Enhancement the wastewater treatment performance of multistage living machine by underwater lamp.

Source separation and decentralized domestic wastewater treatment represent effective strategies to enhance sewage treatment performance and facilitate water reuse economically. The Living Machine (LM) system has gained widespread adoption for decentralized sewage treatment. While underwater light source has been demonstrated to enhance the treatment performance of open aerobic reactors in LM systems, its influence on the treatment efficiency of a fully multistage LM system remains underreported. In this study, an underwater lamp-added LM system (ULLM) with eight reactors was constructed and investigated. The introduction of underwater light source obviously improved the removal capacity of chemical oxygen demand (COD) and NH4+-N, which was 96.1% and 61.6%, respectively. The diversity of algae, zooplankton, and aquatic animals was notably higher in the light-treated reactors than in the control group (CK) without underwater light source, and substantial alteration in the microbial community of the light-treated reactors was observed compared with CK reactors. At the phylum level, Proteobacteria and Nitrospirae enriched in the underwater light-treated reactors, while Bacteroidetes and Actinobacteria exhibited a decrease after light exposure. At the genus level, Nitrospira and Rhodanobacter were enriched in the ULLM system. Importantly, the prevalence of these two dominant genera was sustained until the final operational stage, indicating their potential key roles in enhancing wastewater treatment performance. The addition of underwater light source proves to be an effective strategy for augmenting the treatment efficiency of the multistage living machine systems, resulting in substantial improvements in pollutant removal. These findings contribute valuable insights into optimizing LM systems for decentralized wastewater treatment.

Dynamic nutrient removal potential of a novel submerged macrophyte Rotala rotundifolia, and its growth and physiological response to reduced light available.

Rotala rotundifolia is a novel submerged macrophyte able to survive across the winter under temperature as low as 4 °C. Dynamic nutrient removal potential of R. rotundifolia was estimated using the Eco-tank system simulating natural eutrophic waters. The growth and physiological response of R. rotundifolia by cutting and division propagation to light (100%, 60%, and 20% natural light) were investigated. The results showed that R. rotundifolia was superior in removing N and P from eutrophic waters. As influent concentrations of NH4+-N and total phosphorus (TP) were 4.81-5.87 and 0.61-0.78 mg L-1, effluent concentrations of NH4+-N, total nitrogen (TN), and TP were separately 0.06-1.10, 0.40-1.59, and 0.05-0.17 mg L-1, with removal efficiencies of 93.6%, 84.6%, and 82.5% at a flow rate of 200 L d-1. The growth and morphology of the plant under two propagation patterns were influenced by light and the responses were quite different. The biomass of the plant by cutting was higher at low light conditions, and the plant allocated more biomass on above ground. However, there was no significant difference in the height. By division, the plant preferred to high light. The biomass and height were significantly higher at 100% natural light. The peroxidase (POD), superoxide dismutase (SOD) and root activities of plant by cutting showed a trend of decrease and followed by an increase with light reduction, while by division, they increased with reduced light available. Variations of chlorophyll and soluble protein of the plant by cutting and division were contrary to the changes of POD activity. These results suggest that R. rotundifolia can be used to effectively remove nitrogen and phosphorus in eutrophic waters, and high light promotes the growth of the plant by division, while suitable shade is needed for the plant by cutting.

Mechanisms of 1,4-Dioxane Biodegradation and Adsorption by Bio-Zeolite in the Presence of Chlorinated Solvents: Experimental and Molecular Dynamics Simulation Studies.

