Using UV/peracetic acid as pretreatment for subsequent bio-treatment of antibiotic-containing wastewater treatment: Mitigating microbial inhibition and antibiotic resistance genes proliferation.

UV/peracetic acid (PAA) treatment presents a promising approach for antibiotic removal, but its effects on microbial community and proliferation of antibiotic resistance genes (ARGs) during the subsequent bio-treatment remain unclear. Thus, we evaluated the effects of the UV/PAA on tetracycline (TTC) degradation, followed by introduction of the treated wastewater into the bio-treatment system to monitor changes in ARG expression and biodegradability. Results demonstrated effective TTC elimination by the UV/PAA system, with carbon-centered radicals playing a significant role. Crucially, the UV/PAA system not only eliminated antibacterial activity but also inhibited potential ARG host growth, thereby minimizing the emergence and dissemination of ARGs during subsequent bio-treatment. Additionally, the UV/PAA system efficiently removed multi-antibiotic resistant bacteria and ARGs from the bio-treatment effluent, preventing ARGs from being released into the environment. Hence, we propose a multi-barrier strategy for treating antibiotic-containing wastewater, integrating UV/PAA pre-treatment and post-disinfection with bio-treatment. The inhibition of ARGs transmission by the integrated system was verified through actual soil testing, confirming its effectiveness in preventing ARGs dissemination in the surrounding natural ecosystem. Overall, the UV/PAA treatment system offers a promising solution for tackling ARGs challenges by controlling ARGs proliferation at the source and minimizing their release at the end of the treatment process.

Predicting the Posture of High-Rise Building Machines Based on Multivariate Time Series Neural Network Models.

High-rise building machines (HBMs) play a critical role in the successful construction of super-high skyscrapers, providing essential support and ensuring safety. The HBM's climbing system relies on a jacking mechanism consisting of several independent jacking cylinders. A reliable control system is imperative to maintain the smooth posture of the construction steel platform (SP) under the action of the jacking mechanism. Long Short-Term Memory (LSTM), Gated Recurrent Unit (GRU), and Temporal Convolutional Network (TCN) are three multivariate time series (MTS) neural network models that are used in this study to predict the posture of HBMs. The models take pressure and stroke measurements from the jacking cylinders as inputs, and their outputs determine the levelness of the SP and the posture of the HBM at various climbing stages. The development and training of these neural networks are based on historical on-site data, with the predictions subjected to thorough comparative analysis. The proposed LSTM and GRU prediction models have similar performances in the prediction process of HBM posture, with medians R2 of 0.903 and 0.871, respectively. However, the median MAE of the GRU prediction model is more petite at 0.4, which exhibits stronger robustness. Additionally, sensitivity analysis showed that the change in the levelness of the position of the SP portion of the HBM exhibited high sensitivity to the stroke and pressure of the jacking cylinder, which clarified the position of the cylinder for adjusting the posture of the HBM. The results show that the MTS neural network-based prediction model can change the HBM posture and improve work stability by adjusting the jacking cylinder pressure value of the HBM.

Hair cell-specific Myo15 promoter-mediated gene therapy rescues hearing in DFNB9 mouse model.

Adeno-associated viral (AAV) vectors are increasingly used as vehicles for gene delivery to treat hearing loss. However, lack of specificity of the transgene expression may lead to overexpression of the transgene in nontarget tissues. In this study, we evaluated the expression efficiency and specificity of transgene delivered by AAV-PHP.eB under the inner ear sensory cell-specific Myo15 promoter. Compared with the ubiquitous CAG promoter, the Myo15 promoter initiates efficient expression of the GFP fluorescence reporter in hair cells, while minimizing non-specific expression in other cell types of the inner ear and CNS. Furthermore, using the Myo15 promoter, we constructed an AAV-mediated therapeutic system with the coding sequence of OTOF gene. After inner ear injection, we observed apparent hearing recovery in Otof-/- mice, highly efficient expression of exogenous otoferlin, and significant improvement in the exocytosis function of inner hair cells. Overall, our results indicate that gene therapy mediated by the hair cell-specific Myo15 promoter has potential clinical application for the treatment of autosomal recessive deafness and yet for other hereditary hearing loss related to dysfunction of hair cells.

