Cycloaddition of Phenyltriazolinedione with Carbazole-Alkynes and Yne-Carbamates to Access Diazacyclobutenes.

Previously, we described the synthesis of stable, bicyclic examples of the rather rare diazacyclobutene (DCB) motif by means of a cycloaddition between triazolinediones and electron-rich thiolated alkynes. Here, we report the investigation of the cycloaddition of triazolinediones with related electron-rich yne-carbamates and carbazole-alkynes. Bicyclic DCBs arising from yne-carbamates were isolated in 8-65% yield, while those arising from carbazole-alkynes were isolated in 28-59% yield. Mechanistic studies and characterization of isolable byproducts shed light on the underlying issues leading to poor to moderate yields.

Enolase inhibitors as therapeutic leads for Naegleria fowleri infection.

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate that these agents are potent inhibitors of N. fowleri ENO ( Nf ENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC 50 value of 0.14 ± 0.04 µM) that was toxic to trophozoites (EC 50 value of 0.21 ± 0.02 µM) while the reported CC 50 was >300 µM. Molecular docking simulation revealed that HEX binds strongly to the active site of Nf ENO with a binding affinity of -8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream of Nf ENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the conclusion of the experiment, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. Brains of six of the eight survivors were positive for amoebae, suggesting the agent at the tested dose suppressed, but did not eliminate, infection. These findings suggest that HEX is a promising lead for the treatment of PAM.

Glucose metabolism in the pathogenic free-living amoebae: Tempting targets for treatment development.

Pathogenic free-living amoebae (pFLA) are single-celled eukaryotes responsible for causing intractable infections with high morbidity and mortality in humans and animals. Current therapeutic approaches include cocktails of antibiotic, antifungal, and antimicrobial compounds. Unfortunately, the efficacy of these can be limited, driving the need for the discovery of new treatments. Pan anti-amebic agents would be ideal; however, identifying these agents has been a challenge, likely due to the limited evolutionary relatedness of the different pFLA. Here, we discuss the potential of targeting amoebae glucose metabolic pathways as the differences between pFLA and humans suggest specific inhibitors could be developed as leads for new therapeutics.

Enhancing drug delivery with supramolecular amphiphilic macrocycle nanoparticles: selective targeting of CDK4/6 inhibitor palbociclib to melanoma.

Drug delivery systems based on amphiphilic supramolecular macrocycles have garnered increased attention over the past two decades due to their ability to successfully formulate nanoparticles. Macrocyclic (MC) materials can self-assemble at lower concentrations without the need for surfactants and polymers, but surfactants are required to form and stabilize nanoparticles at higher concentrations. Using MCs to deliver both hydrophilic and hydrophobic guest molecules is advantageous. We developed two novel types of amphiphilic macrocycle nanoparticles (MC NPs) capable of delivering either Nile Red (NR) (a hydrophobic model) or Rhodamine B (RhB) (a hydrophilic model) fluorescent dyes. We extensively characterized the materials using various techniques to determine size, morphology, stability, hemolysis, fluorescence, loading efficiency (LE), and loading capacity (LC). We then loaded the CDK4/6 inhibitor Palbociclib (Palb) into both MC NPs using a solvent diffusion method. This yielded Palb-MC NPs in the size range of 65-90 nm. They exhibited high stability over time and in fetal bovine serum with negligible toxicity against erythrocytes. Cytotoxicity was minimal when tested against RAW macrophages, human fibroblast HDFn, and adipose stromal cells (ASCs) at higher concentrations of MC NPs. Cell viability studies were conducted with different concentrations of MC NPs, Palb-MC NPs, and free Palb against RAW macrophages, human U-87 GBM, and human M14 melanoma cell lines in vitro. Flow cytometry experiments revealed that blank MC NPs and Palb-MC NPs were selectively targeted to melanoma cells, resulting in cell death compared to the other two cell lines. Future work will focus on studying the biological effect of MC NPs including their binding affinity with molecules/receptors expressed on the M14 and other melanoma cell surfaces by molecular docking simulations. Subsequently, we will evaluate the MCs as a component of combination therapy in a murine melanoma model.

Enhancing Drug Delivery with Supramolecular Amphiphilic Macrocycle Nanoparticles: Selective Targeting of CDK4/6 Inhibitor Palbociclib to Melanoma.

