Search results for: ligands

Authors: M. François, L. Sigot, C. Vallières

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Volatile Organic Compounds (VOCs) are a real health issue, particularly in domestic indoor environments. Among these VOCs, acetaldehyde is frequently monitored in dwellings ‘air, especially due to smoking and spontaneous emissions from the new wall and soil coverings. It is responsible for respiratory complaints and is classified as possibly carcinogenic to humans. Adsorption processes are commonly used to remove VOCs from the air. Metal-Organic Frameworks (MOFs) are a promising type of material for high adsorption performance. These hybrid porous materials composed of metal inorganic clusters and organic ligands are interesting thanks to their high porosity and surface area. The HKUST-1 (also referred to as MOF-199) is a copper-based MOF with the formula [Cu₃(BTC)₂(H₂O)₃]n (BTC = benzene-1,3,5-tricarboxylate) and exhibits unsaturated metal sites that can be attractive sites for adsorption. The objective of this study is to investigate the impact of HKUST-1 pretreatment on acetaldehyde adsorption. Thus, dynamic adsorption experiments were conducted in 1 cm diameter glass column packed with 2 cm MOF bed height. MOF were sieved to 630 µm - 1 mm. The feed gas (Co = 460 ppmv ± 5 ppmv) was obtained by diluting a 1000 ppmv acetaldehyde gas cylinder in air. The gas flow rate was set to 0.7 L/min (to guarantee a suitable linear velocity). Acetaldehyde concentration was monitored online by gas chromatography coupled with a flame ionization detector (GC-FID). Breakthrough curves must allow to understand the interactions between the MOF and the pollutant as well as the impact of the HKUST-1 humidity in the adsorption process. Consequently, different MOF water content conditions were tested, from a dry material with 7 % water content (dark blue color) to water saturated state with approximately 35 % water content (turquoise color). The rough material – without any pretreatment – containing 30 % water serves as a reference. First, conclusions can be drawn from the comparison of the evolution of the ratio of the column outlet concentration (C) on the inlet concentration (Co) as a function of time for different HKUST-1 pretreatments. The shape of the breakthrough curves is significantly different. The saturation of the rough material is slower (20 h to reach saturation) than that of the dried material (2 h). However, the breakthrough time defined for C/Co = 10 % appears earlier in the case of the rough material (0.75 h) compared to the dried HKUST-1 (1.4 h). Another notable difference is the shape of the curve before the breakthrough at 10 %. An abrupt increase of the outlet concentration is observed for the material with the lower humidity in comparison to a smooth increase for the rough material. Thus, the water content plays a significant role on the breakthrough kinetics. This study aims to understand what can explain the shape of the breakthrough curves associated to the pretreatments of HKUST-1 and which mechanisms take place in the adsorption process between the MOF, the pollutant, and the water.

Keywords: acetaldehyde, dynamic adsorption, HKUST-1, pretreatment influence

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Authors: M. Kowalik, J. Masternak, K. Kazimierczuk, O. V. Khavryuchenko, B. Kupcewicz, B. Barszcz

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Recently, the growing interest of chemists in metal-organic coordination polymers (MOCPs) is primarily derived from their intriguing structures and potential applications in catalysis, gas storage, molecular sensing, ion exchanges, nonlinear optics, luminescence, etc. Currently, we are devoting considerable effort to finding the proper method of synthesizing new coordination polymers containing S- or N-heteroaromatic carboxylates as linkers and characterizing the obtained Pb(II) compounds according to their structural diversity, luminescence, and thermal properties. The choice of Pb(II) as the central ion of MOCPs was motivated by several reasons mentioned in the literature: i) a large ionic radius allowing for a wide range of coordination numbers, ii) the stereoactivity of the 6s2 lone electron pair leading to a hemidirected or holodirected geometry, iii) a flexible coordination environment, and iv) the possibility to form secondary bonds and unusual non-covalent interactions, such as classic hydrogen bonds and π···π stacking interactions, as well as nonconventional hydrogen bonds and rarely reported tetrel bonds, Pb(lone pair)···π interactions, C–H···Pb agostic-type interactions or hydrogen bonds, and chelate ring stacking interactions. Moreover, the construction of coordination polymers requires the selection of proper ligands acting as linkers, because we are looking for materials exhibiting different network topologies and fluorescence properties, which point to potential applications. The reaction of Pb(NO₃)₂ with 1H-pyrrole-2-carboxylic acid (2prCOOH) leads to the formation of a new four-nuclear Pb(II) polymer, [Pb4(2prCOO)₈(H₂O)]ₙ, which has been characterized by CHN, FT-IR, TG, PL and single-crystal X-ray diffraction methods. In view of the primary Pb–O bonds, Pb1 and Pb2 show hemidirected pentagonal pyramidal geometries, while Pb2 and Pb4 display hemidirected octahedral geometries. The topology of the strongest Pb–O bonds was determined as the (4·8²) fes topology. Taking the secondary Pb–O bonds into account, the coordination number of Pb centres increased, Pb1 exhibited a hemidirected monocapped pentagonal pyramidal geometry, Pb2 and Pb4 exhibited a holodirected tricapped trigonal prismatic geometry, and Pb3 exhibited a holodirected bicapped trigonal prismatic geometry. Moreover, the Pb(II) lone pair stereoactivity was confirmed by DFT calculations. The 2D structure was expanded into 3D by the existence of non-covalent O/C–H···π and Pb···π interactions, which was confirmed by the Hirshfeld surface analysis. The above mentioned interactions improve the rigidity of the structure and facilitate the charge and energy transfer between metal centres, making the polymer a promising luminescent compound.