Electrochemically Exfoliated Graphene Additive-Free Inks for 3D Printing Customizable Monolithic Integrated Micro-Supercapacitors on a Large Scale.

Three-dimensional (3D) printing technology with enhanced fidelity can achieve multiple functionalities and boost electrochemical performance of customizable planar micro-supercapacitors (MSCs), however, precise structural control of additive-free graphene-based macro-assembly electrode for monolithic integrated MSCs (MIMSCs) remains challenging. Here, the large-scale 3D printing fabrication of customizable planar MIMSCs is reported utilizing additive-free, high-quality electrochemically exfoliated graphene inks, which is not required the conventional cryogenic assistance during the printing process and any post-processing reduction. The resulting MSCs reveal an extremely small engineering footprint of 0.025 cm2 , exceptionally high areal capacitance of 4900 mF cm-2 , volumetric capacitance of 195.6 F cm-3 , areal energy density of 2.1 mWh cm-2 , and unprecedented volumetric energy density of 23 mWh cm-3 for a single cell, surpassing most previously reported 3D printed MSCs. The 3D printed MIMSC pack is further demonstrated, with the maximum areal cell count density of 16 cell cm-2 , the highest output voltage of 192.5 V and the largest output voltage per unit area of 56 V cm-2 up to date are achieved. This work presents an innovative solution for processing high-performance additive-free graphene ink and realizing the large-scale production of 3D printed MIMSCs for planar energy storage.

Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.

Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.

AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial.

BACKGROUND: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. METHODS: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. FINDINGS: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. INTERPRETATION: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.

Thrombospondin 2 is a novel biomarker of essential hypertension and associated with nocturnal Na+ excretion and insulin resistance.

BACKGROUND: Thrombospondins (TSPs) play important roles in several cardiovascular diseases. However, the association between circulating (plasma) thrombospondin 2 (TSP2) and essential hypertension remains unclear. The present study was aimed to investigate the association of circulating TSP2 with blood pressure and nocturnal urine Na+ excretion and evaluate the predictive value of circulating TSP2 in subjects with hypertension. METHODS AND RESULTS: 603 newly diagnosed essential hypertensive subjects and 508 healthy subjects were preliminarily screened, 47 healthy subjects and 40 newly diagnosed essential hypertensive subjects without any chronic diseases were recruited. The results showed that the levels of circulating TSP2 were elevated in essential hypertensive subjects. The levels of TSP2 positively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and other clinical parameters, including homeostasis model assessment of insulin resistance (HOMA-IR), brachial-ankle pulse wave velocity, and serum triglycerides, but negatively associated with nocturnal urine Na+ concentration and excretion and high-density lipoprotein cholesterol. Results of multiple linear regressions showed that HOMA-IR and nocturnal Na+ excretion were independent factors related to circulating TSP2. Mantel-Haenszel chi-square test displayed linear relationships between TSP2 and SBP (χ2 = 35.737) and DBP (χ2 = 26.652). The area under receiver operating characteristic curve (AUROC) of hypertension prediction was 0.901. CONCLUSION: Our study suggests for the first time that the circulating levels of TSP2 may be a novel potential biomarker for essential hypertension. The association between TSP2 and blood pressure may be, at least in part, related to the regulation of renal Na+ excretion, insulin resistance, and/or endothelial function.

Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and nonhuman primates.

