bluuebunny/crossref_metadata_2025 huggingface dataset:
Flash nanoprecipitation for the production of endosomolytic polymersomes for cytosolic drug delivery
Authors: Pagendarm Hayden M , Stone Payton T , Baljon Jessalyn J , Aziz Mina H , Pastora Lucinda E , Wilson John T
Published: February 2022

The delivery of biomacromolecular drugs to cytosolic targets has been a long-standing engineering challenge due to the presence of multiple biological barriers including cellular and endosomal membranes. Although many promising carriers designed to facilitate endosomal escape have been developed, the clinical translation of these carriers is often limited by complex production processes that are not amenable to scaled-up manufacturing. In this study, we employed flash nanoprecipitation (FNP) for the rapid, scalable, and reproducible assembly of nanocarriers composed of the pH-responsive, endosomolytic diblock copolymer poly[(ethylene glycol)x-block-[((2-diethylamino) ethyl methacrylate)0.6-co-(butyl methacrylate)0.4]y (PEG-b-DEAEMA-co-BMA). We found that varying the second block molecular weight, while holding the first block molecular weight constant, significantly influenced nanoparticle self-assembly and hence nanocarrier properties and function – including drug encapsulation, endosomolytic capacity, cytotoxicity, and in vitro activity of a cytosolically-active drug cargo, a cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonist. We found that while increasing second block molecular weight enhanced the capacity of nanocarriers to induce endosomal destabilization, larger second block molecular weights also lead to increased cytotoxicity, increased particle size and heterogeneity, increased the encapsulation efficiency of small (<0.5 kDa) hydrophilic drugs, decreased the encapsulation efficiency of large (10 kDa) hydrophilic biomacromolecules, and decreased long-term particle stability. Collectively, these results demonstrate the utility of FNP for the rapid and scalable production of uniform PEG-b-DEAEMA-co-BMA nanocarriers and implicate an optimal hydrophilic mass fraction for balancing desirable nanoparticle properties with cytosolic cargo delivery efficiency.
Brønsted Acid-Catalyzed Stereospecific Dearomative Spirocyclization of Benzothiophenyl Analogues of Tertiary cis-β-Benzylstyrenes
Authors: Tohti Anargul , Lerda Victoria , Stokes Benjamin J.
Published: February 2022

3-Substituted benzothiophenyl analogues of tertiary cis-β-benzylstyrenes undergo triflic acid-catalyzed dearomative spirocyclization to afford vicinal quaternary center-containing compounds at room temperature. Hydroarylation of the styrene is a competing process that could be selected for in substrates possessing electron-rich styrenyl alkenes, or an indole in place of the benzothiophene.
Towards Chloride-Free Organic Electrolytes for Rechargeable Aluminum Batteries
Authors: Slim Zaher , Menke Erik
Published: February 2022

The corrosivity of chloride-based electrolytes is a major shortcoming in the practical realization of rechargeable aluminum batteries. Herein, the effect of Cl- on Al speciation and electrochemistry in tetrahydrofuran was measured by employing theoretical and experimental approaches for three systems: Al(OTF)3/THF, Al(OTF)3 plus LiCl in THF, and AlCl3/THF. The high consistency between measured and computed spectroscopic aspects associated with Al(OTF)3/THF electrolyte provided both a rationale for understanding Al complex-ion formation in a Cl- free environment and an approach for examining the effect of Cl- on Al speciation. Room-temperature Al plating was achieved from dilute solutions ([Al] = 0.1M) at potentials ≥ 0V (vs. Al⁄Al3+). Cl- is found to enable facile Al plating and SEM reveals that Al is electrochemically deposited as nanocrystalline grains.
Aluminum Electrodeposition from Chloride-Rich and Chloride-Free Organic Electrolytes
Authors: Slim Zaher , Menke Erik
Published: February 2022

The corrosivity of chloride-based electrolytes is a major shortcoming in the practical realization of rechargeable aluminum batteries. Herein, the effect of Cl- on Al speciation and electrochemistry in tetrahydrofuran was measured by employing theoretical and experimental approaches for three systems: Al(OTF)3/THF, Al(OTF)3 plus LiCl in THF, and AlCl3/THF. The high consistency between measured and computed spectroscopic aspects associated with Al(OTF)3/THF electrolyte provided both a rationale for understanding Al complex-ion formation in a Cl- free environment and an approach for examining the effect of Cl- on Al speciation. Room-temperature Al plating was achieved from dilute solutions ([Al] = 0.1M) at potentials ≥ 0V (vs. Al⁄Al3+). Cl- is found to enable facile Al plating and SEM reveals that Al is electrochemically deposited as nanocrystalline grains.
DL_FFLUX: a parallel, quantum chemical topology force field
Authors: Symons Ben , Bane Michael , Popelier Paul
Published: February 2022