Keywords: coordination polymers, fluorescence properties, lead(II), lone electron pair stereoactivity, non-covalent interactions

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Authors: Sourav Ray, Christoph Stein, Marcus Weber

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A new class of drug candidates, initially derived from mathematical modeling of ligand-receptor interactions, activate the μ-opioid receptor (MOR) preferentially at acidic extracellular pH-levels, as present in injured tissues. This is of commercial interest because it may preclude the adverse effects of conventional MOR agonists like fentanyl, which include but are not limited to addiction, constipation, sedation, and apnea. Animal studies indicate the importance of taking the pH value of the chemical environment of MOR into account when designing new drugs. Hydrogen bonds (HBs) play a crucial role in stabilizing protein secondary structure and molecular interaction, such as ligand-protein interaction. These bonds may depend on the pH value of the chemical environment. For the MOR, antagonist naloxone and agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) form HBs with ionizable residue HIS 297 at physiological pH to modulate signaling. However, such interactions were markedly reduced at acidic pH. Although fentanyl-induced signaling is also diminished at acidic pH, HBs with HIS 297 residue are not observed at either acidic or physiological pH for this strong agonist of the MOR. Molecular dynamics (MD) simulations can provide greater insight into the interaction between the ligand of interest and the HIS 297 residue. Amino acid protonation states are adjusted to the model difference in system acidity. Unbiased and unrestrained MD simulations were performed, with the ligand in the proximity of the HIS 297 residue. Ligand-receptor complexes were embedded in 1-palmitoyl-2-oleoyl-sn glycero-3-phosphatidylcholine (POPC) bilayer to mimic the membrane environment. The occurrence of HBs between the different ligands and the HIS 297 residue of MOR at acidic and physiological pH values were tracked across the various simulation trajectories. No HB formation was observed between fentanyl and HIS 297 residue at either acidic or physiological pH. Naloxone formed some HBs with HIS 297 at pH 5, but no such HBs were noted at pH 7. Interestingly, DAMGO displayed an opposite yet more pronounced HB formation trend compared to naloxone. Whereas a marginal number of HBs could be observed at even pH 5, HBs with HIS 297 were more stable and widely present at pH 7. The HB formation plays no and marginal role in the interaction of fentanyl and naloxone, respectively, with the HIS 297 residue of MOR. However, HBs play a significant role in the DAMGO and HIS 297 interaction. Post DAMGO administration, these HBs might be crucial for the remediation of opioid tolerance and restoration of opioid sensitivity. Although experimental studies concur with our observations regarding the influence of HB formation on the fentanyl and DAMGO interaction with HIS 297, the same could not be conclusively stated for naloxone. Therefore, some other supplementary interactions might be responsible for the modulation of the MOR activity by naloxone binding at pH 7 but not at pH 5. Further elucidation of the mechanism of naloxone action on the MOR could assist in the formulation of cost-effective naloxone-based treatment of opioid overdose or opioid-induced side effects.

Keywords: effect of system acidity, hydrogen bond formation, opioid action, receptor activation

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Authors: Harpreet Singh Kainth

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Rubidium salts have been commonly used as an electrolyte to improve the efficiency cycle of Li-ion batteries. In recent years, it has been implemented into the large scale for further technological advances to improve the performance rate and better cyclability in the batteries. X-ray absorption spectroscopy (XAS) is a powerful tool for obtaining the information in the electronic structure which involves the chemical state analysis in the active materials used in the batteries. However, this technique is not well suited for the industrial applications because it needs a synchrotron X-ray source and special sample file for in-situ measurements. In contrast to this, conventional wavelength dispersive X-ray fluorescence (WDXRF) spectrometer is nondestructive technique used to study the chemical shift in all transitions (K, L, M, …) and does not require any special pre-preparation planning. In the present work, the fluorescent Lα, Lβ₁ , Lβ₃,₄ and Lγ₂,₃ X-ray spectra of rubidium in different chemical forms (Rb₂CO₃ , RbCl, RbBr, and RbI) have been measured first time with high resolution wavelength dispersive X-ray fluorescence (WDXRF) spectrometer (Model: S8 TIGER, Bruker, Germany), equipped with an Rh anode X-ray tube (4-kW, 60 kV and 170 mA). In ₃₇Rb compounds, the measured energy shifts are in the range (-0.45 to - 1.71) eV for Lα X-ray peak, (0.02 to 0.21) eV for Lβ₁ , (0.04 to 0.21) eV for Lβ₃ , (0.15 to 0.43) eV for Lβ₄ and (0.22 to 0.75) eV for Lγ₂,₃ X-ray emission lines. The chemical shifts in rubidium compounds have been measured by considering Rb₂CO₃ compounds taking as a standard reference. A Voigt function is used to determine the central peak position of all compounds. Both positive and negative shifts have been observed in L shell emission lines. In Lα X-ray emission lines, all compounds show negative shift while in Lβ₁, Lβ₃,₄, and Lγ₂,₃ X-ray emission lines, all compounds show a positive shift. These positive and negative shifts result increase or decrease in X-ray energy shifts. It looks like that ligands attached with central metal atom attract or repel the electrons towards or away from the parent nucleus. This pulling and pushing character of rubidium affects the central peak position of the compounds which causes a chemical shift. To understand the chemical effect more briefly, factors like electro-negativity, line intensity ratio, effective charge and bond length are responsible for the chemical state analysis in rubidium compounds. The effective charge has been calculated from Suchet and Pauling method while the line intensity ratio has been calculated by calculating the area under the relevant emission peak. In the present work, it has been observed that electro-negativity, effective charge and intensity ratio (Lβ₁/Lα, Lβ₃,₄/Lα and Lγ₂,₃/Lα) are inversely proportional to the chemical shift (RbCl > RbBr > RbI), while bond length has been found directly proportional to the chemical shift (RbI > RbBr > RbCl).

