bluuebunny/crossref_metadata_2025 huggingface dataset:
Flow cell to study crystallisation processes in-situ using terahertz time-domain spectroscopy
Authors: Li Qi , Kölbel Johanna , Threlfall Terry , Zeitler Axel
Published: February 2022

A versatile setup based on terahertz time-domain spectroscopy was developed to monitor the process of crystallisation and characterise the structure of the crystals as well as the dynamics of the solvent in situ. The setup can be used to investigate crystallisation processes over a wide range of temperature, either under static conditions or during continuous flow. An attached optical imaging probe can be used to monitor the process in parallel to the terahertz spectroscopy investigation. The implementation of terahertz spectroscopy offers a great opportunity to investigate the dielectric relaxation dynamics of the solvent and the vibrational modes characteristic for the crystalline phases simultaneously. The details of the crystallisation setup are demonstrated at the example of the crystallisation process of magnesium sulphate heptahydrate from its aqueous phase.
Cesium immobilization in metakaolin-based geopolymers elucidated by 133Cs solid state NMR spectroscopy
Authors: Arbel Haddad Michal , Harnik Yonatan , Schlosser Yaron , Goldbourt Amir
Published: February 2022

Geopolymers are promising candidates for nuclear-waste immobilization, and more specifically for the immobilization of radioactive cesium. Low-Si metakaolin-based geopolymers cured at temperatures of 40°C in the presence of Cs ions generate a mixture of amorphous and crystalline phases including a Cs-bearing zeolite F phase. Using a combination of 133Cs solid-state NMR and X-ray powder diffraction measurements we were able to show that Cs preferentially binds to zeolite F even when zeolite F is not the dominant phase in the matrix. Moreover, post-leaching NMR experiments indicate that zeolite F binds Cs more efficiently than the remaining crystalline or amorphous phases. Tailoring geopolymer formulations so that a large fraction of zeolite F is generated may therefore be a promising route for the production of immobilization matrices for cesium.
A computational study of the properties of low- and high-index Pd, Cu and Zn surfaces
Authors: Kabalan Lara , Kowalec Igor , Catlow Richard , Logsdail Andrew
Published: February 2022

We report a detailed Density Functional Theory (DFT) based investigation of the structure and stability of bulk and surface structures for the Group 10-12 elements Pd, Cu and Zn, considering the effect of the choice of exchange-correlation density functionals and computation parameters. For the initial bulk structures, the lattice parameter and cohesive energy are calculated, which are then augmented by calculation of surface energies and work functions for the lower-index surfaces. Of the 22 density functionals considered, we highlight the mBEEF density functional as providing the best overall agreement with experimental data. The optimal density functional choice is applied to the study of higher index surfaces for the three metals, and Wulff constructions performed for nanoparticles with a radius of 11nm, commensurate with nanoparticle sizes commonly employed in catalytic chemistry.
Water Capture Mechanisms at Zeolitic Imidazolate Framework Interfaces
Authors: Wagner Jackson , Hunter Kelly , Paesani Francesco , Xiong Wei
Published: February 2022

Water capture mechanisms of zeolitic imidazolate framework ZIF-90 are revealed by differentiating the water clustering at interior interfaces of ZIF-90 and the center pore filling step, using vibrational sum-frequency generation spectroscopy (VSFG) at a one-micron spatial resolution. Spectral lineshapes of VSFG and IR spectra suggest that OD modes of heavy water in both water clustering and center pore filling steps experience similar environments, which is unexpected as weaker hydrogen bond interactions are involved in initial water clustering at interior surfaces. VSFG intensity shows similar dependence on the relative humidity as the adsorption isotherm, suggesting that water clustering and pore filling occur simultaneously. MD simulations based on MB-pol corroborate the experimental observations, indicating that water clustering and center pore filling happen nearly simultaneously within each pore, with water filling the other pores sequentially. The integration of nonlinear optics with computational simulations provides critical mechanistic insights into the pore filling mechanism that could be applied to the rational design of future MOFs.
Bridging the experiment-calculation divide: machine learning corrections to redox potential calculations in implicit and explicit solvent models
Authors: Hruska Eugen , Gale Ariel , Liu Fang
Published: February 2022

Prediction of redox potentials is essential for catalysis and energy storage. Although density functional theory (DFT) calculations have enabled rapid redox potential predictions for numerous compounds, prominent errors persist compared to experimental measurements. In this work, we develop machine learning (ML) models to reduce the errors of redox potential calculations in both implicit and explicit solvent models. Training and testing of the ML correction models are based on the diverse ROP313 dataset with experimental redox potentials measured for organic and organometallic compounds in a variety of solvents. For the implicit solvent approach, our ML models can reduce both the systematic bias and the number of outliers. ML corrected redox potentials also demonstrate less sensitivity to DFT functional choice. For the explicit solvent approach, we significantly reduce the computational costs by embedding the microsolvated cluster in implicit bulk solvent, obtaining converged redox potential results with a smaller solvation shell. This combined implicit-explicit solvent model, together with GPU-accelerated quantum chemistry methods, enabled rapid generation of a large dataset of explicit-solvent-calculated redox potentials for 165 organic compounds, allowing detailed investigation of the error sources in explicit solvent redox potential calculations.
Using transient equilibria (TREQ) to measure the thermodynamics of slowly assembling supramolecular systems
Authors: Hennecker Christopher , Lachance-Brais Christophe , Sleiman Hanadi , Mittermaier Anthony
Published: February 2022

