Order Of Affinity Research Articles

Towards Novel Antiplasmodial Agents-Design, Synthesis and Antimalarial Activity of Second-Generation β-Carboline/Chloroquine Hybrids.

As the resistance of Plasmodium to the existing antimalarials increases, there is a crucial need to expand the antimalarial drug pipeline. We recently identified potent antimalarial compounds, namely harmiquins, hybrids derived from the β-carboline alkaloid harmine and 4-amino-7-chloroquinoline, a key structural motif of chloroquine (CQ). To further explore the structure-activity relationship, we synthesised 13 novel hybrid compounds at the position N-9 of the β-carboline ring and evaluated their efficacy in vitro against Plasmodium falciparum 3D7 and Dd2 strains (CQ sensitive and multi-drug resistant, respectively). All compounds exhibit persistent antimalarial activity against both strains of P. falciparum. The most interesting derivatives had low nanomolar activity against both strains (IC50 (33) = 4.7 ± 1.3 nM against Pf3D7 and 6.5 ± 2.5 nM against PfDd2; IC50 (37) = 4.6 ± 0.6 nM against 3D7 and 10.5 ± 0.4 nM against Dd2). Resistance indices (RIs) ranged from 0.9 to 5.3 compared to CQ (RI = 14.4), highlighting their superior consistency in activity against both strains. The cytotoxicity screening performed on HepG2 revealed over 3 orders of magnitude higher IC50 for most of the compounds, with SIs from 711.0 to 8081.8. Spectroscopic studies explored the affinities of newly synthesised compounds for DNA, RNA, and HSA. Both tested hybrids, 34 and 39, were intrinsically fluorescent in an aqueous medium, characterised by remarkable Stokes shifts of emission maxima (Δλ = +103 and +93 nm for 34 and 39, respectively). Fluorimetric experiments revealed that compound 34, with its shorter and more flexible linker, exhibited at least an order of magnitude higher affinity toward ds-DNAs versus ds-RNA and two orders of magnitude higher affinity toward GC-DNAs compared to 39. The behaviour of the investigated compounds upon binding to HSA is very similar, showing a strong hypsochromic shift of the emission maximum (almost Δλ = -70 nm) and demonstrating their effectiveness as fluorimetric probes for distinguishing between DNA/RNA and proteins.

A Self-Consistent Molecular Mechanism of β2-Microglobulin Aggregation.

Despite the consensus on the origin of dialysis-related amyloidosis (DRA) being β2-microglobulin (β2m) aggregation, the debate on the underlying mechanism persists because of the continuous emergence of β2m variant- and pH-dependent contradictory results. By characterizing the native monomeric (initiation) and aggregated fibrillar (termination) states of β2m via a combination of two enhanced sampling approaches, we here propose a mechanism that explains the heterogeneous behavior of wild-type (WT) and pathogenic (V27M and D76N) β2m variants in physiological and disease-pertinent acidic pH environments. It appears that the higher retainment of monomeric native folds at neutral pH (native-like) distinguishes pathogenic β2m mutants from the WT (moderate loss). However, at acidic pH, all three variants behave similarly in producing a substantial amount of partially unfolded states (conformational switch, propensity), though with different extents (WT < V27M < D76N). Whereas at the fibrillar end, all β2m variants display a pH-dependent protofilament separation pathway and a higher protofilament binding affinity (stability) at acidic pH, where the relative order of binding affinity (WT < V27M < D76N) remains consistent with pH modulation. Combining these observations, we conclude that β2m variants possibly shift from native-like aggregation to conformational switch-initiated fibrillation as the pH is altered from neutral to acidic. The combined propensity-stability approach based on the initiation and termination points of β2m aggregation not only assists us in deciphering the mechanism but also emphasizes the protagonistic roles of both terminal points in the overall aggregation process.