Keywords: chemical shift in L emission lines, bond length, electro-negativity, effective charge, intensity ratio, Rubidium compounds, WDXRF spectrometer

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Authors: H. Arceo, S. Rincon, C. Ben-Youssef, J. Rivera, A. Zepeda

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Biodiesel has emerged as a material with great potential as a renewable energy replacement to current petroleum-based diesel. Recently, biodiesel production is focused on the development of more efficient, sustainable process with lower costs of production. In this sense, a “green” approach to biodiesel production has stimulated the use of sustainable heterogeneous acid catalysts, that are better alternatives to conventional processes because of their simplicity and the simultaneous promotion of esterification and transesterification reactions from low-grade, highly-acidic and water containing oils without the formation of soap. The focus of this methodology is the development of new heterogeneous catalysts that under ordinary reaction conditions could reach yields similar to homogeneous catalysis. In recent years, metal organic frameworks (MOF) have attracted much interest for their potential as heterogeneous acid catalysts. They are crystalline porous solids formed by association of transition metal ions or metal–oxo clusters and polydentate organic ligands. This hybridization confers MOFs unique features such as high thermal stability, larger pore size, high specific area, high selectivity and recycling potential. Thus, MOF application could be a way to improve the biodiesel production processes. In this work, we evaluated the catalytic activity of MOF [(4,4-bipyridine)2(O₂CCH₃)2Zn]n (MOF Zn-I) for the synthesis of biodiesel from canola oil. The reaction conditions were optimized using the response surface methodology with a compound design central with 24. The variables studied were: Reaction temperature, amount of catalyst, molar ratio oil: MetOH and reaction time. The preparation MOF Zn-I was performed by mixing 5 mmol 4´4 dipyridine dissolved in 25 mL methanol with 10 mmol Zn(O₂CCH₃)₂ ∙ 2H₂O in 25 mL water. The crystals were obtained by slow evaporation of the solvents at 60°C for 18 h. The prepared catalyst was characterized using X-ray diffraction (XRD) and Fourier transform infrared spectrometer (FT-IR). The prepared catalyst was characterized using X-ray diffraction (XRD) and Fourier transform infrared spectrometer (FT-IR). Experiments were performed using commercially available canola oil in ace pressure tube under continuous stirring. The reaction was filtered and vacuum distilled to remove the catalyst and excess alcohol, after which it was centrifuged to separate the obtained biodiesel and glycerol. 1H NMR was used to calculate the process yield. GC-MS was used to quantify the fatty acid methyl ester (FAME). The results of this study show that the acid catalyst MOF Zn-I could be used as catalyst for biodiesel production through heterogeneous transesterification of canola oil with FAME yield 82 %. The optimum operating condition for the catalytic reaction were of 142°C, 0.5% catalyst/oil weight ratio, 1:30 oil:MeOH molar ratio and 5 h reaction time.

Keywords: fatty acid methyl ester, heterogeneous acid catalyst, metal organic framework, transesterification

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Authors: Milu T. Cherian, Sergio C. Chai, Morgan A. Casal, Taosheng Chen

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This study aims to use CINPA1, a recently discovered small-molecule inhibitor of the xenobiotic receptor CAR (constitutive androstane receptor) for understanding the binding modes of CAR and to guide CAR-mediated gene expression profiling studies in human primary hepatocytes. CAR and PXR are xenobiotic sensors that respond to drugs and endobiotics by modulating the expression of metabolic genes that enhance detoxification and elimination. Elevated levels of drug metabolizing enzymes and efflux transporters resulting from CAR activation promote the elimination of chemotherapeutic agents leading to reduced therapeutic effectiveness. Multidrug resistance in tumors after chemotherapy could be associated with errant CAR activity, as shown in the case of neuroblastoma. CAR inhibitors used in combination with existing chemotherapeutics could be utilized to attenuate multidrug resistance and resensitize chemo-resistant cancer cells. CAR and PXR have many overlapping modulating ligands as well as many overlapping target genes which confounded attempts to understand and regulate receptor-specific activity. Through a directed screening approach we previously identified a new CAR inhibitor, CINPA1, which is novel in its ability to inhibit CAR function without activating PXR. The cellular mechanisms by which CINPA1 inhibits CAR function were also extensively examined along with its pharmacokinetic properties. CINPA1 binding was shown to change CAR-coregulator interactions as well as modify CAR recruitment at DNA response elements of regulated genes. CINPA1 was shown to be broken down in the liver to form two, mostly inactive, metabolites. The structure-activity differences of CINPA1 and its metabolites were used to guide computational modeling using the CAR-LBD structure. To rationalize how ligand binding may lead to different CAR pharmacology, an analysis of the docked poses of human CAR bound to CITCO (a CAR activator) vs. CINPA1 or the metabolites was conducted. From our modeling, strong hydrogen bonding of CINPA1 with N165 and H203 in the CAR-LBD was predicted. These residues were validated to be important for CINPA1 binding using single amino-acid CAR mutants in a CAR-mediated functional reporter assay. Also predicted were residues making key hydrophobic interactions with CINPA1 but not the inactive metabolites. Some of these hydrophobic amino acids were also identified and additionally, the differential coregulator interactions of these mutants were determined in mammalian two-hybrid systems. CINPA1 represents an excellent starting point for future optimization into highly relevant probe molecules to study the function of the CAR receptor in normal- and pathophysiology, and possible development of therapeutics (for e.g. use for resensitizing chemoresistant neuroblastoma cells).