Supramolecular chemistry involves the non-covalent assembly of monomers into materials with unique properties and wide-ranging applications. Thermal analysis is a key analytical tool in this field, as it provides quantitative thermodynamic information on both the structural stability and nature of the underlying molecular interactions. However there exist many supramolecular systems whose kinetics are so slow under conditions approaching equilibrium that thermodynamic data are inaccessible. We have developed a simple and rapid spectroscopic method for extracting thermodynamic parameters from these systems. It is based on repeatedly raising and lowering the temperature during assembly and identifying the points of transient equilibrium as they are passed on the up- and down-scans. In a proof-of-principle application to the co-assembly of polydeoxyadenosine containing 15 adenosines (polyA15) and cyanuric acid (CA), we found that roughly 30% of the CA binding sites on the polyA chains were unoccupied, with implications for the assembly of high-valence systems.
Unusual Rearrangement-Remercuration Reactions of Allylic Silanols
Authors: Sathyamoorthi Shyam , Nagamalla Someshwar , Dhokale Ranjeet , Seidl Frederick , Mague Joel
Published: February 2022

We present the first examples of rearrangement reactions of allylic silanol substrates into linear ketone and 5-membered cyclic silanediol organomercurial products. Both reactions are mediated by Hg(OTf)2 but differ in the use of base, solvent, and temperature. The substrate scope of both transformations was explored, and the product organomercurials were shown to be valuable synthons. Mechanistic studies suggest that both products are the result of a series of transformations, cascading in one pot. DFT analysis provides a basis for understanding the rearrangement of a 6-endo intermediate into the 5-exo cyclic silanediol product.
A monoanionic pentadentate ligand platform for scandium-pnictogen multiple bonds
Authors: Patrick Evan , Yang Yan , Piers Warren , Maron Laurent , Gelfand Benjamin
Published: February 2022

A new monoanionic pentadentate ligand is designed to accommodate Sc=E bonds (E = N, P). The imido complex is stable enough to isolate and characterize, and reacts rapidly with CO2. The phosphinidene, on the other hand, is highly reactive and induces C-C bond cleavage to yield a phosphido-pyridyl complex which also undergoes rapid reacton with CO2.
A Soft-Solid Co-Crystalline Electrolyte Combining Advantages of Organics and Ceramics: Thermally, Electrochemically Stable, Highly Conductive (Adiponitrile)2LiPF6
Authors: Fall Birane , Prakash Prabhat , Aguirre Jordan , Chereddy Sumanth , Chinnam Parameswara Rao , Dikin Dmitriy , Venkatnathan Arun , Wunder Stephanie L. , Zdilla Michael J.
Published: February 2022

The solid electrolyte (ADN)2LiPF6 is described. The structure exhibits adiponitrile (ADN)-based channels based on XRD analysis, through which the -C≡N-solvated Li+ ions migrate. High conductivity (σ ~ 10-4 S/cm) and high lithium ion transference number (tLi+ = 0.54) results from weak interactions between “hard” (charge-dense) Li+ ions and “soft” (electronically polarizable) -C≡N, compared with the stronger interactions of previously reported “hard” ether oxygen contacts of polyethylene oxide (PEO) or glymes. The surface of the crystal is a liquid nanolayer that binds the grains so that ionically conductive pellets are easily formed without high pressure/temperature treatments. (ADN)2LiPF6(s) has a wide electrochemical stability window of 0 to 5 V. Li0/(ADN)2LiPF6/LiFePO4 half cells exhibit cycling for > 50 cycles at C/20, C/10, C/5 rates with capacities of 140 mAh-g-1 to 100 mAh-g-1 and efficiencies > 95%. MD simulations and PWDFT calculations offer insights into the molecular basis of the physical and conductivity properties.
Anion Dependent Particle Size Control of Platinum Nanoparticles Synthesized in Ethylene Glycol
Authors: Schröder Johanna , Neumann Sarah , Quinson Jonathan , Arenz Matthias , Kunz Sebastian
Published: February 2022

The polyol synthesis is a well-established method to form so-called “surfactant-free” NPs that can be tailored, e.g., in size. The standard procedure of reducing H2PtCl6 or H2PtBr6 in presence of NaOH has been intensively investigated as well as the influence of the counter cation of the base. However, the base anion influence has not been explored yet. The results of this work show that the size control rather depends on the precursor (metal salt) and surprisingly not the anion type of the base. The latter is surprising as the concentration of the base anion is often an important factor for the size control. The thermal reduction of the precursors H2PtCl6, H2Pt(OH)6, or Pt(acac)2 in presence of the bases NaOH or Na(acac) lead to comparable size control depending on the precursors, i.e., precursor anions. The reduction of H2PtCl6 or H2Pt(OH)6 in presence of NaOH supports the idea of the size being determined by the OH-/Pt molar ratio. Reducing the two precursors in presence of Na(acac) leads to similar results in particle size control for the same acac-/Pt or OH-/Pt ratios. In contrast, the reduction of Pt(acac)2 in presence of the bases NaOH (previous reports) or Na(acac) (shown in the present work) leads to larger NPs of ca. 3 nm, independent of the concentration of the base anions. Hence the anion effect seems originate predominantly in the character of the precursor (precursor anion dependence) and then for certain precursors as H2PtCl6 or H2Pt(OH)6 in the base anion/Pt ratio determining the NP size in the reduction.
Quantum Dynamics of Water from Møller-Plesset Perturbation Theory via a Neural Network Potential
Authors: Lan Jinggang , Wilkins David , Rybkin Vladimir , Iannuzzi Marcella , Hutter Juerg
Published: February 2022