DL_FFLUX performs molecular dynamics for flexible molecules endowed with polarisable QTAIM atomic multipole moments, predicted by the machine learning method Gaussian Process Regression. Newly optimised and parallelised using domain-decomposition MPI, DL_FFLUX now operates in reasonable time frames. DL_FFLUX is delivered as an add-on to the widely distributed molecular dynamics code DL_POLY 4.08. For the systems studied here (10**3-10**5 atoms), DL_FFLUX adds minimal computational cost to the standard DL_POLY package. The parallel DL_FFLUX preserves the quality of the scaling of the MPI implementation in standard DL_POLY. For the first time it is feasible to use the full capability of DL_FFLUX to study systems that are large enough to be of real world interest. For example, a fully flexible, high-rank polarised (up to and including quadrupole moments) 1 ns simulation of a system of 10,125 atoms (3,375 water molecules) takes 30 hours (wall time) on 18 cores.
Nacre-like alumina composites reinforced by zirconia particles
Authors: Henry Ronan , Saad Hassan , Dankic-Cottrino Sandrine , Deville Sylvain , Meille Sylvain
Published: February 2022

Nacre-like alumina is a class of bio-inspired ceramic composite manufactured by field-assisted sintering of green bodies made primarily of alumina platelets with an anisotropic microstructure. Here we investigate the addition of zirconia particles to enhance the mechanical properties of the composite. The resulting structure is a nacre- like anisotropic structure which features deflection and reinforcement during crack propagation. Monoclinic zirconia has no impact on the mechanical properties of the composite while tetragonal zirconia improves its fracture resistance properties. Both types of zirconia seem to slow down grain growth during sintering. The addition of zirconia stabilised in the tetragonal phase is thus a good option to obtain a composite with a fine microstructure and higher mechanical properties than a standard nacre-like alumina, with a flexural strength of 626 ± 39 MPa and a crack initiation toughness of 6.1 ± 0.6 MPa.m0.5.
Shaping student confidence and their perception of learning in undergraduate chemistry and biochemistry courses
Authors: Gould Timothy
Published: February 2022

This study examined factors influencing student confidence and their perception of learning in the context of undergraduate chemistry and biochemistry courses. Anonymous online surveys were used to measure the extent to which small group work influenced student confidence in solving problems compared to working individually, as well as how various course factors and the amount of effort and pleasure students experienced during their coursework influenced their perception of learning. Upon examining over 2500 student responses to more than 150 unique problems/exercises across 3 different courses, student confidence in solving problems improved to an average of approximately 8 out of 10 when they worked in small groups, compared to that of 6.5 out of 10 when working alone. Students ranked (i) opportunities to revisit assessments, (ii) the class environment, and (iii) instructor feedback as course factors that were most influential on their learning. There was little if any correlation between student effort and their perception of learning, and their perception of learning only slightly correlated with the amount of pleasure they experienced during their coursework. Taken together, these data highlight the importance of facilitating regular small group work, multistage assessments, good feedback and a pleasurable learning environment for students.
Cationic Effects on the Effective Hydrogen Atom Bond Dissociation Free Energy of High Valent Manganese Imido Complexes
Authors: Leonard Nadia , Chantarojsiri Teera , Ziller Joseph , Yang Jenny
Published: February 2022

Local electric fields can alter energy landscapes to impart enhanced reactivity in enzymes and at surfaces. There has been renewed interest on their use in molecular systems, where they can be installed using charged functionalities. Manga-nese(V) salen nitrido complexes (salen = N,N’-ethylenebis(salicylideneaminato)) appended with a crown ether unit con-taining a Na+ (1-Na), K+, (1-K), Ba2+ (1-Ba), Sr2+ (1-Sr), La3+ (1-La), or Eu3+ (1-Eu) cation were investigated to experimen-tally demonstrate the effect of cation-induced electric fields on pKa, E1/2, and the effective bond dissociation free energy (BDFE) of N–H bonds. The series, which includes the manganese (V) salen nitrido without a crown appended, spans 4 units of charge. Bounds for the pKa values of the transient imido complexes were determined by UV-visible and 1H NMR spectroscopy. These values, together with the reduction potentials for the Mn(VI/V) couple measured by cyclic voltamme-try in acetonitrile, were used to calculated the N–H BDFEs of the imidos. Despite spanning >700 mV and >9 pKa units across the series, the hydrogen atom BDFE only spans ~ 5 kcal/mol (between 76 and 81 kcal/mol). These results suggest that incorporation of cationic functionalities is an effective strategy for accessing wide ranges of reduction potentials and pKa while minimally affecting BDFE, which is essential to modulating electron, proton, or hydrogen atom transfer path-ways.
Prediction of the chemical context for Buchwald-Hartwig coupling reactions
Authors: Genheden Samuel , Mårdh Agnes , Lahti Gustav , Engkvist Ola , Olsson Simon , Kogej Thierry
Published: February 2022

We present machine learning models for predicting the chemical context for Buchwald-Hartwig coupling reactions. Using reaction data from in-house electronic lab notebooks, we train two models: one based on single-label data and one based on multi-label data. Both models show excellent top-3 accuracy around 90%, which suggests strong predictivity. There seems to be an advantage of including multi-label data because the multi-label model shows higher accuracy and better sensitivity for the individual contexts than the single-label model. Although the models are performant, we also show that such models need to be re-trained periodically. There is a strong temporal characteristic to the usage of different contexts. Therefore, a model trained on historical data will decrease in usefulness with time as newer and better contexts emerge and replace older ones. We hypothesize that these significant transitions in the context-use will likely affect any model predicting chemical contexts trained on historical data. Consequently, training such models warrants careful planning of what data is used for training and how often the model needs to be re-trained.
Simultaneous monitoring of monoclonal antibody variants by strong cation-exchange chromatography hyphenated to mass spectrometry to assess biosimilar-ity of rituximab-based biotherapeutics
Authors: Di Marco Fiammetta , Berger Thomas , Esser-Skala Wolfgang , Rapp Erdmann , Regl Christof , Huber Christian G.
Published: February 2022