Keywords: antagonist, chemoresistance, constitutive androstane receptor (CAR), multi-drug resistance, structure activity relationship (SAR), xenobiotic resistance

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Authors: Natalia V. Beloglazova, Pieterjan Lenain, Martin Hedstrom, Dietmar Knopp, Sarah De Saeger

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In recent years polycyclic aromatic hydrocarbons (PAHs), which represent a hazard to humans and entire ecosystem, have been receiving an increased interest due to their mutagenic, carcinogenic and endocrine disrupting properties. They are formed in all incomplete combustion processes of organic matter and, as a consequence, ubiquitous in the environment. Benzo(a)pyrene (BaP) is on the priority list published by the Environmental Agency (US EPA) as the first PAH to be identified as a carcinogen and has often been used as a marker for PAHs contamination in general. It can be found in different types of water samples, therefore, the European Commission set up a limit value of 10 ng L–1 (10 ppt) for BAP in water intended for human consumption. Generally, different chromatographic techniques are used for PAHs determination, but these assays require pre-concentration of analyte, create large amounts of solvent waste, and are relatively time consuming and difficult to perform on-site. An alternative robust, stand-alone, and preferably cheap solution is needed. For example, a sensing unit which can be submerged in a river to monitor and continuously sample BaP. An affinity sensor based on capacitive transduction was developed. Natural antibodies or their synthetic analogues can be used as ligands. Ideally the sensor should operate independently over a longer period of time, e.g. several weeks or months, therefore the use of molecularly imprinted polymers (MIPs) was discussed. MIPs are synthetic antibodies which are selective for a chosen target molecule. Their robustness allows application in environments for which biological recognition elements are unsuitable or denature. They can be reused multiple times, which is essential to meet the stand-alone requirement. BaP is a highly lipophilic compound and does not contain any functional groups in its structure, thus excluding non-covalent imprinting methods based on ionic interactions. Instead, the MIPs syntheses were based on non-covalent hydrophobic and π-π interactions. Different polymerization strategies were compared and the best results were demonstrated by the MIPs produced using electropolymerization. 4-vinylpyridin (VP) and divinylbenzene (DVB) were used as monomer and cross-linker in the polymerization reaction. The selectivity and recovery of the MIP were compared to a non-imprinted polymer (NIP). Electrodes were functionalized with natural receptor (monoclonal anti-BaP antibody) and with MIPs selective towards BaP. Different sets of electrodes were evaluated and their properties such as sensitivity, selectivity and linear range were determined and compared. It was found that both receptor can reach the cut-off level comparable to the established ML, and despite the fact that the antibody showed the better cross-reactivity and affinity, MIPs were more convenient receptor due to their ability to regenerate and stability in river till 7 days.

Keywords: antibody, benzo(a)pyrene, capacitive sensor, MIPs, river water

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Authors: Sibghat Mansoor Rana, Muhammad Islam, Hamid Saeed, Hummera Rafique, Muhammad Majid, Muhammad Tahir Aqeel, Fariha Imtiaz, Zaman Ashraf

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The 1,3,4-oxadiazole derivatives Ox-6a-f have been synthesized by incorporating flur- biprofen moiety with the aim to explore the potential of target molecules to decrease the oxidative stress. The title compounds Ox-6a-f were prepared by simple reactions in which a flurbiprofen –COOH group was esterified with methanol in an acid-catalyzed medium, which was then reacted with hydrazine to afford the corresponding hydrazide. The acid hydrazide was then cyclized into 1,3,4-oxadiazole-2-thiol by reacting with CS2 in the presence of KOH. The title compounds Ox-6a-f were synthesized by the reaction of an –SH group with various alkyl/aryl chlorides, which involves an S-alkylation reaction. The structures of the synthesized Ox-6a-f derivatives were ascer- tained by spectroscopic data. The in silico molecular docking was performed against target proteins cyclooxygenase-2 COX-2 (PDBID 5KIR) and cyclooxygenase-1 COX-1 (PDBID 6Y3C) to determine the binding affinity of the synthesized compounds with these structures. It has been inferred that most of the synthesized compounds bind well with an active binding site of 5KIR compared to 6Y3C, and especially compound Ox-6f showed excellent binding affinity (7.70 kcal/mol) among all synthesized compounds Ox-6a-f. The molecular dynamic (MD) simulation has also been performed to check the stability of docking complexes of ligands with COX-2 by determining their root mean square deviation and root mean square fluctuation. Little fluctuation was observed in case of Ox-6f, which forms the most stable complex with COX-2. The comprehensive antioxidant potential of the synthesized compounds has been evaluated by determining their free radical scavenging activity, including DPPH, OH, nitric oxide (NO), and iron chelation assay. The derivative Ox-6f showed promising results with 80.23% radical scavenging potential at a dose of 100 μg/mL while ascorbic acid exhibited 87.72% inhibition at the same dose. The anti-inflammatory activity of the final products has also been performed, and inflammatory markers were assayed, such as a thiobarbituric acid-reducing substance, nitric oxide, interleukin-6 (IL-6), and COX-2. The derivatives Ox-6d and Ox-6f displayed higher anti-inflammatory activity, exhibiting 70.56% and 74.16% activity, respectively. The results were compared with standard ibuprofen, which showed 84.31% activity at the same dose, 200 μg/mL. The anti-inflammatory potential has been performed by following the carrageen-induced hind paw edema model, and results showed that derivative Ox-6f exhibited 79.83% reduction in edema volume compared to standard ibuprofen, which reduced 84.31% edema volume. As dry lab and wet lab results confirm each other, it has been deduced that derivative Ox-6f may serve as the lead structure to design potent compounds to address oxidative stress.