We report the static and dynamical properties of liquid water at the level of second-order Møller-Plesset per- perturbation theory (MP2) with classical and quantum nuclear dynamics using a neural network potential. We examined the temperature-dependent radial distribution functions, diffusion, and vibrational dynamics. MP2 theory predicts over-structured liquid water as well as a lower diffusion coefficient at ambient conditions compared to experiments, which may be attributed to the incomplete basis set. A better agreement with experimental structural properties and the diffusion constant are observed at an elevated temperature of 340 K from our simulations. Although the high-level electronic structure calculations are expensive, training a neural network potential requires only a few thousand frames. The approach is promising as it involves modest human effort and is straightforwardly extensible to other simple liquids.
Manganese-Catalyzed Dehydrogenative Silylation of Alkenes Following Two Paral-lel Pathways
Authors: Weber Stefan , Glavic Manual , Stöger Berthold , Pittenauer Ernst , Veiros Luis , Kirchner Karl
Published: February 2022

We report on an additive-free Mn(I)-catalyzed dehydrogenative silylation of terminal alkenes. The most active pre-catalyst is the bench-stable alkyl bisphosphine Mn(I) complex fac-[Mn(dippe)(CO)3(CH2CH2CH3)]. The catalytic pro-cess is initiated by migratory insertion of a CO ligand into the Mn-alkyl bond to yield an acyl intermediate which un-dergoes rapid Si-H bond cleavage of the silane HSiR3 forming the active 16e- Mn(I) silyl catalyst [Mn(dippe)(CO)2(SiR3)] together with liberated butanal. A broad variety of aromatic and aliphatic alkenes was efficient-ly and selectively converted into E-vinylsilanes and allylsilanes, respectively, at room temperature. Mechanistic insights are provided based on experimental data revealing that two parallel reaction pathways are operative: an acceptorless reaction pathway involving dihydrogen release and a pathway requiring an alkene as sacrificial hydrogen acceptor.
Cadmium-Containing Quantum Dots Used in Electronic Displays: Implications for Toxicity and Environmental Transformations
Authors: Bechu Aude , Liao Jeffrey , Huang Chang , Ahn Chany , McKeague Maureen , Ghoshal Subhasis , Moores Audrey
Published: February 2022

Cadmium-containing quantum dot nanoparticles (QDs) are integrated into electronic displays because of their ability to efficiently convert colors. There are conflicting accounts as to whether these particles present a hazard to the environment, as they have been studied either as (1) embedded QDs in display screen films or (2) as model QDs with small, hydrophilic ligands. We synthesized QDs featuring the core-shell structure and the thick polymer coating present in commercial devices, to probe their fate under low pH conditions. The role of dioxygen was also explored in this context. We also used liver cells to compare the toxicity of pristine QDs to those subjected to acid dissolution.
Precise manipulation of electron transfers in clustered five redox sites
Authors: Izu Hitoshi , Kondo Mio , Okamura Masaya , Tomoda Misa , Lee Sze Koon , Akai Takuya , Praneeth Vijayendran , Kanaike Mari , Kawata Satoshi , Masaoka Shigeyuki
Published: February 2022

Electron transfers in multinuclear metal complexes are the origin of their unique functionalities both in natural and artificial systems. However, electron transfers in multinuclear metal complexes are generally complicated, and predicting and controlling these electron transfers is extremely difficult. Herein, we report the precise manipulation of the electron transfers in multinuclear metal complexes. The development of a rational synthetic strategy afforded a series of pentanuclear metal complexes composed of metal ions and 3,5-bis(2-pyridyl)pyrazole (Hbpp) as a platform to probe the phenomena. Electrochemical and spectroscopic investigations clarified the overall picture of the electron transfers in the pentanuclear complexes. In addition, unique electron transfer behaviours, in which the reduction of a metal centre occurs during the oxidation of the overall complex (reduction-upon-oxidation process), were discovered. We also elucidated the two dominant factors that determine the manner of the electron transfers. Our results provide comprehensive guidelines for interpreting the complicated electron transfers in multinuclear metal complexes.
Mechanical properties of unidirectional, porous polymer/ceramic composites for biomedical applications
Authors: Seuba Jordi , Maire Eric , Adrien Jérôme , Meille Sylvain , Deville Sylvain
Published: February 2022

Ceramics are brittle, so imagine what porous ceramics are like. This weakness is often a major obstacle in many applications. The addition of a ductile phase such as a polymer to a porous ceramics can help overcome this intrinsic limitation. Yet, most studies so far have focused on the processing and characterization of dense composites, and to some extent to porous ceramic composites. Unidirectionality, with macropores arranged along a common direction, is another strategy to improve the strength of porous ceramics, while being beneficial for a wide range of other applications involved with mass, gas or species transport. Here we combine the two approaches and show a simple processing strategy to obtain highly porous, unidirectional ceramic/polymer composites. We infiltrated ice-templated porous zirconia scaffolds with a dilute solution of polymer (polycaprolactone or epoxy). After the evaporation of the solvent, porous ceramic composites with a porosity greater than 60% were obtained. We performed a complete mechanical characterization to assess the relative importance of the properties of the ceramic and polymer phases. Our results demonstrate that the addition of a ductile polymer (PCL) can increase both the strength and the toughness of the composites while maintaining a high porosity. However, the addition of a brittle polymer (epoxy) has seemingly no impact on the fracture properties. This approach could provide porous materials that are easier to handle for biomedical applications.
Chemoselective Facile Synthesis of the Dicyanophosphide Anion via Electrochemical Activation of White Phosphorus: An Avenue to Organophosphorus Compounds
Authors: Mei Yanbo , Yan Zeen , Liu Liu Leo
Published: February 2022