The use of bioaugmented zeolite (bio-zeolite) can be an effective technology for irreversibly removing recalcitrant organic pollutants in aqueous mixtures. Removal of 1,4-dioxane by a bio-zeolite (Pseudonocardia dioxanivorans CB1190-bioaugmented ZSM-5) in the presence of several chlorinated volatile organic compounds (CVOCs) was superior to removal by adsorption using abiotic zeolite. Mixtures containing 1,1-dichloroethene (1,1-DCE) were an exception, which completely inhibited the bio-zeolite system. Specific adsorption characteristics were studied using adsorption isotherms in single-solute and bisolute systems accompanied by Polanyi theory-based Dubinin-Astakhov (DA) modeling. Adsorption behavior was examined using characteristic energy (Ea/H) from modified DA models and molecular dynamics simulations. While the tight-fit of 1,4-dioxane in the hydrophobic channels of ZSM-5 appears to drive 1,4-dioxane adsorption, the greater hydrophobicity of trichloroethene and cis-1,2-dichloroethene cause them have a greater affinity over 1,4-dioxane for adsorption sites on the zeolite. 1,4-Dioxane was desorbed and displaced by CVOCs except 1,1-DCE because of its low Ea/H value, explaining why bio-zeolite only biodegraded 1,4-dioxane in 1,1-DCE-free CVOC mixtures. Understanding the adsorption mechanisms of solutes in complex mixtures is crucial for the implementation of sorption-based treatment technologies for the removal of complex contaminant mixtures from aquatic environments.

Influence of metal ions on sulfonamide antibiotics biochemical behavior in fiber coexisting system.

Metal ions and fiber are common compounds in the livestock and poultry manure, which will affect the fate of organic compounds in aqueous environment. However, limited research has addressed the effect of coexisting metal ions and fiber on the biodegradation of sulfonamide antibiotics. Accordingly, a compositing study was performed to assess the effect of metal ions (Fe3+ and Cu2+) on the biodegradation of sulfadimethoxine sodium salt (SDM) in the presence of fiber. The enhanced adsorption of SDM onto fiber in the presence of metal ions can be attributed to the π+-π electron donor acceptor (EDA) interaction. The microbial (Phanerochaete chrysosprium) could easily attach onto fiber forming attached microbial, and the degradation rates of SDM of immobilized bacteria in the presence of Fe3+ were 100%, which were significantly higher than those of free bacteria (45%). This study indicates that Fe3+ and fiber could enhance the biodegradation of SDM. Fiber acts as adsorbent, carrier, and substrate which enhanced the removal of SDM.

Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma.

Somatic mutation of isocitrate dehydrogenase 1 (IDH1) is now recognized as the most common initiating event for secondary glioblastoma, a brain tumor type arising with high frequency in the frontal lobe. A puzzling feature of IDH1 mutation is the selective manifestation of glioma as the only neoplasm frequently associated with early postzygotic occurrence of this genomic alteration. We report here that IDH1(R132H) exhibits a growth-inhibitory effect that is abrogated in the presence of glutamate dehydrogenase 2 (GLUD2), a hominoid-specific enzyme purportedly optimized to facilitate glutamate turnover in human forebrain. Using murine glioma progenitor cells, we demonstrate that IDH1(R132H) exerts a growth-inhibitory effect that is paralleled by deficiency in metabolic flux from glucose and glutamine to lipids. Examining human gliomas, we find that glutamate dehydrogenase 1 (GLUD1) and GLUD2 are overexpressed in IDH1-mutant tumors and that orthotopic growth of an IDH1-mutant glioma line is inhibited by knockdown of GLUD1/2. Strikingly, introduction of GLUD2 into murine glioma progenitor cells reverses deleterious effects of IDH1 mutation on metabolic flux and tumor growth. Further, we report that glutamate, a substrate of GLUD2 and a neurotransmitter abundant in mammalian neocortex, can support growth of glioma progenitor cells irrespective of IDH1 mutation status. These findings suggest that specialization of human neocortex for high glutamate neurotransmitter flux creates a metabolic niche conducive to growth of IDH1 mutant tumors.

Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.

Previously undescribed prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit markers either of proliferation or of angiogenesis and mesenchyme. Upon recurrence, tumors frequently shift toward the mesenchymal subclass. Chromosomal locations of genes distinguishing tumor subclass parallel DNA copy number differences between subclasses. Functional relevance of tumor subtype molecular signatures is suggested by the ability of cell line signatures to predict neurosphere growth. A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.

Synergistic interactions in core microbiome Rhizobiales accelerate 1,4-dioxane biodegradation.

