bluuebunny/crossref_metadata_2025 huggingface dataset:
Addressing Missing Data in Untargeted Metabolomics: Identifying Missingness Type and Evaluating the Impact of Imputation Meth-ods on Experimental Replication
Authors: Davis Trenton J. , Firzli Tarek R. , Higgins Keppler Emily A. , Richardson Matt , Bean Heather D.
Published: February 2022

Missing data is a significant issue in metabolomics that is often neglected when conducting data pre-processing, particularly when it comes to imputation. This can have serious implications for downstream statistical analyses and lead to misleading or uninterpretable inferences. In this study, we aim to identify the primary types of missingness that affect untargeted metab-olomics data and compare strategies for imputation using two real-world comprehensive two-dimensional gas chromatog-raphy (GC×GC) data sets. We also present these goals in the context of experimental replication whereby imputation is con-ducted in a within-replicate-based fashion—the first description and evaluation of this strategy—and introduce an R package MetabImpute to carry out these analyses. Our results conclude that, in these two data sets, missingness was most likely of the missing at-random (MAR) and missing not-at-random (MNAR) types as opposed to missing completely at-random (MCAR). Gibbs sampler imputation and Random Forest gave the best results when imputing MAR and MNAR compared against single-value imputation (zero, minimum, mean, median, and half-minimum) and other more sophisticated approach-es (Bayesian principal components analysis and quantile regression imputation for left-censored data). When samples are replicated, within-replicate imputation approaches led to an increase in the reproducibility of peak quantification compared to imputation that ignores replication, suggesting that imputing with respect to replication may preserve potentially im-portant features in downstream analyses for biomarker discovery.
Microscopic picture of molecular double doping
Authors: Bathe Thomas , Dong Chuan-Ding , Schumacher Stefan
Published: February 2022

Double doping, in which a single dopant molecule induces two charge carriers in an organic semiconductor (OSC), was recently experimentally observed and promises to enhance the efficiency of molecular doping. Here we present a theoretical investigation of p-type molecular double doping in a CN6-CP:bithiophene–thienothiophene OSC system. Our analysis is based on density functional theory (DFT) calculations for the electronic ground state. In a molecular complex with two OSC oligomers and one CN6-CP dopant molecule we explicitly demonstrate double integer charge transfer and find formation of two individual polarons on the OSC molecules and a di-anion dopant molecule. We show that the vibrational modes and related infrared absorption spectrum of this complex can be traced back to those of the charged dopant and OSC molecules in their isolated forms. The near-infrared optical absorption spectrum calculated by time-dependent DFT shows both features of typical intra-molecular polaron excitations and weak inter-molecular charge transfer excitations associated with the doping-induced polaron states.
Sequence-sorted redox-switchable hetero[3]rotaxanes
Authors: Gaedke Marius , Hupatz Henrik , Witte Felix , Rupf Susanne , Douglas Clara , Schröder Hendrik V. , Fischer Lukas , Malischewski Moritz , Paulus Beate , Schalley Christoph A.
Published: February 2022

From a library of five crown ether macrocycles with different ring sizes and redox-active moieties, such as tetrathiafulvalene (TTF) and naphthalene dimiide (NDI), directional heterocircuit[3]rotaxanes were constructed. Using an axle with two binding sites with different steric accessibility, the concept of integrative self-sorting was applied to program the sequence of functional units in heteropseudo[3]rotaxanes. Depending on binding strength and ring size of the smaller macrocycles, different heteropseudo[3]rotaxane selectivities and stabilities were determined by 2D NMR spectroscopy and tandem mass spectrometry. A heteropseudo[3]rotaxane with rotaxane-like behaviour was isolated chromatographically, displaying electrochemically "frustrated" properties. A robust synthetic procedure was developed allowing the synthesis of four new hetero[3]rotaxanes incorporating specific sequences of functional units. Sequence pseudoisomeric rotaxanes which have the naphthalene diimide subunit at two different positions show distinct electrochemical properties. DFT calculations suggest that this differences could arise from a folding of the structure, in which the redox-active moieties stack with a stopper unit. This study presents a blueprint for the construction of hetero[3]rotaxanes with sequential control of the functional units along the track of the axle and paves the way to extend the functionality of mechanically interlocked molecules.
Sequence-sorted redox-switchable hetero[3]rotaxanes
Authors: Gaedke Marius , Hupatz Henrik , Witte Felix , Rupf Susanne Margot , Douglas Clara , Schröder Hendrik V. , Fischer Lukas , Malischewski Moritz , Paulus Beate , Schalley Christoph A.
Published: February 2022