The increasing importance of biosimilars in the biopharmaceutical market leads to high demands for enhanced protein characterization methods. Different manufacturing processes can lead to a significant variability of biotherapeutics arising from chemical and enzymatic post translational modifications (PTMs), resulting in the co-existence of a plethora of proteoforms with different physicochemical properties. Thus, biosimilarity to the originator product must be proven rigorously. Among these PTMs, N-terminal pyroglutamate formation, C-terminal lysine clipping, glycosylation, glycation, and deamidation lead to differences in the net charge of the protein, resulting in charge variants (CV). To unravel the heterogeneity of these proteoforms, Strong Cat-ion eXchange (SCX) High-Performance Liquid Chromatography (HPLC) is routinely used. However, the use of non-volatile salts makes the technique incompatible for hyphenation to mass spectrometry (MS). Recently, an approach employing volatile salts and a pH gradient was applied for CV analysis, opening the era of SCX-HPLC-MS approaches. Here, we apply an already established SCX-HPLC-MS approach by Füssl et al. to characterize two Rituximab-based biotherapeutics, the originator MabThera® and its Indian copy product Reditux™. The study assessed molecular differences between the two drug products and constitutes the basis for biosimilarity characterization using a fast SCX-HPLC-MS approach.
meso-Antracenyl-BODIPY dyad as a new photocatalyst in ATRA reac-tions
Authors: Abuhadba Sara , Tsuji Miu , MANI TOMOYASU , Esipova Tatiana
Published: February 2022

We demonstrate that because of the efficient generation of triplet excited state under UV or visible-light irradiation, meso-antracenyl-BODIPY donor-acceptor dyad can catalyze ATRA reactions between bromomalonate and alkenes. This finding paves the way for the design and application of the new type of heavy atom-free organic chromophores for photocatalysis.
Wildfire Smoke Impacts on Indoor Air Quality Assessed Using Crowdsourced Data in California
Authors: Liang Yutong , Sengupta Deep , Campmier Mark Joseph , Apte Joshua , Lunderberg David M. , Goldstein Allen
Published: February 2022

Wildfires have become the dominant source of particulate matter (PM2.5, < 2.5 µm diameter) leading to unhealthy air quality index occurrences in the western United States. Since people mainly shelter indoors during wildfire smoke events, the infiltration of wildfire PM2.5 into indoor environments is a key determinant of human exposure, and is potentially controllable with appropriate awareness, infrastructure investment, and public education. Using time-resolved observations outside and inside over 1400 buildings from the crowdsourced PurpleAir sensor network in California, we found that infiltration ratios (indoor PM­2.5 of outdoor origin/outdoor PM2.5) were reduced on average from 0.4 during non-fire days to 0.2 during wildfire days. Even with reduced infiltration, mean indoor concentration of PM2.5 nearly tripled during wildfire events, with lower infiltration in newer buildings and those utilizing air conditioning or filtration.
Biocatalytic One-Carbon Ring Expansion of Aziridines to Azetidines via a Highly Enantioselective [1,2]-Stevens Rearrangement
Authors: Miller David , Lal Ravi , Marchetti Luca , Arnold Frances
Published: February 2022

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new, abiologcal activity of engineered ‘carbene transferase’ enzymes. A laboratory-evolved variant of cytochrome P450BM3, P411-AzetS, not only overrides the inherent reactivity of aziridinium ylides to undergo cheletropic extrusion of ethylene, it also exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement, a notoriously challenging reaction class for asymmetric catalysis. These unprecedented selectivities enable an entirely new strategy for the synthesis of chiral azetidine products from readily available synthetic precursors. The utility of this reaction is highlighted by the synthesis of an enantiopure azetidine on gram scale. The exquisite selectivity of the enzyme enables new-to-nature ring-expansion chemistry that overcomes a longstanding synthetic problem
Cu-Catalyzed Cross-Coupling of Nitroarenes with Aryl Boronic Acids to Construct Diarylamines.
Authors: Guan Xinyu , Driver Tom
Published: February 2022

The development and study of a simple copper-catalyzed reaction of nitroarenes with aryl boronic acids to form diarylamines that uses phenyl silane as the stoichiometric terminal reductant is described. This cross-coupling reaction requires as little as 2 mol % of CuX and 4 mol% of diphosphine for success and tolerates a broad range of functional groups on either the nitroarene or the aryl boronic acid with to afford the amine in good yield. Mechanistic investigations established that the cross-coupling reaction proceeds via a nitrosoarene intermediate and that copper is required to catalyze both the deoxygenation of the nitroarene to afford the nitrosoarene and C–NAr bond formation of the nitrosoarene with the aryl boronic acid.
Porphyrin as a Versatile Visible-Light-Activatable Organic/Metal Hybrid Photoremovable Protecting Group
Authors: Sekhar Adiki Raja , Chitose Youhei , Janoš Jiří , Israeli Dangoor Sahar , Ramundo Andrea , Satchi Fainaro Ronit , Slavíček Petr , Klán Petr , Weinstain Roy
Published: February 2022