Pathogenic mutations in the OTOF gene cause autosomal recessive hearing loss (DFNB9), one of the most common forms of auditory neuropathy. There is no biological treatment for DFNB9. Here, we designed an OTOF gene therapy agent by dual-adeno-associated virus 1 (AAV1) carrying human OTOF coding sequences with the expression driven by the hair cell-specific promoter Myo15, AAV1-hOTOF. To develop a clinical application of AAV1-hOTOF gene therapy, we evaluated its efficacy and safety in animal models using pharmacodynamics, behavior, and histopathology. AAV1-hOTOF inner ear delivery significantly improved hearing in Otof-/- mice without affecting normal hearing in wild-type mice. AAV1 was predominately distributed to the cochlea, although it was detected in other organs such as the CNS and the liver, and no obvious toxic effects of AAV1-hOTOF were observed in mice. To further evaluate the safety of Myo15 promoter-driven AAV1-transgene, AAV1-GFP was delivered into the inner ear of Macaca fascicularis via the round window membrane. AAV1-GFP transduced 60%-94% of the inner hair cells along the cochlear turns. AAV1-GFP was detected in isolated organs and no significant adverse effects were detected. These results suggest that AAV1-hOTOF is well tolerated and effective in animals, providing critical support for its clinical translation.

Computer Vision Interaction Design in Sustainable Urban Development: A Case Study of Roof Garden Landscape Plants in Marine Cities.

The rapid urbanization and the increasing need for sustainable development have led to the emergence of green roof landscapes in ocean cities. These rooftop gardens provide numerous environmental benefits and contribute to the overall well-being of urban dwellers. However, optimizing the design and interaction experience of green roof landscapes requires the integration of intelligent technologies. This paper explores the application of computer visual design techniques, specifically 3DMAX modeling and virtual reality, in the intelligent interaction design of green roof landscape plants in ocean cities. Designers can use computer visual design (3DMAX) and other technologies to interact intelligently with the roof landscape in order to improve landscape design. Through case studies, this indicated that computer vision is excellent for image processing of rooftop landscapes and also demonstrates a high degree of compatibility between computer vision and green rooftop landscape plant design in marine cities. This paper highlights the significance of intelligent interaction design and computer visual design techniques in optimizing the integration of green roof landscape plants in ocean cities. It emphasizes the potential of 3DMAX modeling and VR technology in creating immersive and engaging experiences for designers, users, and stakeholders alike. The findings contribute to the growing body of knowledge in the field of sustainable urban development and provide insights for designers, policymakers, and researchers seeking to enhance green roof landscapes in ocean cities. The dissertation highlights the potential of using computer vision design techniques to enhance the roof garden landscaping process and advocates for more efficient and effective ways to design, visualize, and improve rooftop gardens by utilizing software equipped with computer vision technology such as 3DMAX, ultimately contributing to the advancement of sustainable urban landscapes.

Phosphorus recovery from sewage sludge ash (SSA): An integrated technical, environmental and economic assessment of wet-chemical and thermochemical methods.

Incineration is a promising disposal method for sewage sludge (SS), enriching more than 90% of phosphorus (P) in the influent into the powdered product, sewage sludge ash (SSA), which is convenient for further P recovery. Due to insufficient bioavailable P and enriched heavy metals (HMs) in SSA, it is limited to be used directly as fertilizer. Hence, this paper provides an overview of P transformation in SS incineration, characterization of SSA components, and wet-chemical and thermochemical processes for P recovery with a comprehensive technical, economic, and environmental assessment. P extraction and purification is an important technical step to achieve P recovery from SSA, where the key to all technologies is how to achieve efficient separation of P and HMs at a low economic and environmental cost. It can be clear seen from the review that the economics of P recovery from SSA are often weak due to many factors. For example, the cost of wet-chemical methods is approximately 5∼6 €/kg P, while the cost of recovering P by thermochemical methods is about 2∼3 €/kg P, which is slightly higher than the current P fertilizer (1 €/kg P). So, for now, legislation is significant for promoting P recovery from SSA. In this regard, the relevant experience in Europe is worth learning from countries that have not yet carried out P recovery from SSA, and to develop appropriate policies and legislation according to their own national conditions.