From a library of five crown ether macrocycles with different ring sizes and redox-active moieties, such as tetrathiafulvalene (TTF) and naphthalene dimiide (NDI), directional heterocircuit[3]rotaxanes were constructed. Using an axle with two binding sites with different steric accessibility, the concept of integrative self-sorting was applied to program the sequence of functional units in heteropseudo[3]rotaxanes. Depending on binding strength and ring size of the smaller macrocycles, different heteropseudo[3]rotaxane selectivities and stabilities were determined by 2D NMR spectroscopy and tandem mass spectrometry. A heteropseudo[3]rotaxane with rotaxane-like behaviour was isolated chromatographically, displaying electrochemically "frustrated" properties. A robust synthetic procedure was developed allowing the synthesis of four new hetero[3]rotaxanes incorporating specific sequences of functional units. Sequence pseudoisomeric rotaxanes which have the naphthalene diimide subunit at two different positions show distinct electrochemical properties. DFT calculations suggest that this differences could arise from a folding of the structure, in which the redox-active moieties stack with a stopper unit. This study presents a blueprint for the construction of hetero[3]rotaxanes with sequential control of the functional units along the track of the axle and paves the way to extend the functionality of mechanically interlocked molecules.
Uncovering the key role of distortion in tetrazine ligations guides the design of bioorthogonal tools with high reactivity and superior stability
Authors: Svatunek Dennis , Wilkovitsch Martin , Hartmann Lea , Houk Kendall , Mikula Hannes
Published: February 2022

The tetrazine/trans-cyclooctene ligation stands out from the bioorthogonal toolbox due to its exceptional reaction kinetics, enabling multiple molecular technologies in vitro and in living systems. Highly reactive 2-pyridyl-substituted tetrazines have become state-of-the-art for time-critical processes and selective reactions at very low concentration. It is widely accepted that the enhanced reactivity of these chemical tools is attributed to the electron-withdrawing effect of the heteroaryl substituent. In contrast, we show that observed reaction rates are way too high to be explained on this basis. Computational investigation of this phenomenon revealed that distortion of the tetrazine caused by intramolecular N-N repulsion plays a key role in accelerating the cycloaddition step. While we show that the limited stability of tetrazines under physiological conditions strongly correlates with the electron-withdrawing effect of the substituent, intramolecular destabilization increases the reactivity without reducing stability. Guided by these fundamental insights we demonstrate application in the design of highly reactive tetrazines with superior stability, finally evading the reactivity/stability trade-off for bioorthogonal tetrazine tools.
Paper Spray Ionisation Ion Mobility Mass Spectrometry of Sebum Classifies Biomarker Classes for the Diagnosis of Parkinson’s Disease
Authors: Sarkar Depanjan , Sinclair Eleanor , Lim Sze Hway , Walton-Doyle Caitlin , Jafri Kaneez , Milne Joy , P.C. Vissers Johannes , Richardson Keith , Trivedi Drupad , Silverdale Monty , Barran Perdita
Published: February 2022

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and identification of robust biomarkers to complement clinical diagnosis will accelerate treatment options. Here we demonstrate the use of direct infusion of sebum from skin swabs using paper spray ionisation coupled with ion mobility mass spectrometry (PS-IM-MS) to determine the regulation of molecular classes of lipids in sebum that are diagnostic of PD. A PS-IM-MS method for sebum samples that takes three minutes per swab was developed and optimised. The method was applied to skin swabs collected from 150 people and elucidates ~ 4200 features from each subject which were independently analysed. The data included high molecular weight lipids (>600 Da.) that differ significantly in the sebum of people with PD. Putative metabolite annotations of several lipid classes, predominantly triglycerides and larger acyl glycerides, were obtained using accurate mass, tandem mass spectrometry and collision cross section measurements.
Palladium-Catalyzed Late-Stage C-H Deuteration of Arenes
Authors: Farizyan Mirxan , Mondal Arup , Mal Sourjya , Deufel Fritz , van Gemmeren Manuel
Published: February 2022