Next-generation sequencing (NGS) has revolutionized taxa identification within contaminant-degrading communities. However, uncovering a core degrading microbiome in diverse polluted environments and understanding its associated microbial interactions remains challenging. In this study, we isolated two distinct microbial consortia, namely MA-S and Cl-G, from separate environmental samples using 1,4-dioxane as a target pollutant. Both consortia exhibited a persistent prevalence of the phylum Proteobacteria, especially within the order Rhizobiales. Extensive analysis confirmed that Rhizobiales as the dominant microbial population (> 90 %) across successive degradation cycles, constituting the core degrading microbiome. Co-occurrence network analysis highlighted synergistic interactions within Rhizobiales, especially within the Shinella and Xanthobacter genera, facilitating efficient 1,4-dioxane degradation. The enrichment of Rhizobiales correlated with an increased abundance of essential genes such as PobA, HpaB, ADH, and ALDH. Shinella yambaruensis emerged as a key degrader in both consortia, identified through whole-genome sequencing and RNA-seq analysis, revealing genes implicated in 1,4-dioxane degradation pathways, such as PobA and HpaB. Direct and indirect co-cultivation experiments confirmed synergistic interaction between Shinella sp. and Xanthobacter sp., enhancing the degradation of 1,4-dioxane within the core microbiome Rhizobiales. Our findings advocate for integrating the core microbiome concept into engineered consortia to optimize 1,4-dioxane bioremediation strategies.

Self-assembling a 1,4-dioxane-degrading consortium and identifying the key role of Shinella sp. through dilution-to-extinction and reculturing.

IMPORTANCE: Assembling a functional microbial consortium and identifying key degraders involved in the degradation of 1,4-dioxane are crucial for the design of synergistic consortia used in enhancing the bioremediation of 1,4-dioxane-contaminated sites. However, due to the vast diversity of microbes, assembling a functional consortium and identifying novel degraders through a simple method remain a challenge. In this study, we reassembled 1,4-dioxane-degrading microbial consortia using a simple and easy-to-operate method by combining dilution-to-extinction and reculture techniques. We combined differential analysis of community structure and metabolic function and confirmed that Shinella species have a stronger 1,4-dioxane degradation ability than Xanthobacter species in the enriched consortium. In addition, a new dioxane-degrading bacterium was isolated, Shinella yambaruensis, which verified our findings. These results demonstrate that DTE and reculture techniques can be used beyond diversity reduction to assemble functional microbial communities, particularly to identify key degraders in contaminant-degrading consortia.

Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice.

BACKGROUND: Vimentin, an intermediate filament protein, crucially contributes to the pathogenesis of inflammatory bowel disease (IBD) by interacting with genetic risk factors, facilitating pathogen infection, and modulating both innate and adaptive immune responses. This study aimed to demonstrate preclinical proof-of-concept for targeting vimentin therapeutically in IBD across diverse etiologies. METHODS: The small molecule compound ALD-R491 was assessed for vimentin binding using microscale thermophoresis, off-target effects via Eurofins screening, and therapeutic effects in mice with dextran sulfate sodium (DSS)-induced acute colitis and in IL-10 KO with spontaneous colitis. Parameters measured included body weight, survival, disease activity, colon length, and histology. The study analyzed intestinal proinflammatory cytokines, Th17/Treg cells, and epithelial barrier molecules, along with gut microbiota profiling. RESULTS: ALD-R491 specifically bound vimentin with a dissociation constant (KD) of 328 ± 12.66 nM and no off-target effects. In the DSS model, orally administered ALD-R491 exhibited dose-dependent therapeutic effects, superior to 5-ASA and Tofacitinib. In the IL-10 KO model, ALD-R491 significantly delayed colitis onset and progression, with near-zero disease activity index scores over a 15-week treatment. ALD-R491 consistently showed in both models a reduced proinflammatory cytokine expression, including TNF-α, IL-1ß, IL-6, IL-17, IL-22, a rebalanced Th17/Treg axis by reducing RORγt while enhancing FoxP3 expression, and an improved epithelial barrier integrity by increasing intestinal expressions of Mucin-2, ZO-1 and Claudin5. The intestinal dysbiosis was restored with enriched presence of probiotics. CONCLUSIONS: Targeting vimentin exhibits significant therapeutic effects on various facets of IBD pathogenesis, representing a compelling approach for the development of highly effective treatments in IBD.

Optimize the Preparation of Novel Pyrite Tailings Based Non-sintered Ceramsite by Plackett-Burman Design Combined With Response Surface Method for Phosphorus Removal.