Assessment of cell-binding capacity of shed rAAV particles after gene therapy vector administration: implications for environmental risk and hygiene recommendations

ABSTRACT Background Currently, adeno-associated viruses (AAVs) are the most commonly used in vivo gene therapy (GT) vector platform. Risks posed to the environment, including the public, have not been well studied in the past. There is uncertainty concerning the necessary level of biocontainment and appropriate hygiene behavior for the handling of secreta/excreta of GT patients during the shedding phase. Research design and methods Here, feces and urine samples from non-human primates, treated with an AAV9-based vector at 2 × 1013 vector genomes per kilogram body weight (vg/kg), were analyzed for vector presence and subsequently analyzed for their capacity to bind to cells. Results Both sample types contained particles which bound to cells at concentrations in the range of ~104 (and higher) vg/mL of culture medium. Novel control rAAV vector displayed a ~2-3 orders of magnitude higher affinity to cells than shed particles. Conclusions The lower binding capacity of the shed vector particles speaks in favor of a more relaxed containment and hygiene approach in the context of GT. It is recommended that current hygiene and contact-avoidance-based containment measures after GT administration are reduced. The results also support the efforts to achieve a simplification of the regulatory review process of medicinal genetically modified organisms.

Cooperative Anion-π and C-H-Cl Interactions in Multifunctional Naphthalene-Based Receptors for Chloride Recognition: Cage-Size Modulation Through Substitution Patterns.

This study introduces a novel approach for chloride recognition utilizing multifunctional naphthalene-based receptors. By strategically modifying the substitution patterns on tetrafluoropyridines, a series of new receptors with customized cavities and enhanced binding capabilities were developed. Density functional theory (DFT) calculations and experimental studies combining NMR spectroscopy and mass spectrometry confirmed the efficacy of these receptors in capturing chloride ions. The relative chloride affinity order determined experimentally is in agreement with DFT predictions. The synergistic effect of anion-π and C-H…Cl interactions, mediated by the TFP groups, played a crucial role in achieving high binding affinity. This work provides valuable insights for designing future anion receptors with improved performance.

Enzymatic biocatalysis processes on the semicrystalline and morphological order of native cassava starches (Manihot esculenta)

Enzymatic biocatalysis has emerged as a green technology in starch modification with divergent results at the morphological level depending on the origin of the starch source. Therefore, various enzymatic biocatalysts were implemented to evaluate their effect on the morphological and semi-crystalline characteristics of native cassava starches. The degree of affinity of the biocatalysts and the conversion rate on native cassava starches were determined by kinetic parameters such as the Michaelis-Menten constant, whose results revealed the following order of affinity from highest to lowest: α-amylase, amyloglucosidase, pullulanase, and β-amylase. In addition, greater biocatalytic activity of α-amylase and β-amylase was evidenced on the amorphous zones of the polymer associated with the decrease in the amylose content and a significant increase in the degree of relative crystallinity. According to morphological analyses and XDR, the action of amyloglucosidase promoted exo-erosion phenomena and the appearance of lacerations on the granular surface of starch with the consequent decrease in the semicrystalline order. The pullulanase caused slightly eroded fragmented granules with greater biocatalytic activity on the crystalline lamellae, associated with a significant increase in the apparent amylose content. FTIR analysis in the 1,200-900 cm-1 region, corresponding to the starch fingerprint, allowed us to detect notable changes in the degree of molecular order after the enzymatic attack; this result was consistent with the degree of relative crystallinity estimated by X-ray diffraction. Likewise, the results allowed us to notice significant changes in the semi-crystalline order and morphological characteristics during the modification with α-amylase (AAM) and amyloglucosidase (AMG) associated with their greater affinity and preferential action on the amorphous structures located on the granular surface of native cassava starch.