We describe a palladium catalyzed non-directed late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acyl sulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features an extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labelling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, amongst other applications, will prove useful as a tool in drug development processes and for mechanistic studies.
Mixed Halide Bulk Perovskite Triplet Sensitizers: Interplay between Band Alignment, Mid-gap Traps and Phonons
Authors: Bieber Alexander , VanOrman Zachary , Drozdick Hayley , Weiss Rachel , Wieghold Sarah , Nienhaus Lea
Published: February 2022

Photon upconversion, particularly via triplet-triplet annihilation (TTA), could prove beneficial in expanding the efficiencies and overall impacts of optoelectronic devices across a multitude of technologies. The recent development of bulk metal halide perovskites as triplet sensitizers is one potential step toward the industrialization of upconversion-enabled devices. Here, we investigate the impact of varying additions of bromide into a lead iodide perovskite thin film on the TTA upconversion process in the annihilator molecule rubrene. We find an interplay between the bromide content and the overall device efficiency. In particular, a higher bromide content results in higher internal upconversion efficiencies, enabled by more efficient charge extraction at the interface, likely due to a more favorable band alignment. However, the external upconversion efficiency decreases, as the absorption cross section in the near infrared is reduced. The highest upconversion performance is found in our study for a bromide content of 5%. This result can be traced back to a high absorption cross section in the near infrared and higher photoluminescence quantum yield in comparison to the iodide-only perovskite, as well as an increased driving force for charge transfer.
Photocatalytic hydrogen generation and electron storage capability of mesoporous TiO2 aerogels with adjustable surface area
Authors: Rose Alexandra , Hofmann Anja , Voepel Pascal , Milow Barbara , Marschall Roland
Published: February 2022

Mesoporous TiO2 aerogels with surface area larger than 600 m2 g-1 have been prepared via acid-catalyzed sol-gel synthesis and supercritical drying. Varying temperature treatment in air results in changes in the morphology of the aerogels and their specific surface area. Increasing the calcination temperature to 500 °C results in decreased surface area, however in strongly increased hydrogen evolution rates in photocatalytic experiments. Moreover, electron storage capabilities of different TiO2 aerogels are investigated. The ability to store photogenerated electrons in the surface states of the aerogels upon illumination of dispersions in water-methanol mixtures increases with lower calcination temperature. Furthermore, the extent of electron storage also depends on hole scavenger concentration. Finally, nitrogen reduction to ammonia in the dark is performed with photogenerated stored electrons in TiO2 aerogels, separating the charge carrier photogeneration from the dark reduction reaction.
Amyloid Plaque Polymorphism is Associated with Distinct Lipid Accumulations Revealed by Trapped Ion Mobility Mass Spectrometry Imaging (TIMS MSI)
Authors: Michno Wojciech , Wehrli Patrick , Koutarapu Srinivas , Marsching Christian , Minta Karolina , Ge Junyue , Meyer Sven , Zetterberg Henrik , Blennow Kaj , Henkel Corinna , Oetjen Janina , Hopf Carsten , Hanrieder Jörg
Published: February 2022