Photoremovable protecting groups (PPGs) represent one of the main contemporary implementations of photochemistry in diverse fields of research and practical applications. For the past half century, organic and metal-complex PPGs were considered mutually exclusive classes, each of which providing unique sets of physical and chemical properties thanks to their distinctive structures. Here, we introduce the meso-methylporphyrin group as a prototype hybrid-class PPG that unites traditionally exclusive elements of organic and metal-complex PPGs within a single structure. We show that the porphyrin scaffold allows extensive modularity by functional separation of the metal-binding chromophore and up to four sites of leaving group release. The insertion of metal ions can be used to tune their spectroscopic, photochemical, and biological properties. We provide a detailed description of the photoreaction mechanism studied by steady-state and transient absorption spectroscopies and quantum-chemical calculations. Our approach applied herein could facilitate access to a hitherto untapped chemical space of potential PPG scaffolds.
Modified desolvation method enables simple one-step synthesis of gelatin nanoparticles from different gelatin types with any bloom values
Authors: Khramtsov Pavel , Burdina Oksana , Lazarev Sergey , Novokshonova Anastasia , Bochkova Maria , Timganova Valeria , Kiselkov Dmitriy , Zamorina Svetlana , Rayev Mikhail
Published: February 2022

Gelatin nanoparticles found numerous applications in drug delivery, bioimaging, immunotherapy, and vaccine development as well as in biotechnology and food science. Synthesis of gelatin nanoparticles is usually made by a two-step desolvation method, which, despite providing stable and homogeneous nanoparticles, has many limitations, namely complex procedure, low yields, and poor reproducibility of the first desolvation step. Herein, we present a modified one-step desolvation method, which enables the quick, simple, and reproducible synthesis of gelatin nanoparticles. Using the proposed method one can prepare gelatin nanoparticles from any type of gelatin with any bloom number, even with the lowest ones, which remains unattainable for the traditional two-step technique. The method relies on quick one-time addition of poor solvent (preferably isopropyl alcohol) to gelatin solution in the absence of stirring. We applied the modified desolvation method to synthesize nanoparticles from porcine, bovine, and fish with bloom values from 62 to 225 on the hundreds-of-milligram scale. Synthesized nanoparticles had average diameters between 130 and 190 nm and narrow size distribution. Yields of synthesis were 62-82% and can be further increased. Gelatin nanoparticles have good colloidal stability and withstand autoclaving. Moreover, they were non-toxic to human immune cells.
Chemoselective nickel-catalyzed coupling through substrate photoexcitation
Authors: Das Pradipta , Woods Eliot , Ly Jack , Olding Jack , Presley Kayla , Romanoff Brennan , Grusenmeyer Tod , Weiss Emily , Kalow Julia
Published: February 2022

Metallaphotoredox catalysis combines the well-established mechanisms of transition-metal-catalyzed cross-coupling reactions with one-electron redox manipulations enabled by light. In most cases, a transition metal or organic dye serves as the photoredox catalyst while a ground-state Pd or Ni catalyst performs the organometallic steps. Cross-coupling mechanisms that rely on direct photoexcitation of a light-absorbing substrate have the potential to access distinct mechanisms and deliver unique selectivity based on the substrate’s excited-state properties. In this report, we describe a photoinduced, Ni-catalyzed Suzuki–Miyaura cross coupling reaction that selectively functionalizes BODIPY chromophores, a versatile class of tunable, bright, photostable fluorophores. Using a bis-iodo BODIPY substrate, the selectivity for mono- vs. bis-arylation was found to be governed by a remote substituent that subtly alters the excited-state properties of the substrate. Consistent with a substrate photoexcitation mechanism, high chemoselectivity is also observed in mixtures of chromophores with distinct excited-state properties. This reaction is compatible with a variety of substituted BODIPY chromophores and boronic acids and esters, enabling the rapid synthesis of unsymmetrically-substituted chromophores.
Development and validation of AMBER-FB15-compatible force field parameters for phosphorylated amino acids
Authors: Stoppelman John P. , Ng Tracey T. , Nerenberg Paul S. , Wang Lee-Ping
Published: February 2022

Phosphorylation of select amino acid residues is one of the most common tools for regulating protein structure and function. While computational modeling can be used to explore the detailed structural changes associated with phosphorylation, most molecular mechanics force fields developed for the simulation of phosphoproteins have been noted to be inconsistent with experimental data. In this work, we parameterize force fields for blocked dipeptide forms of the phosphorylated amino acids serine, threonine, and tyrosine using the ForceBalance software package with the goal of improving agreement with experiment for these residues. Our optimized force field, denoted as FB18, is parameterized using high-quality \textit{ab initio} potential energy scans and is designed to be fully compatible with the AMBER-FB15 protein force field. When utilized in MD simulations together with the TIP3P-FB water model, we find that FB18 consistently enhances the prediction of experimental quantities such as $^3J$ NMR couplings and intramolecular hydrogen-bonding propensities in comparison to previously published models. As was reported with AMBER-FB15, we also see improved agreement with the reference QM calculations in regions at and away from local minima. We thus believe that the FB18 parameter set provides a promising route for the further investigation of the varied effects of protein phosphorylation.
Unveiling the Complex Configurational Landscape of the Intralayer Cavities in a Crystalline Carbon Nitride
Authors: Pauly Magnus , Kroger Julia , Duppel Viola , Murphey Corban , Cahoon James , Lotsch Bettina , Maggard Paul
Published: February 2022