Trace metal interaction with thermophilic phototrophic anaerobic bacterium Chloroflexus aurantiacus

Towards improving the knowledge of possible paleo-microorganisms interaction with trace metals (micro-nutrients and toxicants), we studied adsorption of Mn, Zn, Sr, Cd, and Pb onto modern Chloroflexus aurantiacus, thermophilic anoxygenic phototrophic bacterium which could be highly abundant in the Precambiran aquatic environments. Acid-base surface titrations allowed quantifying the number of proton-active surface groups, whereas non-electrostatic linear programming method (LPM) was used to assess the surface site concentrations and adsorption reaction constants between divalent cations (Zn, Mb, Sr, Cd, Pb) and bacterial surface, based on results of pH-dependent adsorption edge and constant-pH ‘langmuirian’ adsorption experiments. The total proton/hydroxyl binding site number of Chl. aurantiacus surfaces was sizably lower than that of other phototrophic anaerobic bacteria studied previously using similar experimental and modeling approach. Divalent metals exhibited a decreasing order of adsorption affinity (Pb > Cd ≥ Zn ≥ Mn > Sr), which reflected the order of cation hydrolysis and was similar to adsorption order on other phototrophic bacteria. At the same time, adsorption of Zn increased with increasing of temperature, from 4 °C to 60 °C and was stronger under light compared to the darkness. This suggested some active metabolic control involved in this metal interaction with bacterial surfaces. Overall, Chl. aurantiacus exhibited trace metal adsorption parameters (site number and binding constants) which were lower compared to other anoxygenic phototrophic bacteria (Rhodopseudomonas palustris; Rhodobacter blasticus) and cyanobacteria. This may reflect different bioavailability of trace metals in the paleo-ocean, given that thermophilic Chl. aurantiacus are among the oldest phototrophs on the planet.

In Silico Analysis of Antibacterial Activity of Fatty Acids in Swietenia humilis Zucc. Seed Extract Against Staphylococcus aureus sortase A enzyme

This study utilised molecular docking to predict the binding affinity of various fatty acids (FAs) found in Swietenia humilis to the sortase A (SrtA) protein target from Staphylococcus aureus. Binding energies, measured in kcal/mol, indicated the strength and stability of ligand-protein interactions, with lower values signifying stronger binding. The binding affinities of eight FAs as the active constituents in n-hexane extract of S. humilis and the positive control, gentamicin, were compared to assess their theoretical antibacterial activity. Palmitoleic acid exhibited the strongest binding affinity (-5.6 kcal/mol) among the FAs, suggesting the highest potential antibacterial activity, followed by linoleic, palmitic, linolenic, arachidic, tricosanoic, stearic, and oleic acids in decreasing order of affinity. Despite having weaker binding energies than gentamicin, a common gram-positive inhibitor from aminoglycoside derivative, FAs showed multiple hydrogen bonds and van der Waals interactions with key residues like ARG197, VAL168, VAL166, and ILE182, contributing to their binding stability. Palmitoleic acid formed multiple hydrogen bonds (ARG197 and GLY119) and significant van der Waals interactions, highlighting its strong theoretical binding. Stearic and oleic acids, although having higher binding energies, also formed critical hydrogen bonds, suggesting moderate potential activity. Gentamicin's single hydrogen bond suggests a highly specific binding site, which may result in high antibacterial activity despite fewer interaction points. The study indicated that FAs like palmitoleic and oleic acid show substantial potential as supplementary antibacterial agents, especially in the context of combating antibiotic resistance. This finding can pave a path for drug design and development to address the S. aureus's resistance.

Purification of industrial toluene from technical to reagent grade using Diahope activated carbon in a pilot-scale fixed-bed column