Peracetic acid disinfection induces antibiotic-resistant E. coli into VBNC state but ineffectively eliminates the transmission potential of ARGs.

The occurrence of a viable but nonculturable (VBNC) state in antibiotic-resistant E. coli (AR E. coli) and inefficient degradation of their antibiotic resistance genes (ARGs) may cause potential health risks during disinfection. Peracetic acid (PAA) is an alternative disinfectant for replacing chlorine-based oxidants in wastewater treatment, and the potential of PAA to induce a VBNC state in AR E. coli and to remove the transformation functionality of ARGs were investigated for the first time. Results show that PAA exhibits excellent performance in inactivating AR E. coli (over 7.0-logs) and persistently inhibiting its regeneration. After PAA disinfection, insignificant changes in the ratio of living to dead cells (∼4%) and the level of cell metabolism, indicating that AR E. coli were induced into VBNC states. Unexpectedly, PAA was found to induce AR E. coli into VBNC state by destroying the proteins containing reactive amino acids at thiol, thioether and imidazole groups, rather than the result of membrane damage, oxidative stress, lipid destruction and DNA disruption in the conventional disinfection processes. Moreover, the result of poor reactivity between PAA and plasmid strands and bases confirmed that PAA hardly reduced the abundance of ARGs and damaged the plasmid's integrity. Transformation assays and real environment validation indicated that PAA-treated AR E. coli could release large abundance of naked ARGs with high-efficiency transformation functionality (∼5.4 × 10-4 - ∼8.3 × 10-6) into the environment. This study has significant environmental implications for assessing the transmission of antimicrobial resistance during PAA disinfection.

Who does better for in-situ eutrophic remediation in anoxic environment improvement and nutrient removal: MgO2 versus CaO2.

The long-term insufficient dissolved oxygen (DO), excessive nitrogen (N) and phosphorus (P) have become the main causes of the troublesome eutrophication. Herein, a 20-day sediment core incubation experiment was conducted to comprehensively evaluate the effects of two metal-based peroxides (MgO2 and CaO2) on eutrophic remediation. Results indicated that CaO2 addition could increase DO and ORP of the overlying water more effectively and improve the anoxic environment of the aquatic ecosystems. However, the addition of MgO2 had a less impact on pH of the water body. Furthermore, the addition of MgO2 and CaO2 removed 90.31% and 93.87% of continuous external P in the overlying water respectively, while the removal of NH4+ was 64.86% and 45.89%, and the removal of TN was 43.08% and 19.16%. The reason why the capacity on NH4+ removal of MgO2 was higher than that of CaO2 is mainly that PO43- and NH4+ can be removed as struvite by MgO2. Compared with MgO2, mobile P of the sediment in CaO2 addition group was reduced obviously and converted to more stable P. Notably, the microbial community structure of sediments was optimized by MgO2 and CaO2, which showed that the relative abundance of anaerobic bacteria decreased and that of aerobic bacteria increased significantly, especially some functional bacteria involved in the nutrient cycle. Taken together, MgO2 and CaO2 have a promising application prospect in the field of in-situ eutrophication management.

[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.

Multimodal Interaction of MU Plant Landscape Design in Marine Urban Based on Computer Vision Technology.

At present, there is a growing focus on the landscape and environment of ocean cities, with an increasing demand for improved ecological sustainability and aesthetic appeal. With the emergence of computer vision design technologies such as 3D and VR, people have overcome the limitations of traditional paper-based design materials. Through the use of computer software, various forms of expression, such as drawings and animations, can be produced, thereby meeting the diverse demands for showcasing plant landscapes. The purpose of this paper is to study the design of marine urban (MU) botanical landscapes based on computer vision technology (CVT) and multimodal interaction design (MID) theory, so that the design of MU botanical landscape can meet people's psychological behavior and visual needs, and at the same time enable people to participate in and experience the landscape, so as to better meet people's needs for viewing, leisure, and entertainment. At the same time, it is hoped that the research of this paper will play a role in promoting the innovation and development of the concept of MU landscape design (LD) in the future, specifically from two levels of theoretical and practical significance. First, at the level of theoretical research: Based on the theory of MID, this paper explores the application of communication and interaction among humans and between humans and the landscape in the design of MU planting, and tries to explore and summarize the content and methods of interactive LD in marine cities with a theoretical basis and research value. The goal is to both enhance the theoretical level of interactive LD, and also provide new reference for future marine city (MC) LD. Second, at the level of practical application: In the field of LD, the new concept of computer vision is introduced to fully understand the visual needs of people and increase the practicality and pleasantness of the MU landscape, hoping to attract more people to come to play and rest. Through the attraction of MU landscapes to tourists, the design and construction of the landscape no longer focus on its appearance, but rather on the participation and experience of people.