Understanding of Alzheimer’s disease (AD) pathophysiology, requires molecular assessment of how key pathological factors, specifically amyloid β (Aβ) plaques, influence the surrounding microenvironment. Here, neuronal lipids are particularly of interest as these are implicated in pathological- and neurodegenerative processes in AD. The exact molecular characteristics of the cellular environment in direct proximity to Aβ plaques are however still not known, not in the least due to high molecular complexity of lipid species but also due to the lacking spatial resolution, sensitivity, and specificity of analytical approaches. Likewise, how such micro environmental changes differ, across structurally polymorphic Aβ features - such as diffuse, immature and mature, fibrillary structures - has been a challenge, requiring complemental, multimodal imaging approaches. Herein, we used matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) trapped ion mobility spectrometry Time-of-Flight (TIMS TOF) in combination with hyperspectral microscopy to probe lipidomic microenvironment associated with structural polymorphism of Aβ plaque in transgenic mouse model of Alzheimer’s disease (tgAPPSWE).Integrated multivariate imaging data analysis revealed alteration of multiple lipid species showing a general, Aβ associated enrichment/depletion patterns. The hyperspectral imaging strategy further delineated unique distribution of PA, PE-Cer and PI lipids to more/less aggregated Aβ fibrillary structures present within individual Aβ plaques at different timepoints of progressing plaque pathology. Using an elaborate on tissue and ex situ validation approach, the unique possibility to obtain gas-phase isobar and isomer separations through TIMS TOF, facilitated unambiguous identification of lipid isomers that showed plaque pathology associated localizations. Finally, we followed AD pathology associated lipid changes over time, identifying plaque growth and maturation to be characterized by peripheral accumulation of PI (40:6). Together, these data demonstrate the potential of multimodal imaging approaches to overcome limitations associated with conventional advanced MS imaging applications. This allowed for differentiation of both distinct lipid components in a complex micro environment, as well as their correlation to disease relevant amyloid plaque polymorphs.
Dimensional control over metal halide perovskite crystallization guided by active learning
Authors: Li Zhi , Nega Philip , Najeeb Mansoor , Dun Chaochao , Zeller Matthias , Urban Jeffrey , Saidi Wissam , Schrier Joshua , Norquist Alexander , Chan Emory
Published: February 2022

Metal halide perovskite (MHP) derivatives, a promising class of optoelectronic materials, have been synthesized with a range of dimensionalities that govern their optoelectronic properties and determine their applications. We demonstrate a data-driven approach combining active learning and high-throughput experimentation to discover, control, and understand the formation of phases with different dimensionalities in the morpholinium (morph) lead iodide system. Using a robot-assisted workflow, we synthesized and characterized two novel MHP derivatives that have distinct optical properties: a one-dimensional (1D) morphPbI3 phase ([C4H10NO][PbI3]) and a 2D (morph)2PbI4 phase ([C4H10NO]2[PbI4]). To efficiently acquire the data needed to construct a machine learning (ML) model of the reaction conditions where the 1D and 2D phases are formed, data acquisition was guided by a diverse-mini-batch-sampling active learning algorithm, using prediction confidence as a stopping criterion. Querying the ML model uncovered the reaction parameters that have the most significant effects on dimensionality control. Based on these insights, we propose a reaction scheme that rationalizes the formation of different dimensional MHP derivatives in the morph-Pb-I system. The data-driven approach presented here, including the use of additives to manipulate dimensionality, will be valuable for controlling the crystallization of a range of materials over large reaction-composition spaces.
Flipping the switch: reverse-demand voltage-sensitive fluorophores
Authors: McCann Jack , Benlian Brittany , Knudson Isaac , Miller Evan
Published: February 2022

Fluorescence microscopy with fluorescent reporters that respond to environmental cues are a powerful method for interrogating biochemistry and biophysics in living systems. Photoinduced electron transfer (PeT) is commonly used as a trigger to modulate fluorescence in response to changes in the biological environment. PeT based indicators rely either on PeT into the excited state (acceptor PeT) or out of the excited state (donor PeT). Our group has been developing voltage-sensitive fluorophores (VF dyes) that respond to changes in biological membrane potential. We hypothesize that the mechanism of voltage sensitivity arises from acceptor PeT (a-PeT) from an electron-rich aniline-containing molecular wire into the excited state fluorophore, resulting in decreased fluorescence at negative membrane potentials. Here, we can reverse the direction of electron flow to access donor-excited PeT (d-PeT) VF dyes by introducing electron-withdrawing (EWG), rather than electron-rich molecular wires. Similar to first-generation aniline containing VF dyes, EWG-containing VF dyes show voltage-sensitive fluorescence, but with the opposite polarity: hyperpolarizing membrane potentials now give fluorescence increases. We use a combination of computation and experiment to estimate a ΔE of ~0.6 eV for voltage sensitivity in d-PeT indicators, show that two of the new reverse VF dyes are voltage sensitive, and provide the first example, to our knowledge, of a molecular sensor that can be tuned across energy regimes to access bi-directional electron flow for fluorescence sensing in living systems.
Towards Accurate Description of Chemical Reaction Energetics by Using Variational Quantum Eigensolver: A Case Study of the C2v Quasi-Reaction Pathway of Beryllium Insertion to H2 Molecule
Authors: Sugisaki Kenji , Kato Takumi , Minato Yuichiro , Okuwaki Koji , Mochizuki Yuji
Published: February 2022

