CD-CODE: crowdsourcing condensate database and encyclopedia.

The discovery of biomolecular condensates transformed our understanding of intracellular compartmentalization of molecules. To integrate interdisciplinary scientific knowledge about the function and composition of biomolecular condensates, we developed the crowdsourcing condensate database and encyclopedia ( cd-code.org ). CD-CODE is a community-editable platform, which includes a database of biomolecular condensates based on the literature, an encyclopedia of relevant scientific terms and a crowdsourcing web application. Our platform will accelerate the discovery and validation of biomolecular condensates, and facilitate efforts to understand their role in disease and as therapeutic targets.

α-Glucosidase inhibitory potential of Oroxylum indicum using molecular docking, molecular dynamics, and in vitro evaluation.

Background: According to the International Diabetes Federation, there will be 578 million individuals worldwide with diabetes by 2030 and 700 million by 2045. One of the promising drug targets to fight diabetes is α-glucosidase (AG), and its inhibitors may be used to manage diabetes by reducing the breakdown of complex carbohydrates into simple sugars. The study aims to identify and validate potential AG inhibitors in natural sources to combat diabetes. Methods: Computational techniques such as structure-based virtual screening and molecular dyncamic simulation were employed to predict potential AG inhibitors from compounds of Oroxylum indicum. Finally, in silico results were validated by in vitro analysis using n-butanol fraction of crude methanol extracts. Results: The XP glide scores of top seven hits OI_13, OI_66, OI_16, OI_44, OI_43, OI_20, OI_78 and acarbose were -14.261, -13.475, -13.074, -13.045, -12.978, -12.659, -12.354 and -12.296 kcal/mol, respectively. These hits demonstrated excellent binding affinity towards AG, surpassing the known AG inhibitor acarbose. The MM-GBSA dG binding energies of OI_13, OI_66, and acarbose were -69.093, -62.950, and -53.055 kcal/mol, respectively. Most of the top hits were glycosides, indicating that active compounds lie in the n-butanol fraction of the extract. The IC50 value for AG inhibition by n-butanol fraction was 248.1 µg/ml, and for that of pure acarbose it was 89.16 µg/ml. The predicted oral absorption rate in humans for the top seven hits was low like acarbose, which favors the use of these compounds as anti-diabetes in the small intestine. Conclusion: In summary, the study provides promising insights into the use of natural compounds derived from O. indicum as potential AG inhibitors to manage diabetes. However, further research, including clinical trials and pharmacological studies, would be necessary to validate their efficacy and safety before clinical use.

Versatile pulse sequence device to conserve hyperpolarization for NMR and MRI studies.

PURPOSE: Levitt and co-workers have described the M2S pulse sequence which transfers between longitudinal and singlet spin order. Building on this work, we describe the construction of a portable M2S pulse sequence generator to increase the relaxation time of polarized compounds. Additionally, we investigate the efficiency of spin order transfer under conditions where physical parameters of the system are not known precisely. THEORY AND METHODS: A portable M2S generator is built. Longitudinally polarized N2O is converted to the singlet state by both adiabatic transfer and by the M2S sequence. Density matrix simulations are used to model the effects of mismatched chemical shift, flip angle, and scalar couplings. RESULTS: Density matrix simulations suggest that to convert 95% of the longitudinal m = 1 triplet state population to the singlet order we must match the Larmor precession frequency to the excitation radiofrequency field by 10%, the scalar couplings must be determined to better than 0.6%, and the flip angle must be calibrated to better than 2%. CONCLUSION: The sequence is robust against many mismatched physical parameters of the species we are converting. Additionally, the instrument's portability allows for the conversion of hyperpolarized species near a polarizer. The lifetime is increased by ∼12-fold. This is highly advantageous in systems where the hyperpolarized media relax rapidly.

Low-temperature dynamic nuclear polarization of gases in Frozen mixtures.

PURPOSE: To present a new cryogenic technique for preparing gaseous compounds in solid mixtures for polarization using dynamic nuclear polarization (DNP). METHODS: (129) Xe and (15) N2 O samples were prepared using the presented method. Samples were hyperpolarized at 1.42K at 5 Tesla. (129) Xe was polarized at 1.65K and 1.42K to compare enhancement. Polarization levels for both samples and T1 relaxation times for the (129) Xe sample were measured. Sample pulverization for the (129) Xe and controlled annealing for both samples were introduced as additional steps in sample preparation. RESULTS: Enhancement increased by 15% due to a temperature drop from 1.65K to 1.42K for the (129) Xe sample. A polarization level of 20 ± 3% for the (129) Xe sample was achieved, a two-fold increase from 10 ± 1% after pulverization of the sample at 1.42K. T1 of the (129) Xe sample was increased by more than three-fold by means of annealing. In the case of (15) N2 O, annealing led to a ∼two-fold increase in the signal level after DNP. CONCLUSION: The presented technique for producing and manipulating solid gas/glassing agent/radical mixtures for DNP led to high polarization levels in (129) Xe and (15) N2 O samples. These methods show potential for polarizing other gases using DNP technology. Magn Reson Med 76:1007-1014, 2016. © 2015 Wiley Periodicals, Inc.