Organophosphorus compounds (OPCs) have gained tremendous interest in the past decades due to their wide applications ranging from synthetic chemistry to materials and biological sciences. We describe herein a practical and versatile approach for the transformation of P4 into useful OPCs with high P atom economy via a key bridging anion [P(CN)2]–. This anion can be prepared on a gram scale directly from P4 through an unprecedented electrochemical process. A variety of OPCs involving phosphinidenes, cyclophosphanes and phospholides have been made readily accessible from P4 in a two-step manner. Our approach has a significant impact on the future preparation of OPCs in laboratory and industrial settings.
Covalent Inhibition of SARS-CoV-2 RBD-ACE2 Interaction by Aptamers with Multiple Sulfur(VI) Fluoride Exchange Modifications
Authors: Qin Zichen , Zhu Yiying , Xiang Yu
Published: February 2022

The SARS-CoV-2 spike protein uses its receptor-binding domain (RBD) to interact with the angiotensin-converting enzyme 2 (ACE2) receptor on host cells, establishing the first step of SARS-CoV-2 infection. Inhibitors of RBD-ACE2 interaction, therefore, have shown great promise in preventing SARS-CoV-2 infection. Currently known RBD-ACE2 inhibitors are all based on reversible binding and must compete with ACE2 or RBD at the equilibrium. On the other hand, covalent inhibitors, such as those based on sulfur(VI) fluoride exchange (SuFEx) chemistry, can form irreversible chemical bonds with target proteins and offer advantages including higher potency and longer duration of inhibition. Here, we report covalent aptamer inhibitors that can block RBD-ACE2 by forming covalent bonds with RBD. These covalent aptamer inhibitors were developed by equipping known RBD aptamers with multiple SuFEx (mSuFEx) modifications. The mSuFEx-aptamer 6C3-7SF underwent strong covalent bonding with RBD and some of its variants at fast rates (t1/2 = 20 ~ 29 min−1) and induced more efficient RBD-ACE2 inhibition (IC50 = 26 ~ 37 nM) than the original aptamer (IC50 > 200 nM) according to an in vitro enzyme-linked immunosorbent assay (ELISA). The covalent bond formation was highly selective to RBD over human serum albumin (HSA) and ACE2, and could occur efficiently in diluted human serum. Peptide fragmentation analyses of the RBD-6C3-7SF adducts revealed multiple sites of covalent bonding on RBD, including K378, R408, Y422, Y424, Y453, and K458. The surprising R408 suggests that context-specific non-N-terminal arginine could be a new type of targetable residue by SuFEx-based covalent inhibitors, which were never reported as reactive with any non-N-terminal arginine in target proteins. In addition, RBD R408 is responsible for binding with ACE2 N90 glycan, and this arginine is conserved in SARS-CoV-2 variants of concern or interest, suggesting that R408 could be the potential site of interest for developing SuFEx-based covalent inhibitors against threatening SARS-CoV-2 variants. Although the compatibility of mSuFEx-based covalent aptamers in cellular and in vivo systems should be further investigated, our study demonstrated the promise of mSuFEx chemistry in constructing potent covalent aptamers to inhibit important protein-protein interactions (PPIs).
Odorant Binding Changes the Electrical Properties of Olfactory Receptors at the Nanoscale
Authors: Lagunas Anna , Belloir Christine , Briand Loic , Gorostiza Pau , Samitier Josep
Published: February 2022

The transduction of odorant binding into cellular signaling by olfactory receptors (ORs) is not understood and knowing its mechanism would enable developing new pharmacology and biohybrid electronic detectors of volatile organic com-pounds bearing high sensitivity and selectivity. The electrical characterization of ORs in bulk experiments is subject to microscopic models and assumptions. We have directly determined the nanoscale electrical properties of ORs immobilized in a fixed orientation, and their change upon odorant binding, using electrochemical scanning tunneling microscopy (EC-STM) in near-physiological conditions. Recordings of current versus time, distance, and electrochemical potential allows determining the OR impedance parameters and their dependence with odorant binding. Our results allow validating OR structural-electrostatic models and their functional activation processes.
Reversible Topochemical Polymerization and Depolymerization of a Crystalline Three-Dimensional Porous Organic Polymer with C–C Bond Linkages
Authors: Sun Chenyue , Oppenheim Julius , Skorupskii Grigorii , Yang Luming , Dincă Mircea
Published: February 2022

Three-dimensionally connected porous organic polymers are of interest because of their potential in adsorption, separation, and sensing, among others. When crystalline, they also afford accurate structure description, which in turn can enable particular functions. However, crystallization of three-dimensional (3D) polymers is challenging. This is especially true when targeting polymerization via stable C–C bonds, whose formation is usually irreversible and does not allow for error correction typically required for crystallization. Here, we report polyMTBA, the first 3D-connected crystalline organic polymer with permanent porosity, here formed via C–C linkages. High crystallinity is achieved by solid-state topochemical reaction within monomer MTBA crystals. polyMTBA is recyclable via thermal depolymerization and is solution-processable via its soluble monomers. These results reveal topochemical polymerization as a compelling methodology for generating stable, crystalline, and porous 3D organic frameworks.
NIR-Responsive Lysosomotropic Phototrigger: ʽAIE + ESIPTʼ Active Naphthalene Based Single Component Photoresponsive Nanocarrier with Two-Photon Uncaging and Real-Time Monitoring Ability
Authors: Roy Biswajit , Mengji Rakesh , Roy Samrat , Pal Bipul , Jana Avijit , Singh N. D. Pradeep
Published: February 2022