Melanin precursors mediated adaption to temperature changes in fungus and animal via inhibition of lipid-mediated ferroptosis.

The discovery of biological activities of natural products plays a vital part in drug development. The mechanism by which organisms respond to temperature changes via biosynthesis of natural products remained largely cryptic. A thermophilic fungus under cold stress turned black and accumulated a polyketide metabolite 1 and lipid mass. Deficiency in 1 caused melanin loss and accumulated extra lipid mass, unexpectedly leading to seriously damaged mitochondria diagnostic for ferroptosis. Further analysis revealed that lipid mass induced by cold stress intensively increased ferroptosis risk and 1 functioned as cell wall reinforcer against mass lipid accumulation and as reactive oxygen species scavenger against lipid peroxidation. We also found that melanin in mice lowered lipid level but enhanced animal resistance to cold stress. Treatment with melanin precursors significantly increased mouse cell survival rate under cold stress. Our results unveiled a metabolite-lipid-ferroptosis-cold relationship, which provided mechanistic insights into the functions of most common metabolites and into diseases related to cold stress. These findings opened a perspective for developing anti-cold and anti-ferroptosis therapeutics and agents.

Polaron induced local spin texture and anomalous Hall effect in the quadrilateral prism-shaped nanotube with Rashba and Dresselhaus spin-orbit coupling.

We theoretically study the spin-texture dynamics and the transverse asymmetric charge deflection induced by the polaron in a quadrilateral prism-shaped nanotube with the Rashba and Dresselhaus spin-orbit coupling (SOC). We reveal the polaron gives rise to the nontrivial local spin textures in the nanotube within the cross section plane. The spins demonstrate oscillations and the oscillating patterns are dependent on the SOC type. For the nanotube containing a segment of the ferromagnetic domain, the sizable asymmetric charge deflections could additionally take place, namely, the anomalous Hall effect. The amount of the deflected charges is determined by the strength and orientations of the ferromagnetic magnetization as well as the SOC type. The work provides a valuable insight of the coherent transport of polaron through a quasi-one-dimensional nanotube with Rashba and Dresselhaus SOC and open avenues for the potential device applications.

Selective ischemic-hemisphere targeting Ginkgolide B liposomes with improved solubility and therapeutic efficacy for cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion injury (CI/RI) remains the main cause of disability and death in stroke patients due to lack of effective therapeutic strategies. One of the main issues related to CI/RI treatment is the presence of the blood-brain barrier (BBB), which affects the intracerebral delivery of drugs. Ginkgolide B (GB), a major bioactive component in commercially available products of Ginkgo biloba, has been shown significance in CI/RI treatment by regulating inflammatory pathways, oxidative damage, and metabolic disturbance, and seems to be a candidate for stroke recovery. However, limited by its poor hydrophilicity and lipophilicity, the development of GB preparations with good solubility, stability, and the ability to cross the BBB remains a challenge. Herein, we propose a combinatorial strategy by conjugating GB with highly lipophilic docosahexaenoic acid (DHA) to obtain a covalent complex GB-DHA, which can not only enhance the pharmacological effect of GB, but can also be encapsulated in liposomes stably. The amount of finally constructed Lipo@GB-DHA targeting to ischemic hemisphere was validated 2.2 times that of free solution in middle cerebral artery occlusion (MCAO) rats. Compared to the marketed ginkgolide injection, Lipo@GB-DHA significantly reduced infarct volume with better neurobehavioral recovery in MCAO rats after being intravenously administered both at 2 h and 6 h post-reperfusion. Low levels of reactive oxygen species (ROS) and high neuron survival in vitro was maintained via Lipo@GB-DHA treatment, while microglia in the ischemic brain were polarized from the pro-inflammatory M1 phenotype to the tissue-repairing M2 phenotype, which modulate neuroinflammatory and angiogenesis. In addition, Lipo@GB-DHA inhibited neuronal apoptosis via regulating the apoptotic pathway and maintained homeostasis by activating the autophagy pathway. Thus, transforming GB into a lipophilic complex and loading it into liposomes provides a promising nanomedicine strategy with excellent CI/RI therapeutic efficacy and industrialization prospects.