Efficient production of hyperpolarized bicarbonate by chemical reaction on a DNP precursor to measure pH.

PURPOSE: To produce hyperpolarized bicarbonate indirectly via chemical reaction from a hyperpolarized precursor and utilize it for the simultaneous regional measurement of metabolism and pH. METHODS: Alpha keto carboxylic acids are first hyperpolarized by dissolution dynamic nuclear polarization (DNP). These precursor molecules are rapidly reacted with hydrogen peroxide (H2O2) to decarboxylate the species, resulting in new target molecules. Unreacted H2O2 is removed from the system by reaction with sulfite. Interrogation of the ratio of dissolved carbon dioxide (CO2) to bicarbonate can be used to determine pH. RESULTS: Conversion of hyperpolarized alpha keto acids to bicarbonate and CO2 results in a minimal loss of the spin order. The reaction can be conducted to completion within seconds and preserves the nuclear spin polarization. CONCLUSION: Through a rapid chemical reaction, we can conserve the nuclear spin order of a DNP precursor to generate multiple hyperpolarized bioprobes otherwise unamenable to polarization. This indirect technique for the production of hyperpolarized agents can be applied to different precursor compounds to generate additional novel probes.

Significance of Chalcone Scaffolds in Medicinal Chemistry.

Chalcone is a simple naturally occurring α,ß-unsaturated ketone with biological importance, which can also be easily synthesized in laboratories by reaction between two aromatic scaffolds. In plants, chalcones occur as polyphenolic compounds of different frameworks which are bioactive molecules that have been in traditional medicinal practice for many years. Chalcone-based lead molecules have been developed, possessing varied potentials such as antimicrobial, antiviral, anti-inflammatory, anticancer, anti-oxidant, antidiabetic, antihyperurecemic, and anti-ulcer effects. Chalcones contribute considerable fragments to give important heterocyclic molecules with therapeutic utilities targeting various diseases. These characteristic features have made chalcone a topic of interest among researchers and have attracted investigations into this widely applicable structure. This review highlights the extensive exploration carried out on the synthesis, biotransformations, chemical reactions, hybridization, and pharmacological potentials of chalcones, and aims to provide an extensive, thorough, and critical review of their importance, with emphasis on their properties, chemistry, and biomedical applications to boost future investigations into this potential scaffold in medicinal chemistry.

Identification of phytoconstituents from Dicliptera paniculata and study of antibacterial activity guided by molecular docking.

According to WHO, antibiotic resistance is one of the biggest healthcare challenges to the global community. Therefore, it is absolutely essential to discover new antibiotics to address the challenge. Dicliptera paniculata (ForssK.) I. Darbysh, a rare medicinal herb of Acanthaceae, is known for its noteworthy uses as a flavoring, spicing, and antibacterial agent. The primary goal of the study is to identify novel antibacterials from D. paniculata. The petroleum ether fraction of the methanol extract of D. paniculata was subjected to GC-MS and identified 14 compounds. Several bacterial target proteins were used for molecular docking. The antibacterial activity of petroleum-ether fraction was evaluated on bacteria whose target protein interacts most strongly with identified molecules. The molecules DP_02, DP_06, and DP_14 exhibited the highest docking scores with Staphylococcus aureus dihydrofolate reductase, which were - 6.283, - 7.705, and - 6.364 kcal/mol, respectively. The MM-GBSA binding energy of compounds DP_02, DP_06, and DP_14 were - 46.736, - 42.366, and - 35.734 kcal/mol, respectively. The MM-GBSA binding energy and decent docking score of the compounds DP_02 and DP_06 were both encouraging, and both of the compounds are drug-like. The finding was validated through studies on antibacterial effectiveness against S. aureus and showed encouraging results. These two molecules might serve as the building blocks for the future development of potent antibiotics.

Potential peptidyl arginine deiminase type 4 inhibitors from Morinda citrifolia: a structure-based drug design approach.