The in-depth understanding of the reported photoelectrochemical properties of the layered carbon nitride, poly(triazine imide)/LiCl (PTI/LiCl), has been limited by the apparent disorder of the Li/H atoms within its framework. To understand and resolve the current structural ambiguities, an optimized one-step flux synthesis (470 oC, 36 h, LiCl/KCl flux) was used to prepare PTI/LiCl and deuterated-PTI/LiCl in high purity. Its structure was characterized by a combination of neutron/X-ray diffraction and transmission electron microscopy. The range of possible Li/H atomic configurations were enumerated for the first time and, combined with total energy calculations, reveals a more complex energetic landscape than previously considered. Experimental data were fitted against all possible structural models, exhibiting the most consistency with a new orthorhombic model (Sp. Grp. Ama2) that also has the lowest total energy. In addition, a new Cu(I)-containing PTI (PTI/CuCl) was prepared with the more strongly scattering Cu(I) cations in place of Li, and which also most closely matched with the partially-disorded structure in Cmc21. Thus, a complex configurational landscape of PTI is revealed to consist of a number of ordered crystalline structures that are new potential synthetic targets, such as with the use of metal-exchange reactions.
Observation of the Ponderomotive Effect in Non-Valence Bound States of Polyatomic Molecular Anions
Authors: Kang Do Hyung , Kim Jinwoo , Noh Heung-Ryoul , Kim Sang Kyu
Published: February 2022

The ponderomotive effect in the non-valence bound states has been experimentally demonstrated for the first time, giving the great promise for the manipulation of the polyatomic molecules by the dynamic Stark effect. Entire quantum levels of the dipole-bound state (DBS) and quadruple-bound state (QBS) of the phenoxide (or 4-bromophenoxide) and 4-cyanophenoxide anions, respectively, show the clear-cut ponderomotive blue-shifts in the presence of the spatiotemporally overlapped non-resonant picosecond control laser pulse. The quasi-free electron in the QBS is found to be more vulnerable to the external oscillating electromagnetic field compared to that in the DBS, suggesting that the non-valence orbital of the former is more diffusive and thus more polarizable compared to that of the latter.
Dynamic Pt-OH-•H2O-Ag Species Mediate Synergetic Electron and Proton Transfer for Catalytic Hydride Reduction of 4-Nitrophenol at Confined Nanoscale Interface
Authors: zhang kun , Ding Meng , shan bingqian , peng bo , zhou jiafeng
Published: February 2022

The nature of interfacial state and/or bonding at heterogeneous nanoscale surface of bimetals remains elusive. For very classical probe reaction of catalytic hydride catalytic reduction of –NO2 to NH2 (herein reduction of 4-NP to 4-AP as an example), three abnormal experimental phenomena cannot be elucidated as such: 1) the hydrogen source of final product of 4-AP is originated from water solvent, rather than NaBH4 reducer; 2) reverse electron transfer between bimetals was observed, which is resisted to the normal thermaldynamic law; 3) even in the absence of any metals, for example just using carbon nanodots as supports, the reaction occurs. These observations indicates that the reduction of –NO2 groups did not follow the classical metal-centered electron and hydride transfer mechanism, i.e., Langmuir-Hinshelwood (L-H) mechanism. We herein provide strong evidence that, the catalytic hydride reduction of 4-NP to 4-AP is though a completely new surface hydrous hydroxyl specie mediated concerted electron and proton transfer process, wherein owing to the space overlapping of p orbitals in hydrous hydroxyl intermediate, an ensemble of interface states are dynamically formed, which could be alternative channels for concerted electron and proton transfer. The main role of second metal of Pt is to regulate the density of surface hydrous hydroxyl intermediate and its interactive strength with metals. This new mechanism not only answers all the abnormal experimental observations above mentioned, but also provide some new insights to water and/or hydroxyl group promoted reaction involved the activation of small molecules (CO2, CO, N2, H2O etc.) in areas of electrochemistry, energy storage and metalloenzyme catalysis.
Catch the next designer drug: A comparison of methods for predicting in vitro pharmacological profiles using molecular fingerprints
Authors: he kedan
Published: February 2022

Facing the growing trend of emerging new psychoactive substances (NPS) and their threat to public health, more effective methods of NPS prediction and identification are of critical importance. In this study, we aimed to compare methods for predicting the pharmacological profile of unknown compounds based on the chemical structures described by molecular fingerprints. We built predictive models based on the high-throughput screening (HTS) data sets using four different machine learning algorithms for a total of 10 targets and validated the performance of the models using in vitro bioassay data collected from the literature for an external NPS compound set. Clustering analysis revealed that the MACCS fingerprint may be more suitable for describing the similarity of pharmacological profiles of NPS, indicated by the highest adjusted Rand index (0.46) between the two clustering trees. The SVM classifiers validated by the external NPS set achieved ROC AUC above 0.80 and MCC above 0.45, therefore were used to generate the multi-target pharmacological profiles. The hit rate for retrieving pharmacologically similar compound pairs using MACCS calculated Tanimoto coefficient was below 1.85%, in contrast, the models were more successful in identifying similar compound pairs (MCC = 0.72), which were otherwise considered dissimilar by molecular fingerprints.
RetroTRAE: retrosynthetic translation of atomic environments with Transformer
Authors: Ucak Umit Volkan , Ashyrmamatov Islambek , Ko Junsu , Lee Juyong
Published: February 2022