We have examined the performance of variational quantum eigensolver along the quasi-reaction pathway of Be insertion to H2 molecule, in which avoided crossing occurs at the transition structure. Numerical simulations revealed that the multireference unitary coupled cluster with partially generalized singles and doubles (MR-UCCpGSD) is a powerful tool to describe the electronic structure of strongly correlated systems.
Profiling the proteome-wide selectivity of diverse electrophiles
Authors: Zanon Patrick R. A. , Yu Fengchao , Musacchio Patricia , Lewald Lisa , Zollo Michael , Krauskopf Kristina , Mrdović Dario , Raunft Patrick , Maher Thomas E. , Cigler Marko , Chang Christopher , Lang Kathrin , Toste F. Dean , Nesvizhskii Alexey I. , Hacker Stephan M.
Published: February 2022

Targeted covalent inhibitors are powerful entities in drug discovery, but their application has so far mainly been limited to addressing cysteine residues. The development of cysteine-directed covalent inhibitors has largely profited from determining their proteome-wide selectivity using competitive residue-specific proteomics. Several probes have recently been described to monitor other amino acids using this technology and many more electrophiles exist to modify proteins. Nevertheless, a direct, proteome-wide comparison of the selectivity of diverse probes is still entirely missing. Here, we developed a completely unbiased workflow to analyse electrophile selectivity proteome-wide and applied it to directly compare 54 alkyne probes containing diverse reactive groups. In this way, we verified and newly identified probes to monitor a total of nine different amino acids as well as the N-terminus proteome-wide. This selection includes the first probes to globally monitor tryptophans, histidines and arginines as well as novel tailored probes for methionines, aspartates and glutamates.
Upper Secondary School and University Level Students’ Perceptions of Extractions in Context: Experiences from a Simple Laboratory Experiment
Authors: Nurmi Tuomas , Siitonen Juha
Published: February 2022

We discuss the pedagogical challenges associated with the current way of introducing extraction in upper secondary school chemistry education. These challenges were identified based on a survey of upper secondary school textbooks and verified through a questionnaire study. To address the identified challenges, we introduce a simple and effective extraction experiment which focuses on building a deeper conceptual understanding of extraction processes. The operationally simple extraction experiment and the accompanying questionnaire revealed that while students have several chemical misconceptions arising from the use of superficial everyday examples, they have all the necessary knowledge for developing a deeper understanding of chemistry. Providing a suitable experimental platform for developing and re-evaluating their knowledge allows the students to reasonably independently re-conceptualize their thinking toward a more coherent view of the surrounding world and the related scientific models. Furthermore, the work analyses the challenges that can be encountered when using everyday examples in teaching, and demonstrates that student-discovered examples of chemical systems can be a powerful method for generating meaningful and relevant ways to introduce scientific phenomena in STEM education.
Boosting efficiency in light-driven water splitting by dynamic irradiation through synchronizing reaction and transport processes
Authors: Sender Maximilian , Huber Fabian , Moersch Maximilian , Kowalczyk Daniel , Hniopek Julian , Klingler Sarah , Schmitt Michael , Kaufhold Simon , Siewerth Kevin , Popp Jürgen , Mizaikoff Boris , Ziegenbalg Dirk , Rau Sven
Published: February 2022