The removing organic impurities from technical-grade toluene (99.1 %) to produce reagent-grade toluene (99.9 %) has been addressed by assessing the mono- and multi-component adsorption of methylbenzothiophene (MBT), ethylcyclopentane (ECP), and xylene (XYL), which represent sulfur, non-aromatic, and aromatic impurities, respectively. Laboratory-scale static-experiments conducted between 10 and 30 °C showed that although toluene sorption on granulated activated carbon (GAC) is exothermic, the sorption capacity for each impurity increased with temperature, indicating endothermic sorption for the impurities. The sorption behavior for MBT and ECP followed the Langmuir model while for XYL followed the Freundlich model with the order of sorption affinity as MBT > ECP > XYL. In pilot-scale dynamic-experiments, the breakthrough curves (BTCs) were evaluated under various bed heights (60 and 120 cm), flow rates (1–3 L min−1), sorbate inlet concentrations (200–400 mg L−1), and optimal temperature (30 °C) obtained in static experiments. In mono-component sorption, the highest sorption capacities for MBT, ECP, and XYL were 97.1, 70.7, and 65.4 mg g−1, respectively, while the corresponding values were 46.0, 43.0, and 22.9 mg g−1 respectively, in multi-component sorption under the same operating conditions. A CFD simulation in COMSOL (v.6.2) revealed sharper BTCs with time delay compared to the experimental data while a good correlation (R2 > 0.99) was observed for BT models. The narrower mass transfer zone for MBT and ECP compared to XYL indicated more effective sorption of these sorbates, respectively. Regenerating GAC up to four cycles with hot N2 (80 °C) showed a satisfactory sorption capacity for industrial toluene impurities, indicating a reversible sorption–desorption process with a cumulative sorption usage rate of 5.5 g L−1. The pilot-scale set-up used in this study successfully purified a large volume (∼475 L) of industrial toluene.

Efficient adsorptive separation of nitrotoluene isomers via a stable and low-cost metal–organic framework with descending affinity order of meta-/ortho-/para-isomers

Obtaining purified nitrotoluenes from their mixture is significant but challenging due to their similar molecular sizes and physical properties. To overcome this challenge, here we report a stable, inexpensive and green-synthesized aluminium-based metal–organic framework (MIL-160) to separate the nitrotoluene mixtures. The appropriate pore size and pore environment permitted MIL-160 to exhibit a rare meta-nitrotoluene (m-NT) preference and always maintain the meta- > ortho- > para-nitrotoluene (m- > o- > p-NT) adsorption order in dynamic breakthrough and pulse modes as well as batch-mode adsorption. Theoretical calculations revealed that the abundant H/O atoms in the confined nanospace provided strong binding sites for selectively capturing nitrotoluene isomers. Specifically, due to difference in shape matching, the strongest host–guest interactions occurred in m-NT@MIL-160, followed by o-NT@MIL-160, and last p-NT@MIL-160. Notably, breakthrough experiments confirmed that a variety of binary and ternary mixtures can be separated via continuous adsorption. The dynamic adsorption stage of ternary mixture directly produced 0.33 mmol g−1 of pure p-NT, and the eluent in the desorption stage contained a high content of m-NT. Additional dynamic adsorption model fitting results indicated that the outstanding dynamic separation performance was also achieved from kinetic factors. These results lay the foundation for the effective separation of nitrotoluene mixtures.

Abstract Mo028: Persistence of Fetal Cardiac Troponin T Modulates Disease Severity in Anthracycline-Induced Cardiomyopathy

Anthracyclines are a key component in the management of pediatric cancers long recognized to carry significant risk of dose-dependent cardiotoxicity. Despite advancements in clinical management, considerable variation in the incidence of cardiotoxicity persists across dosing regimens suggesting modifiers exist. Recently, changes in the splicing of TNNT2, the gene encoding cardiac troponin T (cTnT), were postulated to contribute to anthracycline cardiotoxicity, potentially providing a direct link to the myofilament. Previous studies in our lab have demonstrated that the fetal isoform, cTnT1, is a potent modifier of cardiac function contributing to disease heterogeneity in animal models of cardiomyopathies. Thus, we hypothesize that the persistent expression of cTnT1 predisposes a subset of the population to anthracycline cardiomyopathy. Using molecular dynamics simulations (MD) and isothermal titration calorimetry (ITC), we assessed a range of anthracyclines for their potential to bind the cardiac thin filament (CTF). MD calculated Glide scores showed direct binding to the troponin complex. ITC indicated that this binding occurs at an order of magnitude higher affinity in complexes containing cTnT1. Stopped-flow kinetics of cTnT1 CTFs exposed to Doxorubicin showed an additive reduction in calcium dissociation rates, reinforcing our observations of direct binding to the CTF. Longitudinal 2D echocardiography of Doxorubicin treated mice (3mg/kg/week) indicated that both male and female cTnT1 mice exhibit an additive, dose-dependent reduction in cardiac systolic function compared to non-transgenic (NT) littermates. Consistent with clinical data, female mice exhibited an earlier reduction in % fractional shortening than males as well as delayed recovery after treatment cessation. Transcriptional profiling of mice treated with Doxorubicin revealed a 2- to 7-fold additive increase in type I and type II interferon signaling in cTnT1 mice above that observed in treated NT littermates. These data suggest that cTnT1 may increase binding of anthracyclines at the myofilament, eliciting accelerated cardiac dysfunction, and represent a unique, targetable genetic risk factor involved in anthracycline cardiotoxicity.