Drug delivery systems based on amphiphilic supramolecular macrocycles have garnered increased attention over the past two decades due to their ability to successfully formulate nanoparticles. Macrocyclic (MC) materials can self-assemble at lower concentrations without the need for surfactants and polymers, but surfactants are required to form and stabilize nanoparticles at higher concentrations. Using MCs to deliver both hydrophilic and hydrophobic guest molecules is advantageous. We developed two novel types of amphiphilic macrocycle nanoparticles (MC NPs) capable of delivering either Nile Red (NR) (a hydrophobic model) or Rhodamine B (RhB) (a hydrophilic model) fluorescent dyes. We extensively characterized the materials using various techniques to determine size, morphology, stability, hemolysis, fluorescence, loading efficiency (LE), and loading capacity (LC). We then loaded the CDK4/6 inhibitor Palbociclib (Palb) into both MC NPs using a solvent diffusion method. This yielded Palb-MC NPs in the size range of 65-90 nm. They exhibited high stability over time and in fetal bovine serum with negligible toxicity against erythrocytes. Cytotoxicity was minimal when tested against RAW macrophages, human fibroblast HDFn , and adipose stromal cells (ASCs) at higher concentrations of MC NPs. Cell viability studies were conducted with different concentrations of MC NPs, Palb-MC NPs, and free Palb against RAW macrophages, human U-87 GBM, and human M14 melanoma cell lines in vitro. Flow cytometry experiments revealed that blank MC NPs and Palb-MC NPs were selectively targeted to melanoma cells, resulting in cell death compared to the other two cell lines. Future work will focus on studying the biological effect of MC NPs including their binding affinity with molecules/receptors expressed on the M14 and other melanoma cell surface by molecular docking simulations. Subsequently, we will evaluate the MCs as a component of combination therapy in a murine melanoma model.

Removal of metals and inorganics from rendered fat using polyamine-modified cellulose nanocrystals.

Meatpacking and poultry operations produce an enormous amount of co-products including offal, fat, blood, feathers etc. that are collected and processed by the rendering industry into value-added materials such as various protein meals and rendered fat products. Rendered fats (mainly composed of triglycerides from the adipose tissue of animals or used cooking oil from the restaurant industry) are sold for a variety of applications including animal feed formulations. Nonetheless, in the current context of energy scarcity, their use as feedstocks for the generation of renewable fuels including biodiesel and renewable diesel represents a growing market. The diverse composition of the source material can impose significant challenges in terms of compliance, requiring the control (and reduction) of the concentration of elements such as phosphorus, sulfur, calcium, magnesium, sodium, potassium, and other undesirable metals that can otherwise interfere with critical aspects of the refining process or contaminate the renewable fuel products. To address this critical need, we describe the application of poly(ethylenimine)-modified cellulose nanocrystals as a low-cost material for the removal of unwanted metal/inorganic cations from rendered fat. A total of 28 real samples including poultry, white pork grease, and beef tallow were analyzed. Test results showed that the approach can effectively decrease the concentration of the target elements by 95 ± 2%, suggesting that this treatment protocol could dramatically improve the application of rendered fat products for renewable fuel refining.

Correction: Removal of metals and inorganics from rendered fat using polyamine-modified cellulose nanocrystals.

[This corrects the article DOI: 10.1039/D3SU00116D.].

Enolase Inhibitors as Early Lead Therapeutics against Trypanosoma brucei.

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) was a potent enzyme inhibitor (IC50 value of 0.60 ± 0.23 µM), while a six-membered ring-bearing phosphonate, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX), was less potent (IC50 value of 2.1 ± 1.1 µM). An analog with a larger seven-membered ring, (1-hydroxy-2-oxoazepan-3-yl) phosphonic acid (HEPTA), was not active. Molecular docking simulations revealed that deoxy-SF2312 and HEX had binding affinities of -6.8 and -7.5 kcal/mol, respectively, while the larger HEPTA did not bind as well, with a binding of affinity of -4.8 kcal/mol. None of these compounds were toxic to BSF parasites; however, modification of enzyme-active phosphonates through the addition of pivaloyloxymethyl (POM) groups improved activity against T. brucei, with POM-modified (1,5-dihydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (POMSF) and POMHEX having EC50 values of 0.45 ± 0.10 and 0.61 ± 0.08 µM, respectively. These findings suggest that HEX is a promising lead against T. brucei and that further development of prodrug HEX analogs is warranted.

Predicting Antioxidant Synergism via Artificial Intelligence and Benchtop Data.