Keywords: synthetic chemistry, pharmaceutical chemistry, oxadiazole derivatives, anti-inflammatory, anti-cancer compounds

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Authors: Damien Rinsant, Eugen Andreiadis, Michael Carboni, Daniel Meyer

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Different types of materials have been developed for the solid/liquid uranium extraction processes, such as functionalized organic polymers, hybrid silica or inorganic adsorbents. In general, these materials exhibit a moderate affinity for uranyl ions and poor selectivity against impurities like iron, vanadium or molybdenum. Moreover, the structural organization deficiency of these materials generates ion diffusion issues inside the material. Therefore, the aim of our study is to developed efficient and organized materials, stable in the acid media encountered in uranium extraction processes. Metal organic frameworks (MOFs) are hybrid crystalline materials consisting of an inorganic part (cluster or metal ions) and tailored organic linkers connected via coordination bonds. These hierarchical materials have exceptional surface area, thermal stability and a large variety of tunable structures. However, due to the reversibility of constitutive coordination bonds, MOFs have moderate stability in strongly complexing or acidic media. Only few of them are known to be stable in aqueous media and only one example is described in strong acidic media. However, these conditions are very often encountered in the environmental pollution remediation of mine wastewaters. To tackle the challenge of developing MOFs adapted for uranium extraction from acid mine waters, we have investigated the stability of several materials. To ensure a good stability we have synthetized and characterized different materials based on highly coordinated metal clusters, such as LnOFs and Zirconium based materials. Among the latter, the UiO family shows a great stability in sulfuric acid media even in the presence of 1.4 M sodium sulfate at pH 2. However, the stability in phosphoric media is reduced due to the high affinity between zirconium and phosphate ligand. Based on these results, we have developed a tertiary amine functionalized MOF denoted UiO-68-NMe2 particularly adapted for the extraction of anionic uranyl (VI) sulfate complexes mainly present in the acid mine solutions. The adsorption capacity of the material has been determined upon varying total sulfate concentration, contact time and uranium concentration. The extraction tests put in evidence different phenomena due to the complexity of the extraction media and the interaction between the MOF and sulfate anion. Finally, the extraction mechanisms and the interaction between uranyl and the MOF structure have been investigated. The functionalized material UiO-68-NMe2 has been characterized in the presence and absence of uranium by FT-IR, UV and Raman techniques. Moreover, the stability of the protonated amino functionalized MOF has been evaluated. The synthesis, characterization and evaluation of this type of hybrid material, particularly adapted for uranium extraction in sulfuric acid media by an anionic exchange mechanism, paved the way for the development of metal organic frameworks functionalized by different other chelating motifs, such as bifunctional ligands showing an enhanced affinity and selectivity for uranium in acid and complexing media. Work in this direction is currently in progress.

Keywords: extraction, MOF, ligand, uranium

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Authors: Oleg Reva, Ilya Korotetskiy, Marina Lankina, Murat Kulmanov, Aleksandr Ilin

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Molecular docking approaches are widely used for design of new antibiotics and modeling of antibacterial activities of numerous ligands which bind specifically to active centers of indispensable enzymes and/or key signaling proteins of pathogens. Widespread drug resistance among pathogenic microorganisms calls for development of new antibiotics specifically targeting important metabolic and information pathways. A generally recognized problem is that almost all molecular targets have been identified already and it is getting more and more difficult to design innovative antibacterial compounds to combat the drug resistance. A promising way to overcome the drug resistance problem is an induction of reversion of drug resistance by supplementary medicines to improve the efficacy of the conventional antibiotics. In contrast to well established computer-based drug design, modeling of drug resistance reversion still is in its infancy. In this work, we proposed an approach to identification of compensatory genetic variants reducing the fitness cost associated with the acquisition of drug resistance by pathogenic bacteria. The approach was based on an analysis of the population genetic of Mycobacterium tuberculosis and on results of experimental modeling of the drug resistance reversion induced by a new anti-tuberculosis drug FS-1. The latter drug is an iodine-containing nanomolecular complex that passed clinical trials and was admitted as a new medicine against MDR-TB in Kazakhstan. Isolates of M. tuberculosis obtained on different stages of the clinical trials and also from laboratory animals infected with MDR-TB strain were characterized by antibiotic resistance, and their genomes were sequenced by the paired-end Illumina HiSeq 2000 technology. A steady increase in sensitivity to conventional anti-tuberculosis antibiotics in series of isolated treated with FS-1 was registered despite the fact that the canonical drug resistance mutations identified in the genomes of these isolates remained intact. It was hypothesized that the drug resistance phenotype in M. tuberculosis requires an adjustment of activities of many genes to compensate the fitness cost of the drug resistance mutations. FS-1 cased an aggravation of the fitness cost and removal of the drug-resistant variants of M. tuberculosis from the population. This process caused a significant increase in genetic heterogeneity of the Mtb population that was not observed in the positive and negative controls (infected laboratory animals left untreated and treated solely with the antibiotics). A large-scale search for linkage disequilibrium associations between the drug resistance mutations and genetic variants in other genomic loci allowed identification of target proteins, which could be influenced by supplementary drugs to increase the fitness cost of the drug resistance and deprive the drug-resistant bacterial variants of their competitiveness in the population. The approach will be used to improve the efficacy of FS-1 and also for computer-based design of new drugs to combat drug-resistant infections.