A Comparative Study of Phase I and II Hepatic Microsomal Biotransformation of Phenol in Three Species of Salmonidae: Hydroquinone, Catechol, and Phenylglucuronide Formation.

The in vitro biotransformation of phenol at 11 °C was studied using pre-spawn adult rainbow (Oncorhynchus mykiss) (RBT), brook (Salvelinus fontinalis) (BKT), and lake trout (Salvelinus namaycush) (LKT) hepatic microsomal preparations. The incubations were optimized for time, cofactor concentration, pH, and microsomal protein concentration. Formation of Phase I ring-hydroxylation and Phase II glucuronidation metabolites was quantified using HPLC with dual-channel electrochemical and UV detection. The biotransformation of phenol over a range of substrate concentrations (1 to 180 mM) was quantified, and the Michaelis-Menten kinetics constants, Km and Vmax, for the formation of hydroquinone (HQ), catechol (CAT), and phenylglucuronide (PG) were calculated. Species differences were noted in the Km values for Phase I enzyme production of HQ and CAT, with the following rank order of apparent enzyme affinity for substrate: RBT > BKT = LKT. However, no apparent differences in the Km for Phase II metabolism of phenol to PG were detected. Conversely, while there were no apparent differences in Vmax between species for HQ or CAT formation, the apparent maximum capacity for PG formation was significantly less in LKT than that observed for RBT and BKT. These experiments provide a means to quantify metabolic activation and deactivation of xenobiotics in fish, to compare activation and deactivation reactions across species, and to act as a guide for future predictions of new chemical biotransformation pathways and rates in fish. These experiments provided the necessary rate and capacity (Km and Vmax) inputs that are required to parameterize a fish physiologically based toxicokinetic (PB-TK) model for a reactive chemical that is readily biotransformed, such as phenol. In the future, an extensive database of these rate and capacity parameters on important fish species for selected chemical structures will be needed to allow the effective use of predictive models for reactive, biotransformation chemicals in aquatic toxicology and environmental risk assessment.

Sorption of divalent metal ions by modified carbopol-based adsorbent nanocomposite hydrogel

A new adsorbent, modified Carbopol 934-polyacrylamide network polymer (mCarbo-PAm hydrogel), embedded with silver nanoparticles, has been introduced to remove divalent metal ions. It was prepared by supporting nanosized "Ag" onto a porous modified carbopol 934-polyacrylamide polymer network using free radical polymerization. The nanogels were characterized by different methods, including Fourier Transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD), Thermogravimetric Analysis (TGA) and swelling kinetics. The outcome exhibited that the loading of Ag nanoparticles onto mCarbo-PAm hydrogel was successful in improving the swelling ability of the gel. The nanocomposite hydrogel sorption results indicated that the affinity order was Pb2+(96.52 %) > Cu2+(86.66 %) > Zn2+(69.64 %) at pH 6.7. Which is better than the mCarbo-PAm hydrogel sample: Pb2+(71.78 %) > Cu2+(69.54 %) > Zn2+(33.92 %). The kinetic results showed that sorption follows pseudo-second-order kinetics at pH 6.7. The thermodynamic studies verified that the adsorption processes were nonspontaneous in the case of Pb2+ and spontaneous in the cases of Cu2+ and Zn2+. The observed adsorption process is endothermic in nature. The work also highlights the reusability of the synthesised adsorbent for the metal ion sorption for upto 8 cycles, wherein, no compromise in adsorption capacity was observed till 5th cycle.