Lipid oxidation is a major issue affecting products containing unsaturated fatty acids as ingredients or components, leading to the formation of low molecular weight species with diverse functional groups that impart off-odors and off-flavors. Aiming to control this process, antioxidants are commonly added to these products, often deployed as combinations of two or more compounds, a strategy that allows for lowering the amount used while boosting the total antioxidant capacity of the formulation. While this approach allows for minimizing the potential organoleptic and toxic effects of these compounds, predicting how these mixtures of antioxidants will behave has traditionally been one of the most challenging tasks, often leading to simple additive, antagonistic, or synergistic effects. Approaches to understanding these interactions have been predominantly empirically driven but thus far, inefficient and unable to account for the complexity and multifaceted nature of antioxidant responses. To address this current gap in knowledge, we describe the use of an artificial intelligence model based on deep learning architecture to predict the type of interaction (synergistic, additive, and antagonistic) of antioxidant combinations. Here, each mixture was associated with a combination index value (CI) and used as input for our model, which was challenged against a test (n = 140) data set. Despite the encouraging preliminary results, this algorithm failed to provide accurate predictions of oxidation experiments performed in-house using binary mixtures of phenolic antioxidants and a lard sample. To overcome this problem, the AI algorithm was then enhanced with various amounts of experimental data (antioxidant power data assessed by the TBARS assay), demonstrating the importance of having chemically relevant experimental data to enhance the model's performance and provide suitable predictions with statistical relevance. We believe the proposed method could be used as an auxiliary tool in benchmark analysis routines, offering a novel strategy to enable broader and more rational predictions related to the behavior of antioxidant mixtures.

A cathepsin C-like protease mediates the post-translation modification of Toxoplasma gondii secretory proteins for optimal invasion and egress.

Microbial pathogens use proteases for their infections, such as digestion of proteins for nutrients and activation of their virulence factors. As an obligate intracellular parasite, Toxoplasma gondii must invade host cells to establish its intracellular propagation. To facilitate invasion, the parasites secrete invasion effectors from microneme and rhoptry, two unique organelles in apicomplexans. Previous work has shown that some micronemal invasion effectors experience a series of proteolytic cleavages within the parasite's secretion pathway for maturation, such as the aspartyl protease (TgASP3) and the cathepsin L-like protease (TgCPL), localized within the post-Golgi compartment and the endolysosomal system, respectively. Furthermore, it has been shown that the precise maturation of micronemal effectors is critical for Toxoplasma invasion and egress. Here, we show that an endosome-like compartment (ELC)-residing cathepsin C-like protease (TgCPC1) mediates the final trimming of some micronemal effectors, and its loss further results in defects in the steps of invasion, egress, and migration throughout the parasite's lytic cycle. Notably, the deletion of TgCPC1 completely blocks the activation of subtilisin-like protease 1 (TgSUB1) in the parasites, which globally impairs the surface-trimming of many key micronemal invasion and egress effectors. Additionally, we found that Toxoplasma is not efficiently inhibited by the chemical inhibitor targeting the malarial CPC ortholog, suggesting that these cathepsin C-like orthologs are structurally different within the apicomplexan phylum. Collectively, our findings identify a novel function of TgCPC1 in processing micronemal proteins within the Toxoplasma parasite's secretory pathway and expand the understanding of the roles of cathepsin C protease. IMPORTANCE Toxoplasma gondii is a microbial pathogen that is well adapted for disseminating infections. It can infect virtually all warm-blooded animals. Approximately one-third of the human population carries toxoplasmosis. During infection, the parasites sequentially secrete protein effectors from the microneme, rhoptry, and dense granule, three organelles exclusively found in apicomplexan parasites, to help establish their lytic cycle. Proteolytic cleavage of these secretory proteins is required for the parasite's optimal function. Previous work has revealed that two proteases residing within the parasite's secretory pathway cleave micronemal and rhoptry proteins, which mediate parasite invasion and egress. Here, we demonstrate that a cathepsin C-like protease (TgCPC1) is involved in processing several invasion and egress effectors. The genetic deletion of TgCPC1 prevented the complete maturation of some effectors in the parasites. Strikingly, the deletion led to a full inactivation of one surface-anchored protease, which globally impaired the trimming of some key micronemal proteins before secretion. Therefore, this finding represents a novel post-translational mechanism for the processing of virulence factors within microbial pathogens.

Lignocellulosic-Based Nanoparticles with Photoluminescent Properties for Bioimaging.