Keywords: complete genome sequencing, computational modeling, drug resistance reversion, Mycobacterium tuberculosis

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Authors: Valentina V. Goftman, Vladislav A. Pankratov, Alexey V. Markin, Tangi Aubert, Zeger Hens, Sarah De Saeger, Irina Yu. Goryacheva

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The most important requirements for biochemical applicability of quantum dots (QDs) are: 1) the surface cap should render intact or improved optical properties; 2) mono-dispersion and good stability in aqueous phase in a wide range of pH and ionic strength values; 3) presence of functional groups, available for bioconjugation; 4) minimal impact from the environment on the QDs’ properties and, vice versa, minimal influence of the QDs’ components on the environment; and 5) stability against chemical/biochemical/physical influence. The latter is especially important for in vitro and in vivo applications. For example, some physical intracellular delivery strategies (e.g., electroporation) imply a rapid high-voltage electric field impulse in order to temporarily generate hydrophilic pores in the cell plasma membrane, necessary for the passive transportation of QDs into the cell. In this regard, it is interesting to investigate how different capping layers, which can provide high stability and sufficient fluorescent properties of QDs in a water solution, behave under these abnormal conditions. In this contribution, hydrophobic core-shell CdSe/CdS/CdZnS/ZnS QDs (λem=600 nm), produced by means of the Successive Ion Layer Adsorption and Reaction (SILAR) technique, were transferred to a water solution using two of the most commonly used methods: (i) encapsulation in an amphiphilic brush polymer based on poly(maleic anhydride-alt-1-octadecene) (PMAO) modified with polyethylene glycol (PEG) chains and (ii) silica covering. Polymer encapsulation preserves the initial ligands on the QDs’ surface owing to the hydrophobic attraction between the hydrophobic groups of the amphiphilic molecules and the surface hydrophobic groups of the QDs. This covering process allows maintaining the initial fluorescent properties, but it leads to a considerable increase of the QDs’ size. However, covering with a silica shell, by means of the reverse microemulsion method, allows maintaining both size and fluorescent properties of the initial QDs. The obtained water solutions of polymer covered and silica-coated QDs in three different concentrations were exposed to a low-voltage electric field for a short time and the fluorescent properties were investigated. It is shown that the PMAO-PEG polymer acquires some additional charges in the presence of the electric field, which causes repulsion between the polymer and the QDs’ surface. This process destroys the homogeneity of the whole amphiphilic shell and it dramatically decreases the fluorescent properties (dropping to 10% from its initial value) because of the direct contact of the QDs with the strongly oxidative environment (water). In contrast, a silica shell possesses dielectric properties which allow retaining 90% of its initial fluorescence intensity, even after a longer electric impact. Thus, silica shells are clearly a preferable covering for bio-application of QDs, because – besides the high uniform morphology, controlled size and biocompatibility – it allows protecting QDs from oxidation, even under the influence of an electric field.

Keywords: electric field, polymer coating, quantum dots, silica covering, stability

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Authors: Arsyam Mawardi, Sony Suhandono, Azzania Fibriani, Fifi Fitriyah Masduki

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Malaria is an infectious disease caused by Plasmodium sp. This disease has a high prevalence in Indonesia, especially in Jayapura. The vaccine that is currently being developed has not been effective in overcoming malaria. This is due to the high polymorphism in the Plasmodium genome especially in areas that encode Plasmodium surface proteins. Merozoite Surface Protein 1 (MSP1) Plasmodium falciparum is a surface protein that plays a role in the invasion process in human erythrocytes through the interaction of Glycophorin A protein receptors and sialic acid in erythrocytes with Reticulocyte Binding Proteins (RBP) and Duffy Adhesion Protein (DAP) ligands in merozoites. MSP1 can be targeted to be a specific antigen and predicted epitope area which will be used for the development of diagnostic and malaria vaccine therapy. MSP1 consists of 17 blocks, each block is dimorphic, and has been marked as the K1 and MAD20 alleles. Exceptions only in block 2, because it has 3 alleles, among others K1, MAD20 and RO33. These polymorphisms cause allelic variations and implicate the severity of patients infected P. falciparum. In addition, polymorphism of MSP1 in Jayapura isolates has not been reported so it is interesting to be further identified and projected as a specific antigen. Therefore, in this study, we analyzed the allele polymorphism as well as detected the MSP1 epitope antigen candidate on block 2 P. falciparum. Clinical samples of selected malaria patients followed the consecutive sampling method, examining malaria parasites with blood preparations on glass objects observed through a microscope. Plasmodium DNA was isolated from the blood of malarial positive patients. The block 2 MSP1 gene was amplified using PCR method and cloned using the pGEM-T easy vector then transformed to TOP'10 E.coli. Positive colonies selection was performed with blue-white screening. The existence of target DNA was confirmed by PCR colonies and DNA sequencing methods. Furthermore, DNA sequence analysis was done through alignment and formation of a phylogenetic tree using MEGA 6 software and insilico analysis using IEDB software to predict epitope candidate for P. falciparum. A total of 15 patient samples have been isolated from Plasmodium DNA. PCR amplification results show the target gene size about ± 1049 bp. The results of MSP1 nucleotide alignment analysis reveal that block 2 MSP1 genes derived from the sample of malarial patients were distributed in four different allele family groups, K1 (7), MAD20 (1), RO33 (0) and MSP1_Jayapura (10) alleles. The most commonly appears of the detected allele is MSP1_Jayapura single allele. There was no significant association between sex variables, age, the density of parasitemia and alel variation (Mann Whitney, U > 0.05), while symptomatic signs have a significant difference as a trigger of detectable allele variation (U < 0.05). In this research, insilico study shows that there is a new epitope antigen candidate from the MSP1_Jayapura allele and it is predicted to be recognized by B cells with 17 amino acid lengths in the amino acid sequence 187 to 203.