In recent times, organelle-targeted drug delivery systems gained tremendous attention due to the site specific delivery of active drug molecules resulting in enhanced bioefficacy. In this context, the phototriggered drug delivery system (DDS) for releasing an active molecule is superior as it provides spatial and temporal control over the release. So far, near infrared (NIR) light responsive organelle targeted DDS has not yet been developed. Hence, we introduced a two-photon NIR-light responsive lysosome targeted ʽAIE + ESIPTʼ active single component DDS based on naphthalene chromophore. The Two-photon absorption cross-section of our DDS is 142 GM at 850 nm. The DDS was converted into pure organic nanoparticles for biological applications. Our nano-DDS is capable of selective targeting, AIE-luminogenic imaging, and drug release within the lysosome. In vitro studies using cancerous cell lines showed that our single component photoresponsive nanocarrier exhibited enhanced cytotoxicity and real-time monitoring ability of the drug release.
A Linear "Head-to-Tail" Chlorido-Bridged Didysprosium Single-Molecule Magnet Exhibiting 100-s Blocking Temperature near 8 K
Authors: Ding Xia-Li , Zhai Yuan-Qi , Luo Qian-Cheng , Wu Chao , Zheng Yan-Zhen
Published: February 2022

Although single-molecule magnets (SMMs) have been considered as the smallest entity to store binary information, the ability to retain the magnetization in one direction for more than 100 seconds is still below liquid nitrogen boiling point (77 K). One of the effective ways to enhance the magnetic blocking temperature is to couple the anisotropic magnetic centers in a proper manner. However, this has been only succeeded in the radical-bridged SMMs so far. For non-radical bridges the 100-second blocking temperature is still not seen. Here we report the best non-radical bridged dimeric SMM - {[Dy(OtBu)(4-NH2py)5]2(µ-Cl)}[BPh4]3 1 - with an energy barrier to magnetization reversal of 1302(6) K and 100-second blocking temperature near 8 K. Compared to the similar local C5v symmetric mononuclear complex [Dy(OtBu)Cl(py)5]BPh4 2, the much higher performance of dimeric 1 is attributed to the pseudo-D5h symmetry and "head-to-tail" linked Dy(III) principle magnetic via the collinear Dy‒Cl‒Dy exchange-coupling pathway.
Imidazole Promoted Efficient Anomerization of β-D-Glucose Pentaacetate in Solid State and Reaction Mechanism
Authors: Wang Meifeng , Zhang Liyin , Li Yiqun , Gu Liuqun
Published: February 2022

Anomerization of glycosides was rarely performed under basic condition. Here an imidazole promoted anomerization of β-D-glucose pentaacetate in solid state at room temperature was discovered. This unprecedent anomerization in solid state occurred after simple mixing and reaction proceeded continuously to full conversion without stirring or mechanomixing. Current understanding of reaction mechanism involved with inter/intramolecular acyl transfer promoted by two imidazole in concerted manner may promote discovery of more new transformations of glucosides in solid state.
Spatiotemporal urban water profiling for the assessment of environmental and public exposure to antimicrobials (antibiotics, antifungals, and antivirals) in the Eerste River Catchment, South Africa
Authors: Kasprzyk-Hordern Barbara , Holton ELizabeth , Archer Edward , Fidal James , Kjeldson Thomas , Wolfaardt Gideon
Published: February 2022

Antibiotic usage, excretion, and persistence are all important factors in association with the occurrence and dissemination of antimicrobial resistance. Urban water profiling was utilised in the Eerste River catchment (South Africa) to establish antibiotic usage in a catchment where comprehensive prescription records were not readily available and where portions of the community did not have sufficient access to sanitation. This technique enabled the environmental exposure to be quantified throughout the catchment area and the identification of contamination hotspots. Monitoring occurred over a 10-month period. 812 samples were processed using UPLC-MS/MS for the quantitation of 56 antimicrobials and 26 of their metabolites. Spatiotemporal trends were established, with consideration to community behaviour, seasonal changes, and physiochemical properties of the analytes. The Eerste River samples collected upstream from the town of Stellenbosch had the lowest antibiotic loads (< 4 g/day), unafflicted by industrial presence and with only small impact from farming activity. This was followed by sites downstream from a treated wastewater treatment plant (serving 178K people) discharge point (influent: 500-800 g/day and effluent 50-100 g/day), which indicates a high efficiency of wastewater treatment allowing for an effective reduction of ABs and a lower environmental burden compared to the river sites receiving untreated waste from communities in informal settlements (6-12K people) that are not connected to the sewer infrastructure (with AB levels accounting for 100-600 g/day). Temporal trends exhibited reduced daily loads during the summer to early autumn. This is likely due to seasonal patterns in community health. However, weather patterns are also important to consider – particularly for the river sites. South Africa has notable rainfall and temperature seasonality. ARVs, emtricitabine and lamivudine, were the most prevalent drugs throughout the monitoring campaign, followed by tuberculosis drugs and sulfonamides. ARVs were, however, effectively reduced via wastewater treatment processes (>97%). This was also the case for beta-lactams, nitrofurantoin, and trimethoprim. The treatment efficacy for other drugs was more variable, that did not appear to have temporal significance.
NIR-Emitting Benzene-Fused Oligo-BODIPYs for Bioimaging
Authors: Selvaggio Gabriele , Nißler Robert , Nietmann Peter , Patra Atanu , Patalag Lukas Jacek , Janshoff Andreas , Werz Daniel Bodo , Kruss Sebastian
Published: February 2022