We present the new retrosynthesis prediction method RetroTRAE using fragment-based tokenization combined with the Transformer architecture. RetroTRAE represents chemical reactions by using the changes of fragment sets of molecules using the atomic environment fragmentation scheme. Atom environments stand as an ideal, chemically meaningful building blocks together producing a high resolution molecular representation. Describing a molecule with a set of atom environments establishes a clear relationship between translated product-reactant pairs due to conservation of atoms in reactions. Our model achieved a top-1 accuracy of 67.1% within the bioactively similar range for USPTO test dataset, outperforming the other state of the art, translation methods. We investigated the effect of different encoding scenarios on predicting the reactant candidates. We also critically assessed the retrieval process that converts a set of fragments into a molecule with respect to coverage, degeneracy and resolution. Our new template-free model for retrosynthetic prediction provides fast and reliable retrosynthetic route planning for substances whose fragmentation patterns are revealed.
Sensitivity Analysis, Calibration and Uncertainty Quantification for Heavy Oil Viscosity Estimates with a Corresponding States Model
Authors: Volpatto Diego , Oliveira Lucas , Bittencourt Sofia , Silva Danilo , Manoel Edson , Girardi Vinicius
Published: February 2022

The main goal of this work is to assess heavy oil viscosity estimates by a Corresponding States Principle (CSP) model using a Bayesian approach in an efficient way. To determine and select relevant parameters for model calibration, an enhanced Elementary Effects method is used to evaluate sensitivity measures of CSP tuning parameters. With the combination of sensitivity analysis and Bayesian calibration, a unified procedure to automatically tune CSP viscosity model while reducing the number of tuning parameters is devised. Moreover, the Bayesian approach provides additional information on CSP model uncertainties and credible regions inherited from experimental data. To evaluate such uncertainties in CSP viscosity model, it was used five heavy oil samples available in the literature. The viscosity curves constructed by 50th-percentile from Monte Carlo realizations for the CSP calibration show good agreement when compared with classical Least-Squares regression (deterministic), demonstrating the potential of the sensitivity assessment for both Bayesian and deterministic approaches. However, when Bayesian calibration is used, limitations of CSP viscosity estimates are detected through violation of credible regions, suggesting that heavy oil viscosity estimates for relatively low pressure conditions can be insufficiently accurate for the CSP model considered in this study.
Energetic basis of excited-state enzyme design and function
Authors: Lin Chi-Yun , Romei Matthew , Mathews Irimpan , Boxer Steven
Published: February 2022

The last decades have witnessed an explosion of de novo protein designs with a remarkable range of scaffolds. It remains challenging, however, to design catalytic functions that are competitive with naturally occurring counterparts as well as biomimetic or non-biological catalysts. Although directed evolution often offers efficient solutions, the fitness landscape remains opaque. Green fluorescent protein (GFP), which has revolutionized biological imaging and assays, is one of the most re-designed proteins. While not an enzyme in the conventional sense, GFPs feature competing excited-state decay pathways with the same steric and electrostatic origins as conventional ground-state catalysts, and they exert exquisite control over multiple reaction outcomes through the same principles. Thus, GFP is an “excited-state enzyme”. Herein we show that rationally designed mutants and hybrids that contain environmental mutations and substituted chromophores provide the basis for a quantitative model and prediction that describes the influence of sterics and electrostatics on excited-state catalysis of GFPs. As both perturbations can selectively bias photoisomerization pathways, GFPs with fluorescence quantum yields (FQYs) and photoswitching characteristics tailored for specific applications could be predicted and then demonstrated. The underlying energetic landscape, readily accessible via spectroscopy for GFPs, offers an important missing link in the design of protein function that is generalizable to catalyst design.
Multimodal Plasmonic Hybrids: Efficient and Selective Photocatalysts
Authors: Negrín-Montecelo Yoel , Kong Xiang-Tian , Besteiro Lucas , Carbo-Argibay Enrique , Wang Zhiming , Pérez-Lorenzo Moisés , Govorov Alexander , Comesana-Hermo Miguel , Correa-Duarte Miguel A.
Published: February 2022

Important efforts are currently under way in order to implement plasmonic phenomena in the growing field of photocatalysis, striving for improved efficiency and reaction selectivity. A significant fraction of such efforts have been focused on distinguishing, understanding and enhancing specific energy transfer mechanisms from plasmonic nanostructures to their environment. Herein we report a synthetic strategy that brings together two of the main physical mechanisms driving plasmonic photocatalysis into an engineered system by rationally combining the photochemical features of energetic charge carriers and the electromagnetic field enhancement inherent to the plasmonic excitation. We do so by creating hybrid photocatalysts that integrate multiple plasmonic resonators in a single entity, controlling their joint contribution through spectral separation and differential surface functionalization. This strategy allows us to study the combination of different photosensitization mechanisms when activated simultaneously. Our results show that hot electron injection can be combined with an energy transfer process mediated by near-field interaction, leading to a significant increase of the final photocatalytic response of the material. In this manner, we overcome the limitations that hinder photocatalysis driven only by a single energy transfer mechanism, and move the field of plasmonic photocatalysis closer to energy-efficient applications. Furthermore, our multimodal hybrids offer a test system to probe the properties of the two targeted mechanisms and open the door to wavelength-selective photocatalysis and novel tandem reactions.
Patterned Dried Blood Spot Cards for Improved Sampling of Whole Blood
Authors: Baillargeon Keith R. , Brooks Jessica C. , Miljanic Philip R. , Mace Charles R.
Published: February 2022