Keywords: epitope candidate, insilico analysis, MSP1 P. falciparum, polymorphism

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Authors: T. Ul Rehman, S. Agnello, F. M. Gelardi, M. M. Calvino, G. Lazzara, G. Buscarino, M. Cannas

Abstract:

Metal-Organic Frameworks (MOFs) have emerged as promising candidates for detecting metal ions owing to their large surface area, customizable porosity, and diverse functionalities. In recent years, there has been a surge in research focused on MOFs with luminescent properties. These frameworks are constructed through coordinated bonding between metal ions and multi-dentate ligands, resulting in inherent fluorescent structures. Their luminescent behavior is influenced by factors like structural composition, surface morphology, pore volume, and interactions with target analytes, particularly metal ions. MOFs exhibit various sensing mechanisms, including photo-induced electron transfer (PET) and charge transfer processes such as ligand-to-metal (LMCT) and metal-to-ligand (MLCT) transitions. Among these, MIL-53(Al) stands out due to its flexibility, stability, and specific affinity towards certain metal ions, making it a promising platform for selective metal ion sensing. This study investigates the structural, thermal, and luminescent properties of MIL-53(Al) metal-organic framework (MOF) upon Fe3+ cation exchange. Two separate sets of samples were prepared to activate the MOF powder at different temperatures. The first set of samples, referred to as MIL-53(Al), activated (120°C), was prepared by activating the raw powder in a glass tube at 120°C for 12 hours and then sealing it. The second set of samples, referred to as MIL-53(Al), activated (300°C), was prepared by activating the MIL-53(Al) powder in a glass tube at 300°C for 70 hours. Additionally, 25 mg of MIL-53(Al) powder was dispersed in 5 mL of Fe3+ solution at various concentrations (0.1-100 mM) for the cation exchange experiment. The suspension was centrifuged for five minutes at 10,000 rpm to extract MIL-53(Al) powder. After three rounds of washing with ultrapure water, MIL-53(Al) powder was heated at 120°C for 12 hours. For PXRD and TGA analyses, a sample of the obtained MIL-53(Al) was used. We also activated the cation-exchanged samples for time-resolved photoluminescence (TRPL) measurements at two distinct temperatures (120 and 300°C) for comparative analysis. Powder X-ray diffraction patterns reveal amorphization in samples with higher Fe3+ concentrations, attributed to alterations in coordination environments and ion exchange dynamics. Thermal decomposition analysis shows reduced weight loss in Fe3+-exchanged MOFs, indicating enhanced stability due to stronger metal-ligand bonds and altered decomposition pathways. Raman spectroscopy demonstrates intensity decrease, shape disruption, and frequency shifts, indicative of structural perturbations induced by cation exchange. Photoluminescence spectra exhibit ligand-based emission (π-π* or n-π*) and ligand-to-metal charge transfer (LMCT), influenced by activation temperature and Fe3+ incorporation. Quenching of luminescence intensity and shorter lifetimes upon Fe3+ exchange result from structural distortions and Fe3+ binding to organic linkers. In a nutshell, this research underscores the complex interplay between composition, structure, and properties in MOFs, offering insights into their potential for diverse applications in catalysis, gas storage, and luminescent devices.

Keywords: Fe³⁺ cation exchange, luminescent metal-organic frameworks (LMOFs), MIL-53(Al), solid-state analysis

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Authors: Rafia S. Al-lamki, Jun Wang, Simon Pacey, Jordan Pober, John R. Bradley

Abstract:

Tumor necrosis factor alpha (TNF), signaling through TNFR2, may act an autocrine growth factor for renal tubular epithelial cells. Clear cell renal carcinomas (ccRCC) contain cancer stem cells (CSCs) that give rise to progeny which form the bulk of the tumor. CSCs are rarely in cell cycle and, as non-proliferating cells, resist most chemotherapeutic agents. Thus, recurrence after chemotherapy may result from the survival of CSCs. Therapeutic targeting of both CSCs and the more differentiated bulk tumor populations may provide a more effective strategy for treatment of RCC. In this study, we hypothesized that TNFR2 signaling will induce CSCs in ccRCC to enter cell cycle so that treatment with ligands that engage TNFR2 will render CSCs susceptible to chemotherapy. To test this hypothesis, we have utilized wild-type TNF (wtTNF) or specific muteins selective for TNFR1 (R1TNF) or TNFR2 (R2TNF) to treat either short-term organ cultures of ccRCC and adjacent normal kidney (NK) tissue or cultures of CD133+ cells isolated from ccRCC and adjacent NK, hereafter referred to as stem cell-like cells (SCLCs). The effect of cyclophosphamide (CP), currently an effective anticancer agent, was tested on CD133+SCLCs from ccRCC and NK before and after R2TNF treatment. Responses to TNF were assessed by flow cytometry (FACS), immunofluorescence, and quantitative real-time PCR, TUNEL, and cell viability assays. Cytotoxic effect of CP was analyzed by Annexin V and propidium iodide staining with FACS. In addition, we assessed the effect of TNF on isolated SCLCs differentiation using a three-dimensional (3D) culture system. Clinical samples of ccRCC contain a greater number SCLCs compared to NK and the number of SCSC increases with higher tumor grade. Isolated SCLCs show expression of stemness markers (oct4, Nanog, Sox2, Lin28) but not differentiation markers (cytokeratin, CD31, CD45, and EpCAM). In ccRCC organ cultures, wtTNF and R2TNF increase CD133 and TNFR2 expression and promote cell cycle entry whereas wtTNF and R1TNF increase TNFR1 expression and promote cell death of SCLCs. Similar findings are observed in SCLCs isolated from NK but the effect was greater in SCLCs isolated from ccRCC. Application of CP distinctly triggered apoptotic and necrotic cell death in SLCSs pre-treatment with R2TNF as compared to CP treatment alone, with SCLCs from ccRCC more sensitive to CP compared to SLCS from NK. Furthermore, TNF promotes differentiation of SCLCs to an epithelial phenotype in 3D cultures, confirmed by cytokeratin expression and loss of stemness markers Nanog and Sox2. The differentiated cells show positive expression of TNF and TNFR2. These findings provide evidence that selective engagement of TNFR2 drive CSCs to cell proliferation/differentiation, and targeting of cycling cells with TNFR2 agonist in combination with anti-cancer agents may be a potential therapy for RCC.

Keywords: cancer stem cells, ccRCC, cell cycle, cell death, TNF, TNFR1, TNFR2, CD133

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Authors: Claudio Clemente, Valentina Gargiulo, Alessio Occhicone, Giovanni Piero Pepe, Giovanni Ausanio, Michela Alfè

Abstract:

Volatile organic compound (VOC) emissions represent a serious risk to human health and the integrity of the ecosystems, especially at high concentrations. For this reason, it is very important to continuously monitor environmental quality and develop fast and reliable portable sensors to allow analysis on site. Chemiresistors have become promising candidates for VOC sensing as their ease of fabrication, variety of suitable sensitive materials, and simple sensing data. A chemoresistive gas sensor is a transducer that allows to measure the concentration of an analyte in the gas phase because the changes in resistance are proportional to the amount of the analyte present. The selection of the sensitive material, which interacts with the target analyte, is very important for the sensor performance. The most used VOC detection materials are metal oxides (MOx) for their rapid recovery, high sensitivity to various gas molecules, easy fabrication. Their sensing performance can be improved in terms of operating temperature, selectivity, and detection limit. Metal-organic frameworks (MOFs) have attracted a lot of attention also in the field of gas sensing due to their high porosity, high surface area, tunable morphologies, structural variety. MOFs are generated by the self-assembly of multidentate organic ligands connecting with adjacent multivalent metal nodes via strong coordination interactions, producing stable and highly ordered crystalline porous materials with well-designed structures. However, most MOFs intrinsically exhibit low electrical conductivity. To improve this property, MOFs can be combined with organic and inorganic materials in a hybrid fashion to produce composite materials or can be transformed into more stable structures. MOFs, indeed, can be employed as the precursors of metal oxides with well-designed architectures via the calcination method. The MOF-derived MOx partially preserved the original structure with high surface area and intrinsic open pores, which act as trapping centers for gas molecules, and showed a higher electrical conductivity. Core-shell heterostructures, in which the surface of a metal oxide core is completely coated by a MOF shell, forming a junction at the core-shell heterointerface, can also be synthesized. Also, nanocomposite in which MOF structures are intercalated with graphene related materials can also be produced, and the conductivity increases thanks to the high mobility of electrons of carbon materials. As MOF structures, zinc-based MOFs belonging to the ZIF family were selected in this work. Several Zn-based materials based and/or derived from MOFs were produced, structurally characterized, and arranged in a chemo resistive architecture, also exploring the potentiality of different approaches of sensing layer deposition based on PLD (pulsed laser deposition) and, in case of thermally labile materials, MAPLE (Matrix Assisted Pulsed Laser Evaporation) to enhance the adhesion to the support. The sensors were tested in a controlled humidity chamber, allowing for the possibility of varying the concentration of ethanol, a typical analyte chosen among the VOCs for a first survey. The effect of heating the chemiresistor to improve sensing performances was also explored. Future research will focus on exploring new manufacturing processes for MOF-based gas sensors with the aim to improve sensitivity, selectivity and reduce operating temperatures.

Keywords: chemiresistors, gas sensors, graphene related materials, laser deposition, MAPLE, metal-organic frameworks, metal oxides, nanocomposites, sensing performance, transduction mechanism, volatile organic compounds

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