Near-infrared (NIR) fluorophores are emerging tools for biophotonics because of their reduced scattering, increased tissue penetration and low phototoxicity. However, the library of NIR fluorophores is still limited. Here, we report the NIR fluorescence of two benzene-fused oligo-BODIPYs in their hexameric (H) and octameric (O) forms. These dyes emit bright NIR fluorescence (H: maxima 943/1075 nm, O: maxima 976/1115 nm) that can be excited in the NIR (H = 921 nm, O = 956 nm) or non-resonantly over a broad range in the visible region. The emission bands of H show a bathochromic shift and peak sharpening with increasing dye concentration suggesting the presence of J-aggregates. Furthermore, the emission maxima of both H and O shift up to 20 nm in solvents of different polarity. These dyes can be used as NIR ink and imaged remotely on the macroscopic level with a stand-off distance of 20 cm. We furthermore demonstrate their versatility for biophotonics by coating microscale beads and performing microrheology via NIR video particle tracking (NIR-VPT) in biopolymer (F-actin) networks. No photodamaging of the actin filaments takes place, which is typically observed for visible fluorophores and highlights the advantages of these NIR dyes.
Evidence for an N-halohistidyl Intermediate in the Catalytic Cycle of Vanadium Chloroperoxidase (VCPO) and an Artificial Enzyme derived from VCPO: A Computational Investigation
Authors: Anderson Gregory , Behera Raghu Nath , Gomatam Ravi
Published: February 2022

Vanadium haloperoxidases play an important catalytic role in the natural production of antibiotics which are difficult to make in the laboratory. Understanding the catalytic mechanism of these enzymes will aide in the production of artificial enzymes useful in bioengineering the synthesis of drugs and useful chemicals. However, the catalytic mechanism remains not fully understood yet. In this paper, we investigate one of the key steps of the catalytic mechanism using QM/MM. Our investigation reveals a new N-haloxy histidyl intermediate in the catalytic cycle of vanadium chloroperoxidase (VCPO). This new intermediate, in turn, yields an explanation for the known inhibition of the enzyme by substrate under acidic conditions (pH<4). Additionally, we examine the possibility of replacing V in VCPO by Nb or Ta using QM modeling. We report the new result that the Gibbs free energy barrier of several steps of the catalytic cycle are lower in the case of artificial enzymes, incorporating NbO43- or TaO43- instead of VO43-. Our results suggest that these new artificial enzymes may catalyze the oxidation of halide faster than the natural enzyme.
Water transport through epoxy-based powder pipeline coatings
Authors: Zargarnezhad Hossein , Asselin Edouard , Wong Dennis , Lam C.N. Catherine
Published: February 2022

Hydration of epoxy coatings reduces adhesion performance and causes degradation of the material, such as microstructural failures. Quantification of water vapor transport at elevated temperatures is fundamental to understanding polymer coating performance, especially when the coating is exposed to extreme operating conditions. As the water activity increases, the permeability/selectivity of polymers against other permeants changes. In this study, we examined the water permeation kinetics of two common epoxy-based powder coating systems for pipelines (fusion-bonded epoxy, FBE, and high-performance powder coating, HPPC) across a range of industrially-relevant temperatures (from room temperature to 80°C). Specifically, we utilized vapor permeation features of FBE and HPPC films with quantification of equilibrium flux as a function of temperature and pressure. In addition, we analyzed the nonlinear dependency of water transport on the vapor concentration at 65°C. The vapor transport analysis demonstrated that although data for FBE were indicative of a decrease in permeability around 65°C, perhaps due to self-association of water molecules, the coating was likely to experience a plasticization pressure around this temperature. We also examined microstructural changes of the epoxy network due to water transport. Our results revealed evidence of irreversible damage to epoxy coatings under wet-state conditions above 65°C. It appears that the combination of thermal exposure and internal stresses in the glassy epoxy lead to a phase separation of filler particles from the epoxy matrix, as well as to a distinctive cavity formation in the coating membrane. Yet, despite formation of percolating paths for water transport, our results indicate that vapor permeation is primarily restrained due to self-association of water molecules. The vapor transport flux and its permeance are lowered by one order of magnitude in the multilayered HPPC thanks to the moisture-resistant polyethylene topcoat, thus reducing the extent of damage to the underlying substrate. Since barrier protection against gas phase diffusion is controlled by the FBE primer, however, consequences of coating hydration are more pronounced in the overall selectivity toward gaseous transport. Hydrothermal exposure is likely to increase aggregate porosity of the coating and a conservative implementation of standard coating requirements is therefore reasonable to avoid early degradation issues.
Active site sequence representation of human kinases outperforms full sequence for affinity prediction and inhibitor generation: 3D effects in a 1D model
Authors: Born Jannis , Huynh Tien , Stroobants Astrid , Cornell Wendy , Manica Matteo
Published: February 2022