The large amount of untreated pyrite tailings has caused serious environmental problems, and the recycling of pyrite tailings is considered as an attractive strategy. Here, we reported a novel non-sintered ceramsite prepared with pyrite tailings (PTNC) as the main active raw material for phosphorus control, and the dosage effect of ingredients on total phosphorus (TP) removal ability was investigated. The results from Plackett-Burman Design (PBD) suggested the dosages of dehydrated sludge, sodium bicarbonate, and cement were the factors which significantly affect the TP removal ability. The Box-Behnken Design (BBD) based response surface methodology was further employed, and it indicated the interactions between different factors, and the optimized recipe for PTNC was 84.5 g (pyrite tailings), 10 g (cement), 1 g (calcined lime), 1 g (anhydrous gypsum), 3 g (dehydrated sludge), and 0.5 g (sodium bicarbonate). The optimized PTNC was characterized and which presented much higher specific area (7.21 m2/g) than the standard limitation (0.5 m2/g), as well as a lower wear rate (2.08%) rather than 6%. Additionally, the leaching metal concentrations of PTNC were far below the limitation of Chinese National Standard. The adsorption behavior of TP on PTNC was subsequently investigated with batch and dynamic experiments. It was found that the calculated max adsorption amount (qmax) was about 7 mg/g, and PTNC was able to offer a stable TP removal ability under different hydraulic retention time (HRT). The adsorption mechanism was discussed by model fitting analysis combined with XRD and SEM characterization, and cobalt phosphide sulfide was observed as the newly formed substance through the adsorption process, which suggested the existing of both physical and chemical adsorption effect. Our research not only offered an economic preparation method of ceramsite, but also broadened the recycling pathway of pyrite tailings.

Degradation of 1,4-dioxane by biochar activating peroxymonosulfate under continuous flow conditions.

1,4-Dioxane degradation under both batch-scale and column experiments has been investigated within the biochar activated peroxymonosulfate (PMS) system for in-situ remediation of 1,4-dioxane contaminated groundwater. In case of the batch experiments, the 1,4-dioxane degradation efficiencies were significantly increased with the increased biochar pyrolysis temperatures. The optimized 1,4-dioxane degradation efficiency at 89.2% was achieved with 1.0 g L-1 of biochar (E800) and 8.0 mM PMS. In the absence of PMS, the breakthrough rates of 1,4-dioxane in biochar packed column experiments under the dynamic flow conditions were relatively slow compared with those in sand packed columns. Simultaneously, based on the integrated areas (IA) from the 1,4-dioxane breakthrough curves, the degradation efficiency at 70.2% was estimated in biochar packed column (WE800:WSand = 1:9) under continuous injections of 16.0 mM PMS. Electron paramagnetic resonance (EPR) indicated that hydroxyl, sulfate and superoxide radicals were generated within the biochar/PMS systems and alcohol quenching experiments suggested that the dominated hydroxyl and sulfate radicals were responsible for 1,4-dioxane degradation. The findings of this study suggested that the biochar activated PMS system is a promising and cost-effective strategy for the remediation of 1,4-dioxane contaminated groundwater.

ALD-R491 regulates vimentin filament stability and solubility, cell contractile force, cell migration speed and directionality.

Metastasizing cells express the intermediate filament protein vimentin, which is used to diagnose invasive tumors in the clinic. However, the role of vimentin in cell motility, and if the assembly of non-filamentous variants of vimentin into filaments regulates cell migration remains unclear. We observed that the vimentin-targeting drug ALD-R491 increased the stability of vimentin filaments, by reducing filament assembly and/or disassembly. ALD-R491-treatment also resulted in more bundled and disorganized filaments and an increased pool of non-filamentous vimentin. This was accompanied by a reduction in size of cell-matrix adhesions and increased cellular contractile forces. Moreover, during cell migration, cells showed erratic formation of lamellipodia at the cell periphery, loss of coordinated cell movement, reduced cell migration speed, directionality and an elongated cell shape with long thin extensions at the rear that often detached. Taken together, these results indicate that the stability of vimentin filaments and the soluble pool of vimentin regulate the speed and directionality of cell migration and the capacity of cells to migrate in a mechanically cohesive manner. These observations suggest that the stability of vimentin filaments governs the adhesive, physical and migratory properties of cells, and expands our understanding of vimentin functions in health and disease, including cancer metastasis.