The World Health Organization estimates that more than 23 million individuals worldwide suffer from rheumatoid arthritis (RA), a chronic systemic autoimmune disease and experts predict that the number of RA patients may double by 2030. A substantial portion of RA patients do not respond effectively to the treatment that are already available therefore there is an urgent need of innovative new drugs. Over the past several years, Peptidyl Arginine Deiminase Type 4 (PAD4) receptors have become potential therapeutic targets for the treatment of RA. The main objective of the present study is to identify potential PAD4 inhibitors from edible fruits Morinda citrifolia. Structure based virtual screening (VS) of 60 compounds from M. citrifolia were performed to identify PAD4 inhibitors. The virtual screening of compounds resulted ten hits having XP-Glide score greater than the co-ligand (XPGS: - 8.341 kcal/mol). Three hits NF_15, NF_34, and NF_35 exhibited admirable MM-GBSA dG binding energy - 52.577, - 46.777, and - 60.711 kcal/mol, respectively. These three compounds were chosen for 100 ns molecular dynamics (MD) simulations in order to evaluate the stability and interactions. The protein-ligand complex with the highest level of stability was revealed to be NF_35. Therefore, M. citrifolia fruits may be beneficial in the treatment and prevention of rheumatoid arthritis since it contains potential hits. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00147-3.

A review of innovative approaches for onsite management of PFAS-impacted investigation derived waste.

The historic use of aqueous film-forming foam (AFFF) has led to widespread detection of per- and polyfluoroalkyl substance (PFAS) in groundwater, soils, sediments, drinking water, wastewater, and receiving aquatic systems throughout the United States (U.S.). Prior to any remediation activities, in order to identify the PFAS-impacted source zones and select the optimum management approach, extensive site investigations need to be conducted. These site investigations have resulted in the generation of considerable amount of investigation-derived waste (IDW) which predominantly consists of well purging water and drill fluid, equipment washing residue, soil, drill cuttings, and residues from the destruction of asphalt and concrete surfaces. IDW is often impacted by varying levels of PFAS which poses a substantial challenge concerning disposal to prevent potential mobilization of PFAS, logistical complexities, and increasing requirement for storage as a result of accumulation of the associated wastes. The distinct features of IDW involve the intermittent generation of waste, substantial volume of waste produced, and the critical demand for onsite management. This article critically focuses on innovative technologies and approaches employed for onsite treatment and management of PFAS-impacted IDW. The overall objective of this study centers on developing and deploying end-of-life treatment technology systems capable of facilitating unrestricted disposal, discharge, and/or IDW reuse on-site, thereby reducing spatial footprints and mobilization time.

Determination of the singlet state lifetime of dissolved nitrous oxide from high field relaxation measurements.

Longitudinal spin relaxation due to modulation of dipolar interactions often limits the development of hyperpolarized magnetic tracers. Recently, it has been demonstrated that transferring spin order to a singlet state significantly increases the polarization lifetimes in systems where nitrous oxide is dissolved in a liquid solvent. Additionally, previous studies have suggested that the longitudinal relaxation of nitrous oxide is largely dominated by the spin-rotation interaction. Models of spin-relaxation under Brownian motion naïvely predict the angular momentum reorienting correlation time of the spin rotation interaction to be inversely proportional to the viscosity of the solution. This dependence implies the singlet lifetime can be lengthened by increasing the dissolving solvent's viscosity-an extension which is not observed. Our work formulates a model which describes the relaxation of nitrous oxide dissolved in various solvents. We investigate the effect of altering the temperature of the solvent, as well as the effect of varying solute-solvent interactions on the singlet state as well as the longitudinal polarization lifetime. We predict the singlet lifetime for nitrous oxide dissolved in several solvents by fitting rotational and angular momentum correlation times measured at high magnetic field, and relate singlet relaxation to translational diffusion constants.

Development of Fluoride Protective Values for Aquatic Life Using Empirical Bioavailability Models.