Recent advances in deep learning have enabled the development of large-scale multimodal models for virtual screening and de novo molecular design. The human kinome with its abundant sequence and inhibitor data presents an attractive opportunity to develop proteochemometric models that exploit the size and internal diversity of this family of targets. Here we challenge a standard practice in sequence-based affinity prediction models: instead of leveraging the full primary structure of proteins, each target is represented by a sequence of 29 residues defining the ATP binding site. In kinase-ligand binding affinity prediction, our results show that the reduced active site sequence representation is not only computationally more efficient but consistently yields significantly higher performance than the full primary structure. This trend persists across different models, datasets, performance metrics and holds true when predicting affinity for both unseen ligands and kinases. Our interpretability analysis further demonstrates that, even without supervision, the full sequence model can learn to focus on the active site residues to a higher extent. We then investigate a de novo molecular design task and find that the active site provides benefits in the computational efficiency, but otherwise, both kinase representations yield similar optimized affinities (for both SMILES and SELFIES-based molecular generators). Our work challenges the assumption that full primary structure is indispensable for modelling human kinases. We hope that these results will inspire additional investigation into hybrid mechanistic-DL modeling approaches to support the identification and optimization of kinase inhibitors’ candidates.
MEMES: Machine learning framework for Enhanced MolEcular Screening
Authors: Mehta Sarvesh , Laghuvarapu Siddhartha , Pathak Yashaswi , Sethi Aaftaab , Alvala Mallika , Priyakumar U. Deva
Published: February 2022

In drug discovery applications, high throughput virtual screening exercises are routinely performed to determine an initial set of candidate molecules referred to as "hits". In such an experiment, each molecule from large small-molecule drug library is evaluated for physical property such as the docking score against a target receptor. In real-life drug discovery experiments, the drug libraries are extremely large but still a minor representation of the essentially infinite chemical space, and evaluation of physical property for each molecule in the library is not computationally feasible. In the current study, a novel Machine learning framework for Enhanced MolEcular Screening ("MEMES") based on Bayesian optimization is proposed for efficient sampling of chemical space. The proposed framework is demonstrated to identify 90% of top-1000 molecules from a molecular library of size about 100 million, while calculating the docking score only for about 6% of the complete library. We believe that such a framework would tremendously help to reduce the computational effort in not only drug-discovery but also areas that require such high-throughput experiments.
PAM-expanded Streptococcus thermophilus Cas9 C-to-T and C-to-G base editors for programmable base editing in mycobacteria
Authors: Ji Quanjiang , Zhang Hongyuan , Zhang Yifei , Wang Wei-Xiao , Chen Weizhong , Zhang Xia , Huang Xingxu , Chen Wei
Published: February 2022

New therapeutic strategies for rapid and effective treatment of tuberculosis are highly desirable, and their development can be drastically accelerated by facile genetic manipulation methods in Mycobacterium tuberculosis. CRISPR base editors allow for rapid, robust, and programmed single base substitutions and gene inactivation, yet no such systems are currently available in M. tuberculosis. By screening distinct CRISPR base editors, we identified that only the unusual Streptococcus thermophilus Cas9 (St1Cas9) cytidine base editor (CBE), but not the widely used Streptococcus pyogenes Cas9 or Lachnospiraceae bacterium Cpf1 CBEs, are active in mycobacteria. Despite the notable C-to-T conversions, a high portion of undesired byproducts existed with St1Cas9 CBE. We thus engineered St1Cas9 CBE by uracil DNA glycosylase inhibitor (UGI) or uracil DNA glycosylase (UNG) fusion, yielding two new base editors (CTBE and CGBE), capable of C-to-T or C-to-G conversions with dramatically enhanced editing product purity and multiplexed editing capacity. Because wild-type St1Cas9 recognizes a relatively strict PAM sequence for DNA targeting, we evolved a PAM-expanded St1Cas9 variant by structure-guided protein engineering for the base editors, substantially broadening the targeting scope. Our approaches significantly reduce the efforts and time for precise genetic manipulation and will facilitate functional genomics and drug-target exploration in M. tuberculosis and related organisms.
Oxidation resistance of hard boron-rich chalcogenides B6X and B12X (X = S, Se)
Authors: Solozhenko Vladimir L.
Published: February 2022

Oxidation resistance of new boron-rich chalcogenides, orthorhombic B6X and rhombohedral B12X (X = S, Se), was studied by thermal analysis (TG-MS). It has been established that in air boron-rich sulfides remains stable up to ~580ºC, while boron-rich selenides start to oxidize already at ~550ºC.
Characterisation and heterologous biosynthesis of burnettiene A, a new polyene-decalin polyketide from Aspergillus burnettii
Authors: Roux Indra , Bowles Simon , Kalaitzis John A. , Vuong Daniel , Lacey Ernest , Chooi Yit-Heng , Piggott Andrew M.
Published: February 2022

Chemical exploration of the recently described Australian fungus, Aspergillus burnettii, uncovered a new metabolite, burnettiene A. Here, we characterise the structure of burnettiene A as a polyene-decalin polyketide. Bioinformatic analysis of the genome of A. burnettii identified a putative biosynthetic gene cluster for burnettiene A (bue), consisting of eight genes and sharing similarity to the fusarielin gene cluster. Introduction of the reassembled bue gene cluster into Aspergillus nidulans for heterologous expression resulted in the production of burnettiene A under native promoters. Omission of bueE encoding a cytochrome P450 led to the production of preburnettiene A, confirming that BueE is responsible for catalysing the regiospecific multi-oxidation of terminal methyl groups to carboxylic acids. Similarly, bueF was shown to encode an ester-forming methyltransferase, with its omission resulting in the production of the tricarboxylic acid, preburnettiene B. Introduction of an additional copy of the transcription factor bueR under the regulation of the gpdA promoter significantly improved the heterologous production of the burnettienes. Burnettiene A displayed strong in vitro cytotoxicity against mouse myeloma NS-1 cells (MIC 0.8 µg/mL).
Designing Highly Luminescent Molecular Aggregates via Bottom-Up Nanoscale Engineering
Authors: Barotov Ulugbek , Klein Megan , Wang Lili , Bawendi Moungi
Published: February 2022