Dried blood spot (DBS) cards perform many functions for sampling blood that is intended for subsequent laboratory analysis, which include: (i) obviating the need for a phlebotomist by using fingersticks, (ii) enhancing the stability of analytes at ambient or elevated environmental conditions, and (iii) simplifying transportation of samples without a cold chain. However, a significant drawback of standard DBS cards is the potential for sampling bias due to unrestricted filling caused by the hematocrit of blood, which often limits quantitative or reproducible measurements. Alternative microsampling technologies have minimized or eliminated this bias by restricting blood distribution, but these approaches deviate from clinical protocols and present a barrier to broad adoption. Herein, we describe a patterned dried blood spot (pDBS) card that uses wax barriers to control the flow and distribution of blood and provide enhanced sampling by minimizing the hematocrit effect. Patterned cards reproducibly fill four replicate extraction zones independent of the hematocrit. We demonstrate a 3-fold improvement in accuracy for the quantitation of hemoglobin using pDBS cards compared to unpatterned cards. Patterned cards also facilitate the near quantitative recovery (ca. 95%) of sodium with no evidence of a statistically significant difference between dried and liquid blood samples. Similarly, recovery of select amino acids was conserved in comparison to a recent report with improved inter-card precision. We anticipate that this approach presents a viable method for preparing and storing samples of blood in limited resource settings while maintaining current clinical protocols for processing and analyzing dried blood spots.
Origin of The Failure of Density Functional Theories in Predicting Inverted Singlet-Triplet Gaps
Authors: Ghosh Soumen , Bhattacharyya Kalishankar
Published: February 2022

Recent experimental and theoretical studies have shown several new organic molecules that violate Hund’s rule and have the first singlet excited state lower in energy than the first triplet excited state. While many correlated single reference wave function methods have successfully predicted excited state energetics of these low-lying states, linear-response time-dependent density functional theory (LR-TDDFT) fails to predict the correct excited state energy ordering. Herein, we have shown that it is possible to get inverted singlet-triplet gaps within the density functional theory framework by going beyond the singly excited state framework of conventional LR-TDDFT. Going beyond Kohn-Sham density functional theory (KS-DFT), we have demonstrated that a combined wave function and density functional method resulting in amulticonfiguration pair-density functional theory (MC-PDFT), in some cases, can predict inverted singlet-triplet gaps. Consequently, we have identified that both the missing doubly excited configurations and the form of the exchange-correlation functionals are the foremost grounds for the failure of the LR-TDDFT method. We have also compared the accuracy of single reference correlated wave function methods for these low-lying singlet and triplet excited states to multireference second-order perturbation theory.
Identification of Atovaquone and Mebendazole as Repurposed Drugs with Antiviral Activity against SARS-CoV-2 (Version 5)
Authors: Ahmed Mahmoud , Farag Ayman , Wang Ping , Boys Ian N. , L. Eitson Jennifer , Ohlson Maikke B. , Fan Wenchun , McDougal Matthew B. , W. Schoggins John , Sadek Hesham
Published: February 2022

Given the continuing heavy toll of the COVID-19 pandemic, therapeutic options for treatment are urgently needed. Here, we adopted a repositioning approach using in silico molecular modeling to screen FDA-approved drugs with established safety profiles for potential inhibitory effects against SARS-CoV-2. We used structure-based drug design to screen more than 2000 FDA approved drugs against SARS-CoV-2 main protease enzyme (Mpro) substrate-binding pocket. We additionally screened the top hits from both sites for potential covalent binding via nucleophilic thiol attack of Cys 145. High-scoring candidates were then screened for antiviral activity against infectious SARS-CoV-2 in a cell-based viral replication assay, and counter screened for toxicity. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. In addition, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 M), mebendazole (IC50 19 M) and entacapone (IC50 9 M). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential antiviral mechanisms. Although atovaquone is a known DHODH inhibitor, we did not observe inhibition of DHODH by atovaquone at concentrations relevant to the SARS-CoV-2 IC50. Interestingly, metabolomic profiling of atovaquone treated cells demonstrated marked dysregulation of metabolites in the purine metabolism pathway. In summary, a number of our top hits from the in-silico screen demonstrated Mpro inhibitory activity associated with antiviral effects. Atovaquone and mebendazole are the most promising candidates targeting SARS-CoV-2 from our screen, however atovaquone did not significantly inhibit Mpro at therapeutically meaningful concentrations but may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.
Improving Ligand-Ranking of AutoDock Vina by Changing the Empirical Parameters
Authors: Pham T. Ngoc Han , Nguyen Trung Hai , Tam Nguyen Minh , Vu Thien Y , Pham Nhat Truong , Huy Nguyen Truong , Mai Binh Khanh , Tung Nguyen Thanh , Pham Minh Quan , Vu Van V. , Ngo Son Tung
Published: February 2022