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.

Tryptophan-centered metabolic alterations coincides with lipid-mediated fungal response to cold stress.

Tryptophan and its derived metabolites have been assumed to play important roles in the development and survival of organisms. However, the links of tryptophan and its derived metabolites to temperature change remained largely cryptic. Here we presented that a class of prenyl indole alkaloids biosynthesized from tryptophan dramatically accumulated in thermophilic fungus Thermomyces dupontii under cold stress, in which lipid droplets were also highly accumulated and whose conidiophores were highly build-up. Concurrently, disruption of the key NRPS gene involved in the biosynthesis of prenyl indole alkaloids, resulted in decreased lipid and shrunken mitochondria but enlarged vacuoles. Moreover, the Fe3+ and superoxide levels in ΔNRPS were significantly increased but the reactive oxygen species lipid peroxidation and autophagy levels decreased. Metabolomics study revealed that most enriched metabolites in ΔNRPS were mainly composed of tryptophan degraded metabolites including well known ROS scavenger kynurenamines, and lipid-inhibitors, anthranilic acid and indoleacetic acid, and free radical reaction suppressor free fatty acids. Transcriptomic analysis suggested that the key gene involved in tryptophan metabolism, coinciding with the lipid metabolic processes and ion transports were most up-regulated in ΔNRPS under stress. Our results confirmed a lipid-mediated fungal response to cold stress and unveiled a link of tryptophan-based metabolic reprogramming to the fungal cold adaption.

Co-Mn spinel oxides trigger peracetic acid activation for ultrafast degradation of sulfonamide antibiotics: Unveiling critical role of Mn species in boosting Co activity.

Activation of peracetic acid (PAA) to generate powerful oxidizing species has become a promising advanced oxidation processes (AOPs) in wastewater treatment, yet the development of low-cost and high-performance activators is still a primary challenge. Herein, a range of Co-Mn spinel oxides (Co3-xMnxO4) with varying levels of Co and Mn were successfully elaborated, in which Co1.1Mn1.9O4 exhibited remarkable performance in PAA activation, outperforming most reported heterogeneous catalysts. Extensive quenching experiments and electron spin resonance (ESR) analysis indicated that acetylperoxyl radical (CH3C(O)OO●) was the predominated oxidizing species responsible for sulfamethoxazole (SMX) degradation. Density functional theory (DFT) calculations revealed that doping with Mn not only promoted the electron transfer and accelerated reduction of Co(III) to Co(II), but also lowered the energy barrier for PAA activation. Moreover, the prominent chemisorption and activation of PAA with Co1.1Mn1.9O4 was also benefitted from the significant role of Mn in optimizing the distribution of bonding and antibonding states on Co 3d orbitals. Unexpectedly, high levels of Cl-greatly facilitated SMX degradation due to the mass production of HOCl from the chain reactions of various radicals with Cl-. This work provides new insights into bimetallic activation of PAA, and the knowledge obtained will further advance the application of PAA-based AOPs.