Atomic Insight into the Enzymatic Selectivity of Acetyltransferase for Endogenous Polyamines.

The N1-Spermidine/spermine acetyltransferase (SSAT) serves as the rate-limiting enzyme in the polyamine metabolism pathway, specifically catalyzing the acetylation of spermidine, spermine, and other specific polyamines. The source of its enzymatic selectivity remains elusive. Here, we used quantum mechanics and molecular mechanics simulations combined with various technologies to explore the enzymatic mechanism of SSAT for endogenous polyamines from an atomic perspective. The static binding and chemical transformation were considered. The binding affinity was identified to be dependent on protonated state of polyamine. The order of the binding affinity for Spm, Spd, and Put is consistent with the experimental results, which is also verified by the dynamic separation of polyamine and SSAT. Hydrogen bond interactions and salt bridges contribute most, and the common hot residues were identified. In addition, the transfer of acetyl and proton between polyamine and AcCoA was discovered to follow a concert mechanism, and thermodynamic properties are responsible for the catalytic efficiency of SSAT. This work may be helpful for development of polyamine derivatives based on catalysis to regulate polyamine metabolism.

Solvent Exchange Dynamics in M2(dobdc): An Interplay among Binding Strength, Exchange Kinetics, and Cooperativity.

Solvent exchange is a crucial step in ensuring the complete activation of metal-organic frameworks (MOFs); however, the conditions for solvent exchange vary among MOFs, even within the isostructural variants. This study examines the factors contributing to solvent exchange by investigating the isostructural M2(dobdc) (M═Mg, Co, Zn) series. Common solvents N,N-dimethylformamide (DMF), ethanol (EtOH), and methanol (MeOH) are employed to assess the solvent exchange at coordinatively unsaturated sites (CUS) of M2(dobdc). By monitoring both solvents released from the MOF during solvent exchange and the coordination environment of metals within the MOF, a picture is constructed of exchange rates during early stages of solvent exchange as well as expulsion of the last traces of bound solvents. This differentiation is achieved by a combination of bulk monitoring of solvent phase composition and microscopic application of Raman spectroscopy on the single-crystal level. The kinetics of solvent replacement is revealed to have a substantial contribution from cooperativity; this phenomenon is observed in both the forward and reverse directions. Thermogravimetric analysis coupled with IR spectroscopy and density functional theory (DFT) calculations are employed to elucidate the relationship between solvent exchange rates and solvent binding energy. The solvent exchange rates are determined by the kinetic barriers of solvent exchange that do not follow the order of the solvent binding affinity. This work contributes to understanding the solvent exchange of MOFs by examining the interplay among the binding strength, exchange kinetics, and cooperativity. It further provides valuable insights for scrutinizing MOF activation protocols.

Molecular-level insight into the origin-dependent adsorption fractionation of dissolved organic matter on ferrihydrite in aquatic environment: Implications for carbon sink in eutrophic lakes