The derivation of protective values for aquatic life can be enhanced by the development and use of bioavailability models. Recent advances to metals bioavailability modeling are applicable to other analyte groups and should be widely considered. We conducted a meta-analysis of the available aquatic toxicity literature for fluoride to evaluate the utility of hardness, alkalinity, and chloride as toxicity-modifying factors (TMFs) in empirical bioavailability models of freshwater taxa. The resulting optimal multiple linear regression model predicting acute fluoride toxicity to the invertebrate Hyalella azteca included all three TMFs (observed vs. predicted 50% lethal concentrations, R2 = 0.88) and the optimal model predicting toxicity to the fish Oncorhynchus mykiss included alkalinity and hardness (R2 = 0.37). At >20 mg/L chloride, the preliminary final acute values for fluoride were within 1 order of magnitude and ranged from approximately 18.1 to 56.3 mg/L, depending on water chemistry. Sensitivity of H. azteca to low-chloride conditions increased model uncertainty when chloride was <20 mg/L. Because of limited toxicity data, chronic bioavailability models were not developed, and final chronic values were derived using an acute-to-chronic ratio (ACR) approach. Accounting for TMFs, the geometric mean ACR was 5.4 for fish and invertebrate taxa (n = 6). The present assessment highlights the need to expand bioavailability modeling to include inorganic anions, particularly fluoride, and demonstrates that existing promulgated protective values for fluoride are likely overly conservative. More toxicological studies are recommended to further refine multivariate empirical bioavailability models for inorganic anions. Environ Toxicol Chem 2022;41:396-409. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Identifying and Managing Aqueous Film-Forming Foam-Derived Per- and Polyfluoroalkyl Substances in the Environment.

The use of aqueous film-forming foam (AFFF) has resulted in the widespread occurrence of per- and polyfluoroalkyl substances (PFAS) in groundwater, drinking water, soils, sediments, and receiving waters throughout the United States and other countries. We present the research and development efforts to date by the Strategic Environmental Research and Development Program (SERDP) and the Environmental Security Technology Certification Program (ESTCP) to measure PFAS in the environment, characterize AFFF-associated sources of PFAS, understand PFAS fate and behavior in the environment, assess the risk to ecological receptors, develop in situ and ex situ treatment technologies for groundwater, treat soils and investigation-derived wastes, and examine the ecotoxicity of PFAS-free fire suppression formulations. Environ Toxicol Chem 2021;40:24-36. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Designing oscillating cilia that capture or release microscopic particles.

We use computational modeling to capture the three-dimensional interactions between oscillating, synthetic cilia and a microscopic particle in a fluid-filled microchannel. The synthetic cilia are elastic filaments that are tethered to a substrate and are actuated by a sinusoidal force, which is applied to their free ends. The cilia are arranged in a square pattern, and a neutrally buoyant particle is initially located between these filaments. Our computational studies reveal that, depending on frequency of the beating cilia, the particle can be either driven downward toward the substrate or driven upward and expelled into the fluid above the cilial layer. This behavior mimics the performance of biological cilia used by certain marine animals to extract suspended food particles. The findings uncover a new route for controlling the deposition of microscopic particles in microfluidic devices.

Stereoselective Synthesis of Spirooxindole Derivatives Using One-Pot Multicomponent Cycloaddition Reaction and Evaluation of Their Antiproliferative Efficacy.

A highly stereoselective, one-pot, multicomponent method has been developed to synthesize pyrrolizidine- and N-methyl pyrrolidine-substituted spirooxindole derivatives. The [3 + 2] cycloaddition reaction involves the reaction between the dipole azomethine ylides, generated in situ from the reaction between isatin and secondary amino acids such as L-proline or sarcosine, and α,ß-unsaturated carbonyl compounds as the dipolarophile. The reaction condition was optimized to achieve excellent regio- and stereoselectivity. Products were obtained in good yield using ethanol as a solvent at the reflux temperature. The newly synthesized spirooxindole derivatives were evaluated for their antiproliferative efficacy against National Cancer Institute (NCI)-60 cancer cell lines and DNA G-quadruplex (G4) interaction capacity. Compound 14b produced selective cytotoxicity against leukemia, renal, colon, and prostate cancer cell lines at a 10 µM concentration. The G4 interaction studies further suggested that these spirooxindole derivatives were devoid of any activity as DNA G4 ligands.

Comparison of alkaline industrial wastes for aqueous mineral carbon sequestration through a parallel reactivity study.

Thirty-one alkaline industrial wastes from a wide range of industrial processes were acquired and screened for application in an aqueous carbon sequestration process. The wastes were evaluated for their potential to leach polyvalent cations and base species. Following mixing with a simple sodium bicarbonate solution, chemistries of the aqueous and solid phases were analyzed. Experimental results indicated that the most reactive materials were capable of sequestering between 77% and 93% of the available carbon under experimental conditions in four hours. These materials - cement kiln dust, spray dryer absorber ash, and circulating dry scrubber ash - are thus good candidates for detailed, process-oriented studies. Chemical equilibrium modeling indicated that amorphous calcium carbonate is likely responsible for the observed sequestration. High variability and low reactive fractions render many other materials less attractive for further pursuit without considering preprocessing or activation techniques.