The inhibitory effects of different types of Brassica seed meals on the virulence of Ralstonia solanacearum.

BACKGROUND: Understanding the specific inhibitory effects of different Brassica seed meals (BSMs) on soilborne pathogens is important for their application as biocontrol agents for controlling plant disease. In this study, the seed meals of Brassica napus L. (BnSM), Brassica campestris L. (BcSM), and Brassica juncea L. (BjSM), and the combined seed meal of BcSM and BjSM (CSM, 1:1), were selected for investigation. The inhibitory effects of these seed meals on the plant pathogen Ralstonia solanacearum (Smith) and tomato bacterial wilt, were assessed and compared. RESULTS: All the BSMs significantly inhibited the growth of R. solanacearum in vitro. Furthermore, the BSMs could effectively suppress R. solanacearum virulence traits, including motility, exopolysaccharide production, dehydrogenase activity, virulence-related gene expression, and colonization in the soil. Among them, BjSM showed the best inhibiting effects, and CSM displayed synergic toxicity against R. solanacearum. In addition, the predominant antibacterial compounds in BcSM and BjSM were identified as the volatile compounds, 3-butenyl isothiocyanate and allyl isothiocyanate, respectively. Finally, pot experiment verified that the control effects of BjSM and CSM on tomato wilt reached more than 90%. CONCLUSION: This is the first study to report on the ability of different kinds of BSMs to suppress the virulence of R. solanacearum and biocontrol efficiencies against bacterial wilt in tomato plants. Furtherly, the main antibacterial compounds in the BSMs were identified. The results demonstrated that CSM may possess potential for controlling bacterial wilt caused by R. solanacearum. The results provide a fresh perspective for comprehending the mechanism underlying BSM suppression of pathogens and plant disease.

Biodegradation mechanisms of sulfonamides by Phanerochaete chrysosporium - Luffa fiber system revealed at the transcriptome level.

The overuse of antibiotics and subsequent enrichment of antibiotic resistant microbes in the natural and built environments is a severe threat to global public health. In this study, a Phanerochaete chrysosporium fungal-luffa fiber system was found to efficiently biodegrade two sulfonamides, sulfadimethoxine (SDM) and sulfadizine (SDZ), in cow urine wastewater. Biodegradation pathways were proposed on the basis of key metabolites identified using high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (HPLC-QqTOF-MS). Transcriptomic, metabolomic, and free radical analyses were performed to explore the functional groups and detailed molecular mechanisms of SDM and SDZ degradation. A total of 27 UniGene clusters showed significant differences between luffa fiber and luffa fiber-free systems, which were significantly correlated to cellulose catabolism, carbohydrate metabolism, and oxidoreductase activity. Carbohydrate-active enzymes and oxidoreductases appear to play particularly important roles in SDM and SDZ degradation. Electron paramagnetic resonance (EPR) spectroscopy revealed the generation and evolution of OH and R during the biodegradation of SDM and SDZ, suggesting that beyond enzymatic degradation, SDM and SDZ were also transformed through a free radical pathway. Luffa fiber also acts as a co-substrate to improve the activity of enzymes for the degradation of SDM and SDZ. This research provides a potential strategy for removing SDM and SDZ from agricultural and industrial wastewater using fungal-luffa fiber systems.

Identification of novel 1,4-dioxane degraders and related genes from activated sludge by taxonomic and functional gene sequence analysis.