Coupling of excitations between organic fluorophores in J-aggregates leads to coherent delocalization of excitons across multiple molecules, resulting in materials with high extinction coefficients, long-range exciton transport, and, in particular, short radiative lifetimes. Despite these favorable optical properties, uses of J-aggregates as high-speed light sources have been hindered by their low photoluminescence quantum yields. Here, we take a bottom-up approach to design a novel J-aggregate system with a large extinction coefficient, a high quantum yield and a short lifetime. To achieve this goal, we first select a J-aggregating cyanine chromophore and reduce its nonradiative pathways by rigidifying the backbone of the cyanine dye. The resulting conformationally-restrained cyanine dye exhibits strong absorbance at 530 nm and fluorescence at 550 nm with 90% quantum yield and 2.3 ns lifetime. We develop optimal conditions for the self-assembly of highly emissive J-aggregates. Cryogenic transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS) reveal micron-scale extended structures with 2D sheet-like morphology, indicating long-range structural order. These novel J-aggregates have a strong red-shifted absorption at 600 nm, resonant fluorescence with no Stokes shift, 50% quantum yield, and 220 ps lifetime at room temperature. We further stabilize these aggregates in a glassy sugar matrix and study their excitonic behavior using temperature-dependent absorption and fluorescence spectroscopy. These temperature- dependent studies confirm J-type excitonic coupling and superradiance. Our results have implications for the development of a new generation of organic fluorophores that combine high speed, high quantum yield and solution processing.
Simultaneous enhancement of thermally activated delayed fluorescence and photoluminescence quantum yield via homoconjugation
Authors: Montanaro Stephanie , Pander Piotr , Elsegood Mark , Teat Simon , Bond Andrew , Wright Iain , Congrave Daniel , Etherington Marc
Published: February 2022

A fundamental problem facing thermally activated delayed fluorescence (TADF) is to overcome the paradox of efficient electronic transitions and a narrow singlet-triplet energy gap (ΔEST) in a single luminophore. We present a quinoxaline-based TADF iptycene as the first clear example that homoconjugation can be harnessed as a viable design strategy toward this objective. Homoconjugation was introduced in an established TADF luminophore by trimerization through an iptycene core. This homoconjugation was confirmed by electrochemistry. As a direct consequence of homoconjugation we observed synergistic improvements to photoluminescence quantum yield (ΦPL), radiative rate of singlet decay (krS), delayed fluorescence lifetime (τTADF), and rate of reverse intersystem crossing (krISC), while narrowing the ΔEST. The cooperative enhancement is rationalised with TD-DFT calculations including spin-orbit coupling (SOC). A facile synthesis of this system, and the ubiquity of the pyrazine motif in state-of-the-art TADF materials across the electromagnetic spectrum, leads to a great potential for generality.
A Six-Coordinate High-Spin FeIV=O Species of Cucurbit[5]uril: A Highly Potent Catalyst for C-H Hydroxylation of Methane, If synthesised
Authors: Rajaraman Gopalan , Kumar Ravi , Sundararajan Mahesh
Published: February 2022

DFT and ab initio DLPNO-CCSD(T) calculations predict a stable S =2 six-coordinate FeIV=O species with cucurbit[5]uril (CB[5]) as a ligand ([(CB[5])FeIV=O(H2O)]2+(1)). The aggressive reactivity pattern of 1 far exceeds even metalloenzymes such as sMMOs in activating inert substrates such as methane, setting a stage for new generation biomimic catalysts
Off-target profiling of tofacitinib and baricitinib by machine learning: a focus on thrombosis and viral infection.
Authors: Faquetti Maria Luisa , Grisoni Francesca , Schneider Petra , Schneider Gisbert , Burden Andrea
Published: February 2022

Objectives: There are no clear on-target mechanisms that explain the increased risk for thrombosis and viral infection or reactivation associated with Janus kinase (JAK) inhibitors. We aimed to identify and validate off-target binding effects of the JAK inhibitors baricitinib and tofacitinib using computational and experimental methods. Methods: Potential biological targets of baricitinib and tofacitinib were predicted using two established computational methods. Targets related to thrombosis or viral infection/reactivation were experimentally validated using biochemical and cell-based in vitro assays. Results: Overall, 98 targets were predicted by the computational methods (baricitinib n=41; tofacitinib n=58), of which 17 drug-target pairs were related to thrombosis (n=10) or viral infection/reactivation (n=7), and 11 were commercially available for in vitro analysis. Inhibitory activity was identified in vitro for four drug-target pairs – two related to thrombosis in the micromolar range (phosphodiesterase 10A [baricitinib], transient receptor potential cation channel subfamily M subtype 6 [tofacitinib]) and two related to viral infection/reactivation in the nanomolar range (Serine/threonine protein kinase N2 [baricitinib, tofacitinib]). Conclusions: Previously unknown off-target interactions for the two JAK inhibitors were identified. The proposed pharmacological off-target effects include attenuation of pulmonary vascular remodeling, modulation of Hepatitis C viral response and hypomagnesemia. Off-target effects related to an increased risk of thrombosis or viral infection/reactivation for baricitinib and tofacitinib were not identified. Further clinical and experimental research is required to explain the observed thrombosis and viral infection/reactivation risk.