Natural and renewable resources from plants or animals are an important source of biomaterials due to their biocompatibility and high availability. Lignin is a biopolymer present in the biomass of plants, where it is intertwined and cross-linked with other polymers and macromolecules in the cell walls, generating a lignocellulosic material with potential applications. We have prepared lignocellulosic-based nanoparticles with an average size of 156 nm that exhibit a high photoluminescence signal when excited at 500 nm with emission in the near-infrared (NIR) region at 800 nm. The advantage of these lignocellulosic-based nanoparticles is their natural luminescent properties and their origin from rose biomass waste, which eliminates the need for encapsulation or functionalization of imaging agents. Moreover, the in vitro cell growth inhibition (IC50) of lignocellulosic-based nanoparticles is about 3 mg/mL, and no in vivo toxicity was registered up to 57 mg/kg, which suggests that they are suitable for bioimaging applications. In addition, these nanoparticles can circulate in the blood and are excreted in urine. The combined high luminescence signal in NIR, small size, low in vitro toxicity, low in vivo toxicity, and blood circulation support the potential of lignin-based nanoparticles as a novel bioimaging agent.

Exploring the interactive mechanism of acarbose with the amylase SusG in the starch utilization system of the human gut symbiont Bacteroides thetaiotaomicron through molecular modeling.

The α-amylase, SusG, is a principal component of the Bacteroides thetaiotaomicron (Bt) starch utilization system (Sus) used to metabolize complex starch molecules in the human gastrointestinal (GI) tract. We previously reported the non-microbicidal growth inhibition of Bt by the acarbose-mediated arrest of the Sus as a potential therapeutic strategy. Herein, we report a computational approach using density functional theory (DFT), molecular docking, and molecular dynamics (MD) simulation to explore the interactive mechanism between acarbose and SusG at the atomic level in an effort to understand how acarbose shuts down the Bt Sus. The docking analysis reveals that acarbose binds orthosterically to SusG with a binding affinity of -8.3 kcal/mol. The MD simulation provides evidence of conformational variability of acarbose at the active site of SusG and also suggests that acarbose interacts with the main catalytic residues via a general acid-base double-displacement catalytic mechanism. These results suggest that small molecule competitive inhibition against the SusG protein could impact the entire Bt Sus and eliminate or reduce the system's ability to metabolize starch. This computational strategy could serve as a potential avenue for structure-based drug design to discover other small molecules capable of inhibiting the Sus of Bt with high potency, thus providing a holistic approach for selective modulation of the GI microbiota.

A cathepsin C-like protease post-translationally modifies Toxoplasma gondii secretory proteins for optimal invasion and egress.

Microbial pathogens use proteases for their infections, such as digestion of proteins for nutrients and activation of their virulence factors. As an obligate intracellular parasite, Toxoplasma gondii must invade host cells to establish its intracellular propagation. To facilitate invasion, the parasites secrete invasion effectors from microneme and rhoptry, two unique organelles in apicomplexans. Previous work has shown that some micronemal invasion effectors experience a series of proteolytic cleavages within the parasite's secretion pathway for maturation, such as the aspartyl protease (TgASP3) and the cathepsin L-like protease (TgCPL), localized within the post-Golgi compartment (1) and the endolysosomal system (2), respectively. Furthermore, it has been shown that the precise maturation of micronemal effectors is critical for Toxoplasma invasion and egress (1). Here, we show that an endosome-like compartment (ELC)-residing cathepsin C-like protease (TgCPC1) mediates the final trimming of some micronemal effectors, and its loss further results in defects in the steps of invasion, egress, and migration throughout the parasite's lytic cycle. Notably, the deletion of TgCPC1 completely blocks the activation of subtilisin-like protease 1 (TgSUB1) in the parasites, which globally impairs the surface-trimming of many key micronemal invasion and egress effectors. Additionally, we found that TgCPC1 was not efficiently inhibited by the chemical inhibitor targeting its malarial ortholog, suggesting that these cathepsin C-like orthologs are structurally different within the apicomplexan phylum. Taken together, our findings identify a novel function of TgCPC1 in the processing of micronemal proteins within the secretory pathway of Toxoplasma parasites and expand the understanding of the roles of cathepsin C protease. IMPORTANCE: Toxoplasma gondii is a microbial pathogen that is well adapted for disseminating infections. It can infect virtually all warm-blooded animals. Approximately one-third of the human population carries toxoplasmosis. During infection, the parasites sequentially secrete protein effectors from the microneme, rhoptry, and dense granule, three organelles exclusively found in apicomplexan parasites, to help establish their lytic cycle. Proteolytic cleavage of these secretory proteins is required for the parasite's optimal function. Previous work has revealed that two proteases residing within the parasite's secretory pathway cleave micronemal and rhoptry proteins, which mediate parasite invasion and egress. Here, we demonstrate that a cathepsin C-like protease (TgCPC1) is involved in processing several invasion and egress effectors. The genetic deletion of TgCPC1 prevented the complete maturation of some effectors in the parasites. Strikingly, the deletion led to a full inactivation of one surface-anchored protease, which globally impaired the trimming of some key micronemal proteins before secretion. Therefore, this finding represents a novel post-translational mechanism for the processing of virulence factors within microbial pathogens.