This study used integrated omics technologies to investigate the potential novel pathways and enzymes for 1,4-dioxane degradation by a consortium enriched from activated sludge of a domestic wastewater treatment plant. An unclassified genus belonging to Xanthobacteraceae increased significantly after magnetic nanoparticle-mediated isolation for 1,4-dioxane degraders. Species with relatively higher abundance (> 0.3%) were identified to present high metabolic activities in the biodegradation process through shotgun sequencing. The functional gene investigations revealed that Xanthobacter sp. 91, Xanthobacter sp. 126, and a Rhizobiales strain carried novel 1,4-dioxane-hydroxylating monooxygenase genes. Xanthobacter sp. 126 contained the genes coding for glycolate oxidase, which was the main enzyme responsible for utilization of 1,4-dioxane intermediates through the TCA cycle, and further proven by the specific glycolate oxidase inhibitor, α-hydroxy-2-pyridinemethanesulfonic acid. An expanded and detailed degradation pathway of 1,4-dioxane was proposed on the basis of the three major intermediates (2-hydroxy-1,4-dioxane, ethylene glycol, and oxalic acid) confirmed by metabolomics. These findings of microbial community and function as well as the novel pathway will be valuable in predicting natural attenuation or reconstruction of a bacterial consortium for enhanced remediation of 1,4-dioxane-contaminated sites as well as wastewater treatment.

A Small Vimentin-Binding Molecule Blocks Cancer Exosome Release and Reduces Cancer Cell Mobility.

Vimentin is an intermediate filament protein with diverse roles in health and disease far beyond its structural functions. Exosomes or small extracellular vesicles (sEVs) are key mediators for intercellular communication, contributing to tissue homeostasis and the progression of various diseases, especially the metastasis of cancers. In this study, we evaluated a novel vimentin-binding compound (R491) for its anti-cancer activities and its roles in cancer exosome release. The compound R491 induced a rapid and reversible intracellular vacuolization in various types of cancer cells. This phenotype did not result in an inhibition of cancer cell growth, which was consistent with our finding from a protein array that R491 did not reduce levels of major oncoproteins in cancer cells. Morphological and quantitative analyses on the intracellular vacuoles and extracellular exosomes revealed that in response to R491 treatment, the exosomes released from the cells were significantly reduced, while the exosomes retained as intra-luminal vesicles inside the cells were subsequently degraded. Vim+/- cells had lower amounts of vimentin and accordingly, lower amounts of both the retained and the released exosomes than Vim+/+ cells had, while the vimentin-binding compound R491 inhibited only the release of exosomes. Further functional tests showed that R491 significantly reduced the migration and invasion of cancer cells in vitro and decreased the amount of exosome in the blood in mice. Our study suggests that vimentin promotes exosome release, and small-molecule compounds that target vimentin are able to both block cancer exosome release and reduce cancer cell motility, and therefore could have potential applications for inhibiting cancer invasive growth.

SARs of a novel series of s-triazine compounds targeting vimentin to induce methuotic phenotype.

Herein, we describe the design, synthesis and structure-activity relationships of a series of novel s-triazine compounds can induce methuotic phenotype in various types of cancer cells. (E)-1-(4-Chlorophenyl)-3-(4-((4-morpholino-6-styryl-1,3,5-triazine-2-yl)amino)phenyl)urea, compound V6, exhibited a striking methuotic phenotype with a minimal effective concentration of less than 10 nM in U87 glioblastoma cells. Based on structure-activity relationship studies, we designed and synthesized an active probe P1 that retained the full potential of V6 in inducing the methuotic phenotype in U87 glioblastoma cells. Using this probe following affinity-based proteomic profiling strategy, we identified vimentin as the specific target protein of compound V6. Molecular docking revealed that V6 can form hydrogen bonds with vimentin at 273R and 276Y in its rod domain.

A Vimentin-Targeting Oral Compound with Host-Directed Antiviral and Anti-Inflammatory Actions Addresses Multiple Features of COVID-19 and Related Diseases.