Molecular fractionation of dissolved organic matter (DOM) induced by adsorption on minerals plays a significant role in carbon biogeochemical cycling in water environment. However, the molecular-level adsorption of algae-derived DOM (ADOM) on minerals in eutrophic lakes remains poorly understood. Herein, we investigated the ferrihydrite-induced adsorptive fractionation of ADOM and humic DOM for comparison by using spectral analysis, Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and solid characterization methods. We observed higher adsorption rate but lower adsorption capacity for ADOM than humic DOM. Spectroscopy and FT-ICR-MS indicated compounds with large molecular weight (>350 Da), high unsaturated and oxygen-rich were preferentially adsorbed for both ADOM and humic DOM. Specifically, the adsorption affinity order was aromatics > lignin-like > aliphatic compounds. Furthermore, tannin-like and condensed aromatics were predominantly adsorbed in humic DOM and protein-like formulas in ADOM. The solid characterization of ferrihydrite before and after adsorption further confirmed the dominant adsorption of aromatic and carboxylic-containing species in humic DOM and aliphatic materials in ADOM. Additionally, the contribution variation of oxygen atom to double bond in the molecular formula before and after adsorption identified absorbed oxygen-containing substances were predominantly aromatic carboxylic acids for humic DOM, but few aliphatic hydrocarbons substituted with ethers and alcohols for ADOM. These findings provided new insights into mineral-induced carbon sequestration, that is, increased release of ADOM in eutrophic lakes might influence the amount of organic carbon settled by ferrihydrite, and alter its quality from aromatic to aliphatic compounds transfer from water column to sediment through ferrihydrite adsorption.

Synergetic Triple Absorber Based High‐Efficiency Solar Cell Design

AbstractComputational analysis of triple absorber‐based solar cell structure is undertaken. This solar cell device configuration allows better utilization of the incident solar spectrum. Three different absorbers with a band gap in the range 1–1.5 eV are sandwiched between high‐doped p+ and n+ regions in descending order of electron affinity to form an energy‐matched multiple absorber device. A comprehensive analysis of key device parameters influencing performance, including band gap, conduction band alignment, interfacial defects, and thickness, is presented. The optimized triple absorber device shows beyond Shockley–Queisser limit (SQ limit) performance under the constraint of passivated interfaces with defect density below 1013 cm−2. Wide spectrum coverage leads to high short circuit current and an efficiency of 40.3%, which is higher than the SQ limit for single band gap solar cell.

Temperature effects and molecular insights towards the optimization of polyvinyl alcohol as adsorbent of organic pollutants from aqueous solution

One of the easier methods of wastewater treatment is adsorption due to its simplicity in implementation, environmental friendliness, and economic feasibility. Polyvinyl alcohol (PVA) looks promising as an adsorbent due to its biocompatible, non-toxic, water-soluble and eco-friendly nature. The investigation of PVA for its potential in the adsorption of pollutants has been reported in many studies but the mechanistic understanding of the adsorption is poor. The present study used a theoretical approach through density functional theory and Monte Carlo with molecular dynamics simulations to investigate the adsorption mechanism behaviors of model organic molecules (bromothymol blue (BTB), methylene blue (MB), metronidazole (MNZ) and tetracycline (TC)) on PVA surface. The quantum chemical calculations result showed that with the increase in PVA chains (2, 4, 8, 16, and 32 units), the zero-point energy decreases (from −308.79 to −4922.93 kcal/mol) while the dipole moment increases (from 4.37 to 87.52 Debye). Temperature effect on the PVA chain structures showed the same trends for all the chain units and with the increase in temperature (50–600 K), there are no appreciable changes in zero-point energy, enthalpy energy increases while Gibbs free energy decreases. Considering PVA-pollutant complexes, the effects of temperature on the structures showed that there are no appreciable changes in the zero-point energy, Gibbs free and thermal energies increase with an increase in temperature while the kinetic rate of reactions decreases with an increase in temperature. The enthalpy of the reaction showed different trends with antibiotic and dye complexes. In all the thermodynamic properties investigated and the rate of reaction, the order of affinity of the pollutants with PVA followed TC > MNZ > MB > BTB. Monte Carlo simulation was used to investigate the adsorption behavior of the pollutants on the surface of PVA. The negative adsorption energies (−366.56 to −2266.81 kcal/mol) in terms of affinity towards the pollutants on the surface of PVA followed the sequence TC > MNZ > BTB > MB and the molecular dynamic simulation results followed the same order. The obtained results give valuable insights into the mechanism and performance of PVA as an adsorbent. Most of these computational observations are in good agreement with the available experimental results.

Application of Novel Ruthenium (II) Polypyridyl Complexes as Robust DNA Probes, Optical Material and Antimicrobials-An Experimental and DFT Approach.