Comparison between nanocellulose-polyethylenimine composites synthesis methods towards multiple water pollutants removal: A review.

Nanocellulose/polyethylenimine composites have attracted growing attention due to their versatility as new materials for application in different fields. Water remediation is one of the traditional applications of these composites and their investigation as adsorbents for single water pollutants is well established. However, most water resources such as rivers, lakes, and even oceans contain complex mixtures of pollutants. Despite several recently published reviews on water purification technology, they only focused on these material as single pollutant removers and hardly mentioned their capacity to simultaneously recover multiple pollutants. Therefore, there is still a gap in the archived literature considering nanocellulose/polyethylenimine composites targeting water remediation with multiple water pollutants. In this review, methods for synthesizing such composites are classified and compared according to the mechanism of reactions, such as chemical crosslinking and physical adsorption, while outlining advantages and limitations. Then, the water pollutants mainly targeted by those composites are discussed in detail to expound the relationship between the synthesis method and the type and adsorption capacity. Finally, the last section presents challenges and opportunities of these nanocellulose/polyethylenimine composites as emerging sorbents for sustainable multiple water pollutants purification technologies. This review aims to lay out the basis for future developments of these composites for multiple water pollutants.

Cellulose-based hydrogels towards an antibacterial wound dressing.

Hydrogels are promising candidates for wound healing bandages because they can mimic the native skin microenvironment. Additionally, there is increasing growth in the use of naturally derived materials and plant-based biomaterials to produce healthcare products with healing purposes because of their biocompatibility and biodegradation properties. In this study, cellulose extracted from biodiverse sources in Ecuador was used as the raw material for the fabrication of hydrogels with enhanced antifouling properties. Fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM) were used to characterize the cellulose and hydrogels. In vitro and ex vivo tests were performed to evaluate the antimicrobial activity of hydrogels against Gram-negative bacteria as a model. Finally, the hydrogel synthesized with cellulose extracted from pitahaya showed improved antibacterial activity when applied over pigskin as a proof of concept for wound dressing. Therefore, the present results suggest that cellulose-based hydrogels are good candidates for application as wound dressings.

Radiopaque Iodosilane-Coated Lipid Hybrid Nanoparticle Contrast Agent for Dual-Modality Ultrasound and X-ray Bioimaging.

Here, we report the synthesis of robust hybrid iodinated silica-lipid nanoemulsions (HSLNEs) for use as a contrast agent for ultrasound and X-ray applications. We engineered iodinated silica nanoparticles (SNPs), lipid nanoemulsions, and a series of HSLNEs by a low-energy spontaneous nanoemulsification process. The formation of a silica shell requires sonication to hydrolyze and polymerize/condensate the iodomethyltrimethoxysilane at the oil/water interface of the nanoemulsion droplets. The resulting nanoemulsions (NEs) exhibited a homogeneous spherical morphology under transmission electron microscopy. The particles had diameters ranging from 20 to 120 nm with both negative and positive surface charges in the absence and presence of cetyltrimethylammonium bromide (CTAB), respectively. Unlike CTAB-coated nanoformulations, the CTAB-free NEs showed excellent biocompatibility in murine RAW macrophages and human U87-MG cell lines in vitro. The maximum tolerated dose assessment was evaluated to verify their safety profiles in vivo. In vitro X-ray and ultrasound imaging and in vivo computed tomography were used to monitor both iodinated SNPs and HSLNEs, validating their significant contrast-enhancing properties and suggesting their potential as dual-modality clinical agents in the future.

Telescoped Oxidation and Cycloaddition of Urazoles to Access Diazacyclobutenes.