AutoDock Vina (Vina) achieved a very high docking-success rate, p ̂, but give a rather low correlation coefficient, R, for binding affinity with respect to experiments. This low correlation can be an obstacle for ranking of ligand-binding affinity, which is the main objective of docking simulations. In this context, we evaluated the dependence of Vina R coefficient upon its empirical parameters. R is affected more by changing the gauss2 and rotation than other terms. The docking-success rate p ̂ is sensitive to the alterations of the gauss1, gauss2, repulsion, and hydrogen bond parameters. Based on our benchmarks, parameter set1 has been suggested to be the most optimal. The testing study over 800 complexes indicated that the modified Vina provided higher correlation with experiment R_set1=0.556±0.025 compared with R_Default=0.493±0.028 obtained by the original Vina and R_(Vina 1.2)=0.503±0.029 by Vina version 1.2. Besides, the modified Vina can be also applied more widely, giving R≥0.500 for 32/48 targets, compared with the default package, giving R≥0.500 for 31/48 targets. In addition, validation calculations for 1036 complexes obtained from version 2019 of PDBbind refined structures showed that the set1 of parameters gave higher correlation coefficient (R_set1=0.621±0.016) than the default package (R_Default=0.552±0.018) and Vina version 1.2 (R_(Vina 1.2)=0.549±0.017). The version of Vina with set1 of parameters can be downloaded at https://github.com/sontungngo/mvina. The outcomes would enhance the ranking of ligand-binding affinity using Autodock Vina.
Self-limiting Nitrogen/Hydrogen Plasma Radical Chemistry in Plasma-Enhanced Atomic Layer Deposition of Cobalt
Authors: Liu Ji , Lu Hongliang , Zhang David Wei , Nolan Michael
Published: February 2022

Cobalt (Co) is a potential candidate in replacing copper for interconnects and has been applied in the trenches in semiconductor industry over twenty years. A non-oxidizing reactant is required in plasma-enhanced atomic layer deposition (PE-ALD) of thin films of metals to avoid O-contamination. PE-ALD of Co has been demonstrated experimentally with plasma sources of NH3 or a mixture of N2 and H2, but the growth mechanism and key reactions are not clear. In this paper, we have investigated the reactions of plasma generated radicals H, N, NH and NH2 at metal precursor (CoCp2) terminated Co (001) and (100) surfaces using static DFT calculations at 0 K and molecular dynamics simulations at 600 K. N radicals play an important role in eliminating surface-bound Cp ligand (if any) via pyridine (C5H5N) formation and desorption, whereas H radicals have endothermic reactions for eliminating Cp ligand via CpH formation and desorption. The surface NHx species are eliminated by H radicals via NH3 formation and desorption. The simulations of these key reactions show that on Co(001) surface, the remaining Cp ligand and surface NHx species after the metal precursor pulse will be completely removed with N and H radicals, resulting in Co atoms deposited on Co(001) surface at a coverage of 3.03Co/nm2. Whereas, on Co(100) surface, the surface NH2 species cannot be completely removed via NH3 formation and desorption due to overall endothermic reactions. Instead, H radicals react with trench N species, contributed to H transfer at metal precursor pulse, to form NH. These trench N species cannot be eliminated completely on Co(100) surface, which will be the source of N impurities for the deposited Co thin films. At the post-plasma stage, the metal surface will be covered with NHx-terminations with plasma generated NH radicals, which is then ready for the next deposition cycle. Our results explain why ammonia or H2/N2 plasma, which produce NHx species are required to deposit Co thin films using Co metallocene precursors.
Revisiting the Key Optical and Electrical Characteristics in Reporting Photocatalysis of Semiconductors
Authors: Bui Dai-Phat , Pham Minh-Thuan , Tran Hong-Huy , Nguyen Thanh-Dat , Cao Minh Thi , Pham Van Viet
Published: February 2022

Photocatalysis has been studied and considered as a green and effective approach in addressing environmental pollution. However, factors that affect photocatalytic performance have not been systematically studied. In this work, we have presented a comprehensive roadmap for characterizing, interpreting, and reporting semiconductors' electrical and optical properties through routinely used techniques such as diffuse reflectance spectroscopy (DRS), electrochemical techniques (Mott-Schottky plots), photoluminescence (PL), X-ray photoelectron spectroscopy (XPS ), and ultraviolet photoelectron spectroscopy (UPS) in the context of photocatalysis. Having deeply and precisely studied the band structure of three representative photocatalysts, we have presented and highlighted essential information and details, which are critical and beneficial for studies of (1) band alignments, (2) redox potentials, and (3) defects. Further works with a comprehensive understanding of band structure are desirable and hold great promise.
How to Characterize Amorphous Shapes: The Tale of a Reverse Micelle
Authors: Gale Christopher , Derakhshani-Molayousefi Mortaza , Levinger Nancy E.
Published: February 2022

Aerosol-OT reverse micelles represent a chemical construct where surfactant molecules self-assemble to stabilize water nanodroplets ~1-10 nm in diameter. Although commonly assumed to adopt a spherical shape, all-atom molecular dynamics simulations and some experimental studies predict a non-spherical shape. If these aggregates are not spherical, then what shape do they take? Because the tools needed to evaluate the shape of something that lacks regular structure, order, or symmetry are not well developed, we present a set of three intuitive metrics- coordinate-pair eccentricity, convexity, and the curvature distribution- that estimate the shape of an amorphous object and we demonstrate their use on a simulated Aerosol-OT reverse micelle. These metrics are all well-established methods and principles in mathematics, and each provides unique information about the shape. Together, these metrics provide intuitive descriptions of amorphous shapes, facilitate ways to quantify those shapes, and follow their changes over time.