Damage in COVID-19 results from both the SARS-CoV-2 virus and its triggered overactive host immune responses. Therapeutic agents that focus solely on reducing viral load or hyperinflammation fail to provide satisfying outcomes in all cases. Although viral and cellular factors have been extensively profiled to identify potential anti-COVID-19 targets, new drugs with significant efficacy remain to be developed. Here, we report the potent preclinical efficacy of ALD-R491, a vimentin-targeting small molecule compound, in treating COVID-19 through its host-directed antiviral and anti-inflammatory actions. We found that by altering the physical properties of vimentin filaments, ALD-491 affected general cellular processes as well as specific cellular functions relevant to SARS-CoV-2 infection. Specifically, ALD-R491 reduced endocytosis, endosomal trafficking, and exosomal release, thus impeding the entry and egress of the virus; increased the microcidal capacity of macrophages, thus facilitating the pathogen clearance; and enhanced the activity of regulatory T cells, therefore suppressing the overactive immune responses. In cultured cells, ALD-R491 potently inhibited the SARS-CoV-2 spike protein and human ACE2-mediated pseudoviral infection. In aged mice with ongoing, productive SARS-CoV-2 infection, ALD-R491 reduced disease symptoms as well as lung damage. In rats, ALD-R491 also reduced bleomycin-induced lung injury and fibrosis. Our results indicate a unique mechanism and significant therapeutic potential for ALD-R491 against COVID-19. We anticipate that ALD-R491, an oral, fast-acting, and non-cytotoxic agent targeting the cellular protein with multipart actions, will be convenient, safe, and broadly effective, regardless of viral mutations, for patients with early- or late-stage disease, post-COVID-19 complications, and other related diseases. IMPORTANCE With the Delta variant currently fueling a resurgence of new infections in the fully vaccinated population, developing an effective therapeutic drug is especially critical and urgent in fighting COVID-19. In contrast to the many efforts to repurpose existing drugs or address only one aspect of COVID-19, we are developing a novel agent with first-in-class mechanisms of action that address both the viral infection and the overactive immune system in the pathogenesis of the disease. Unlike virus-directed therapeutics that may lose efficacy due to viral mutations, and immunosuppressants that require ideal timing to be effective, this agent, with its unique host-directed antiviral and anti-inflammatory actions, can work against all variants of the virus, be effective during all stages of the disease, and even resolve post-disease damage and complications. Further development of the compound will provide an important tool in the fight against COVID-19 and its complications, as well as future outbreaks of new viruses.

Aqua-[1,3-bis-(benzimidazol-2-yl)-2-oxapropane]-diethano-lmanganese(II) dipicrate ethanol disolvate.

In the title complex, [Mn(C(16)H(14)N(4)O)(C(2)H(5)OH)(2)(H(2)O)](C(6)H(2)N(3)O(7))(2)·2C(2)H(5)OH, the Mn(II) ion is in a distorted octa-hedral coordination environment, defined by an MnN(2)O(4) donor set. The 1,3-bis-(benz-imid-azol-2-yl)-2-oxapropane ligand is tridentate. In the crystal structure, inter-molecular N-H⋯O and O-H⋯O hydrogen bonds link the components into a three-dimensional network. The O atoms of one of the nitro groups are disordered over two sets of sites with refined occupancies of 0.577 (11) and 0.423 (11).

Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation.

Mutations in isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) are found in a subset of gliomas. Among the many phenotypic differences between mutant and wild-type IDH1/2 gliomas, the most salient is that IDH1/2 mutant glioma patients demonstrate markedly improved survival compared with IDH1/2 wild-type glioma patients. To address the mechanism underlying the superior clinical outcome of IDH1/2 mutant glioma patients, we investigated whether overexpression of the IDH1(R132H) protein could affect response to therapy in the context of an isogenic glioma cell background. Stable clonal U87MG and U373MG cell lines overexpressing IDH1(WT) and IDH1(R132H) were generated, as well as U87MG cell lines overexpressing IDH2(WT) and IDH2(R172K). In vitro experiments were conducted to characterize baseline growth and migration and response to radiation and temozolomide. In addition, reactive oxygen species (ROS) levels were measured under various conditions. U87MG-IDH1(R132H) cells, U373MG-IDH1(R132H) cells, and U87MG-IDH2(R172K) cells demonstrated increased sensitivity to radiation but not to temozolomide. Radiosensitization of U87MG-IDH1(R132H) cells was accompanied by increased apoptosis and accentuated ROS generation, and this effect was abrogated by the presence of the ROS scavenger N-acetyl-cysteine. Interestingly, U87MG-IDH1(R132H) cells also displayed decreased growth at higher cell density and in soft agar, as well as decreased migration. Overexpression of IDH1(R132H) and IDH2(R172K) mutant protein in glioblastoma cells resulted in increased radiation sensitivity and altered ROS metabolism and suppression of growth and migration in vitro. These findings provide insight into possible mechanisms contributing to the improved outcomes observed in patients with IDH1/2 mutant gliomas.