The nature of the interaction of DNA with heteroleptic Ruthenium (II) Polypyridyl complexes of the type [Ru (A)2TPIP]2+, where TPIP = 2-(1-p-tolyl-1H pyrazol-4 -yl)-1H-imidazo [4, 5-f[1. 10] phenanthroline and A = 1,10 phenanthroline (1),4,4'-dimethyl-1,10-ortho Phenanthroline (2),2,2' - bipyridine(3) and 4, 4' dimethyl 2, 2'- bipyridine (4), has been investigated by experimentaland molecular docking approaches. The order of the DNA binding affinities of the synthesised complexes is 1 > 2 > 3 > 4. The findings imply that the unsubstitutedcomplex has a better affinity to bind with DNA than the substituted (dmp and dmb) emphasizing the significance of the auxiliary ligand. Additionally, as the medium's ionic strength drops, the DNA/Ru ratio rises, or when water is displaced by glycerol, the intercalation of complexes into DNA increases. DFT calculations at the B3LYP/LANL2MBlevel was used for molecular geometry (Ground State) and electronic characteristic calculations. The HOMO-LUMO gap of the Ru [II]complex is less than the intercalator and hence kinetically labile. Among the complexes, the bpy complex has shown utmost non-linear optical properties (α = -153.9099 10-24esuand β = 3.8498 10-30esu). The docking study shows the significance of the Metal-intercalator's shorter length may increase DNA binding affinity. This study divulges that the Ruthenium (II) polypyridyl complexes bind to DNA preponderantly by intercalation supporting Viscosity studies. All the complexes have a considerable attraction for guanine. The standarddiskdiffusion method reveals that complexes (1,2,3 and 4) have good antibacterial activity.

Potential Common Mechanisms of Cytotoxicity Induced by Organophosphorus Pesticides via NLRP3 Inflammasome Activation.

The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1β, IL-18), in which the order of cytotoxicity was dichlorvos>dipterex>dibrom>paraoxon>fenthion>dimethoate, based on the IC50 values of 274, 410, 551, 585, 2,158, and 1,527,566μM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1β, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate>paraoxon>dichlorvos>dibrom>(fenthion and dipterex) based on K D values of 89.8, 325, 1,460, and 2,690μM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning.

KcsA-Kv1.x chimeras with complete ligand-binding sites provide improved predictivity for screening selective Kv1.x blockers

Despite significant advances in the development of therapeutic interventions targeting autoimmune diseases and chronic inflammatory conditions, lack of effective treatment still poses a high unmet need. Modulating chronically activated T cells through the blockade of the Kv1.3 potassium channel is a promising therapeutic approach, however, developing selective Kv1.3 inhibitors is still an arduous task. Phage display-based high throughput peptide library screening is a rapid and robust approach to develop promising drug candidates; however, it requires solid-phase immobilization of target proteins with their binding site preserved. Historically, the KcsA bacterial channel chimera harboring only the turret region of the human Kv1.3 channel was used for screening campaigns. Nevertheless, literature data suggest that binding to this type of chimera does not correlate well with blocking potency on the native Kv1.3 channels. Therefore, we designed and successfully produced advanced KcsA-Kv1.3, -Kv1.1 and -Kv1.2 chimeric proteins in which both the turret and part of the filter regions of the human Kv1.x channels were transferred. These T+F (turret-filter) chimeras showed superior peptide ligand binding predictivity compared to their T-only versions in novel phage ELISA assays. Phage ELISA binding and competition results supported with electrophysiological data confirmed that the filter region of KcsA-Kv1.x is essential for establishing adequate relative affinity order among selected peptide toxins (Vm24 toxin, Hongotoxin-1, Kaliotoxin-1, Maurotoxin, Stichodactyla toxin) and consequently obtaining more reliable selectivity data. These new findings provide a better screening tool for future drug development efforts and offer insight into the target-ligand interactions of these therapeutically relevant ion channels.