Our previous method to access the diazacyclobutene scaffold did not allow for modification of the substituent originating from the 1,2,4-triazoline-3,5-dione component. We have circumvented this challenge and expanded access to additional structural diversity of the scaffold. A telescoped urazole oxidation and Lewis acid-catalyzed cyclization provided R3-substituted diazacyclobutenes. Calcium hypochlorite-mediated oxidation of urazoles followed by MgCl2-catalyzed cyclization of the resulting triazolinediones with thioalkynes promoted the formation of diazacyclobutenes bearing substitution at the R3 position originating from the triazolinedione component.

Oxadiazon Derivatives Elicit Potent Intracellular Growth Inhibition against Toxoplasma gondii by Disrupting Heme Biosynthesis.

Infections of Toxoplasma gondii can cause severe and sometimes fatal diseases in immunocompromised individuals. The de novo heme biosynthesis pathway is required for intracellular growth and pathogenesis, making it an appealing therapeutic target. We synthesized a small library of derivatives of the herbicide oxadiazon, a known inhibitor of the penultimate reaction within the heme biosynthesis pathway in plants, catalyzed by protoporphyrinogen oxidase (PPO). Seven of the 18 analogs exhibit potent intracellular growth inhibition of wild-type T. gondii (IC50 = 1 to 2.4 µM). An assay of the compounds against Toxoplasma PPO knockout and complementation strains confirmed the mode of action to be due to the potent inhibition of PPO. The most potent compounds have no detectable cytotoxicity against human foreskin fibroblast cells up to 100 µM. This study suggests that oxadiazon derivatives may represent a new molecular scaffold for the effective treatment of T. gondii infections.

Scaled Synthesis of Polyamine-Modified Cellulose Nanocrystals from Bulk Cotton and Their Use for Capturing Volatile Organic Compounds.

We have previously demonstrated that cellulose nanocrystals modified with poly(ethylenimine) (PEI-f-CNC) are capable of capturing volatile organic compounds (VOCs) associated with malodors. In this manuscript, we describe our efforts to develop a scalable synthesis of these materials from bulk cotton. This work culminated in a reliable protocol for the synthesis of unmodified cellulose nanocrystals (CNCs) from bulk cotton on a 0.5 kg scale. Additionally, we developed a protocol for the modification of the CNCs by means of sequential 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) oxidation and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) coupling to modify their surface with poly(ethylenimine) on a 100 g scale. Subsequently, we evaluated the performance of the PEI-f-CNC materials that were prepared in a series of VOC capture experiments. First, we demonstrated their efficacy in capturing volatile fatty acids emitted at a rendering plant when formulated as packed-bed filter cartridges. Secondly, we evaluated the potential to use aqueous PEI-f-CNC suspensions as a spray-based delivery method for VOC remediation. In both cases, the PEI-f-CNC formulations reduced detectable malodor VOCs by greater than 90%. The facile scaled synthesis of these materials and their excellent performance at VOC remediation suggest that they may emerge as a useful strategy for the remediation of VOCs associated with odor.

Bimodal Ultrasound and X-ray Bioimaging Properties of Particulate Calcium Fluoride Biomaterial.

Ultrasound (US) and X-ray imaging are diagnostic methods that are commonly used to image internal body structures. Several organic and inorganic imaging contrast agents are commercially available. However, their synthesis and purification remain challenging, in addition to posing safety issues. Here, we report on the promise of widespread, safe, and easy-to-produce particulate calcium fluoride (part-CaF2) as a bimodal US and X-ray contrast agent. Pure and highly crystalline part-CaF2 is obtained using a cheap commercial product. Scanning electron microscopy (SEM) depicts the morphology of these particles, while energy-dispersive X-ray spectroscopy (EDS) confirms their chemical composition. Diffuse reflectance ultraviolet-visible spectroscopy highlights their insulating behavior. The X-ray diffraction (XRD) pattern reveals that part-CaF2 crystallizes in the face-centered cubic cell lattice. Further analyses regarding peak broadening are performed using the Scherrer and Williamson-Hall (W-H) methods, which pinpoint the small crystallite size and the presence of lattice strain. X-ray photoelectron spectroscopy (XPS) solely exhibits specific peaks related to CaF2, confirming the absence of any contamination. Additionally, in vitro cytotoxicity and in vivo maximum tolerated dose (MTD) tests prove the biocompatibility of part-CaF2. Finally, the results of the US and X-ray imaging tests strongly signal that part-CaF2 could be exploited in bimodal bioimaging applications. These findings may shed a new light on calcium fluoride and the opportunities it offers in biomedical engineering.