a hard and thick anammox biofilm with a special granular morphology, and the nitrite tolerance concentration could reach 500 mg-N·L-1. Operated with an adequate vibration intensity could maintain the biofilm thickness and conducive to improve the stability of the reactor. In addition, this technique also allowed the microorganisms inside the biofilm and those on the surface to reach the same culture conditions. Base on the batch experiments, intermittent vibration caused a decrease in energy consumption from about 7.757 (kW·h)·(kg-N)-1 in group 0-Lv7(60-60) to 0.912 (kW·h)·(kg-N)-1 in group 0-Lv7(5-60). Compared to the internal recycle without vibration, the energy consumption fell by a slice over 65%. Furthermore, the high-throughput sequencing results showed that the relative abundance of Candidatus Kuenenia in reactor 1 increased from 13.2% to 43.9%.

Performance analysis and optimization of ammonium removal in a new biological folded non-aerated filter reactor.

A new type of biological folded non-aerated filter (BFNAF) was found to be superior and feasible for the treatment of NH4+-N wastewater. It was constructed with the folded structure suitable for the nylon biomass carrier. The advantages of the BFNAF included low energy consumption, long reaction path, large biofilm surface area and non-clogging compared to the traditional biological aerated filter. In this study, the effects of hydraulic retention time (HRT), and the influent NH4+-N concentration on the performance of BFNAF were investigated and optimized by the response surface methodology. Under the optimal operating condition (HRT, 10 h; NH4+-N concentration, 52 mg/L), the removal efficiency and removal rate were 94.62 ±â€¯0.63% and 0.106 kg-NH4+ m-3 day-1, respectively. The results showed that the BFNAF reactor could remove NH4+-N from wastewater and realized the nitrification process effectively under natural ventilation conditions.

Nitrogen removal from wastewater via simultaneous nitrification and denitrification using a biological folded non-aerated filter.

A conventional biological filter has been shown to be a viable method for removing nitrogenous compounds from wastewater, but it still has many disadvantages. In this study, a biological folded non-aerated filter (BFNAF) was designed, and its feasibility for nitrogen-loaded wastewater treatment has been confirmed. Effects of the HRT and the COD/N ratio on the performance of BFNAF were investigated. Through response surface method, when the COD/N ratio and the HRT were 5.39 and 10.83 h, removal efficiencies of NH4+, COD and TN reached maximum values of 88.62 ±â€¯0.81%, 76.12 ±â€¯0.57%, and 50.48 ±â€¯1.02%, respectively. In addition, it was found that several denitrifying bacteria, such as Azoarcus, Arcobacter, Flavobacterium, along with many ammonia-oxidizing bacteria and nitrite-oxidizing bacteria, co-existed in the community of the biofilm. All the results showed that the BFNAF could realize the simultaneous nitrification and denitrification (SND) process effectively.

Ultrasonic treatment enhances sludge disintegration and degradation in a photosynthetic bacteria-bioelectrochemical system.

Excess sludge contains a large amount of organic matter, most of which is present in the form of bacteria and extracellular polymeric substances. In this study, a photosynthetic bioelectrochemical system (BES) combined with ultrasonic treatment (UT) was investigated to mineralize sludge. The sludge was disintegrated by the UT, and the supernatant separated from the treated sludge was further degraded through a bioelectrochemical system containing photosynthetic bacteria (PSB-BES). The UT efficiency was enhanced by supernatant separation. The PSB-BES method effectively improved the degradation of the soluble chemical oxygen demand (SCOD) from the supernatant. The SCOD and protein removal were increased 1.4 and 1.5 times, respectively, compared to BES without PSB. In addition, the effects of several key operating factors including illumination, voltage, and temperature were systematically investigated. This study provides a basis for further development of sludge mineralization processes. PRACTITIONER POINTS: The sludge was disintegrated by the ultrasound treatment. The supernatant separated from treated sludge was further degraded by a bioelectrochemical system combined with photosynthetic bacteria. The ultrasonic treatment efficiency was enhanced by supernatant separation. The PSB-BES method effectively improved the soluble chemical oxygen demand (SCOD) degradation from the supernatant. The effects of several key operating factors including light (dark-photo), voltage, and temperature were systematically investigated.

Enhanced performance and microbial community analysis of bioelectrochemical system integrated with bio-contact oxidation reactor for treatment of wastewater containing azo dye.

Feasibility and superiority of the bioelectrochemical system integrated with biocontact oxidation (BES-BCO) for degradation and/or mineralization of azo dyes have been confirmed. In this study, the effects of hydraulic retention time (HRT), applied voltage, and dissolved oxygen (DO) concentration at the bioanode on the performance of BES-BCO and traditional BES were investigated. Using the response surface methodology, the optimum values of HRT, applied voltage, and DO concentration at the bioanode of BES-BCO were investigated to obtain the maximum decolouration and COD removal efficiency and minimum specific energy consumption (SEC). The microbial community structure in BES-BCO was studied for analyzing the change following the introduction of oxygen. The optimised solution was an applied voltage of 0.59V, HRT of 12h, and DO concentration of 0.96mg/L at the bioanode. Under such conditions, the DE, COD removal efficiency, and SEC values were 94.62±0.63%, 89.12±0. 32%, and 687.57±3.86J/g, respectively. In addition, after changing from BES to BES-BCO, the bacterial community structure of the bioanode underwent significant changes. Several aerobic aniline-degrading bacteria and anode-respiration bacteria (ARB) were found to dominate the community of the anode biofilm. The results showed that the removal of azo dye degradation by-products was closely correlated with the o-bioanode and the BCO bacterial community structure.

A novel anammox process combined with vibration technology.

This study investigated a fixed bed anammox bioreactor that uses vibration techniques to treat synthetic inorganic wastewater. Continuous experiments indicated that the activity elevation period could be shorten to one third, when the nitrogen removal rate (NRR) reached 1 kg·N/m3·d with vibration. R2 achieved the maximum NRR of 3.3 kg·N/m3·d under the resonance state, which was 1.8 times higher than the control reactor. Analysis of vibration intensity suggested that anammox activity would be great improved with the increasing vibration. These results indicated that vibration played a key role in system performance. Furthermore, high-throughput sequencing showed that the reactor with the vibration had a higher proportion of anammox bacteria, which increased 7 times than the biofilm formation phase. Meanwhile, the proportion of Proteobacteria and Chloroflexi decreased by 37.1% and 7.78%, respectively. These results suggest that vibration could increase the anammox treatment performance and provide a better condition for the anammox bacteria.