This work elaborates the effect of dynamic irradiation on light-driven molecular water oxidation to counteract catalyst deactivation. It highlights the importance of overall reaction engineering to overcome limiting factors in artificial photosynthesis reactions. Systematic investigation of a homogenous three component ruthenium-based water oxidation system revealed significant potential to enhance the overall catalytic efficiency by synchronizing the timescales of photoreaction and mass transport in a capillary flow reactor. The overall activity could be improved by a factor of more than 10 with respect to the turnover number and a factor of 31 referring to the external energy efficiency by controlling the local availability of photons. Detailed insights into the mechanism of light driven water oxidation could be obtained using complementary methods of investigation like Raman, IR and UV-vis/emission spectroscopy, unraveling the importance of avoiding high concentrations of excited photosensitizers.
Hyperfine Coupling Constants in Local Exact Two-Component Theory
Authors: Franzke Yannick J. , Yu Jason M.
Published: February 2022

We present a highly efficient implementation of the electron-nucleus hyperfine coupling matrix within one-electron exact two-component (X2C) theory. The complete derivative of the X2C Hamiltonian is formed, i.e. the derivatives of the unitary decoupling transformation are considered. This requires solution of the response and Sylvester equations, consequently increasing the computational costs. Therefore, we apply the diagonal local approximation to the unitary decoupling transformation (DLU). The finite nucleus model is employed for both the scalar potential and the vector potential. Two-electron picture-change effects are modeled with the (modified) screened-nuclear spin--orbit approach. Our implementation is fully integral direct and OpenMP-parallelized. An extensive benchmark study regarding the Hamiltonian, the basis set, and the density functional approximation is carried out for a set of 12--17 transition-metal compounds. The error introduced by DLU is negligible and the DLU-X2C Hamiltonian accurately reproduces its four-component ``fully'' relativistic parent results. Functionals with a large amount of Hartree--Fock exchange such as CAM-QTP-02 and omega-B97X-D are generally favorable. The pure density functional r2SCAN performs remarkably and even outperforms the common hybrid functionals TPSSh and CAM-B3LYP. Fully uncontracted basis sets or contracted quadruple-zeta bases are required for accurate results. The capability of our implementation is demonstrated for [Pt(C6Cl5)4]- with more than 4700 primitive basis functions and four rare-earth single molecule magnets: [La(OAr*)3]-, [Lu(NR2)3]-, [Lu(OAr*)3]-, and [TbPc2]-. Here, the spin--orbit DLU-X2C Hamiltonian results in an excellent agreement with the experimental findings of all Pt, La, Lu, and Tb molecules.
Encapsulation of Paramagnetic Chelates in Perfluorocarbon-loaded Fractal Nanoparticles Enables Modulation of Fluorine-19 and Proton Magnetic Resonance Imaging Signal
Authors: Verbeelen Margot , White Paul , Staal Alexander H.J. , Swider-Cios Edyta , Cortenbach Kimberly R.G. , van Riessen N. Koen , Cadiou Cyril , Chuburu Françoise , Srinivas Mangala , Koshkina Olga
Published: February 2022

19F magnetic resonance imaging (19F MRI) is an emerging technique for quantitative imaging of novel therapies, such as cellular therapies and theranostic nanocarriers. A modification of perfluorocarbon (PFC)-loaded, nanocarrier-based 19F MRI probes with paramagnetic chelates can enhance probe’s functionality. Liquid PFC-loaded nanocarriers typically have a core-shell structure with PFC in the core due to the poor miscibility of PFC. However, paramagnetic relaxation enhancement acts only at a distance of a few angstroms. Thus, efficient modulation of 19F signal is possible only with fluorophilic PFC-soluble chelates. Such chelates, however, cannot interact with the surroundings of nanocarriers. Conversely, chelates on the surface typically affect only the aqueous environment but not the 19F signal. We show that the confinement of PFC in biodegradable polymeric nanoparticles with fractal structure enables modulation of longitudinal and transverse 19F relaxation, as well as proton signal, using non-fluorophilic paramagnetic chelates. We compared nanoparticles with fractal multicore versus conventional core-shell structure, where the PFC is encapsulated in the core(s) and the chelate in the surrounding polymeric matrix. Importantly, paramagnetic chelates affected both longitudinal and transverse 19F relaxation in fractal multicore nanoparticles, but not in core-shell nanocapsules. Both relaxation rates of 19F nucleus increased with an increasing concentration of the paramagnetic chelate. Moreover, as the polymeric matrix remained water-permeable, proton enhancement additionally was observed in MRI. In the future, the effects of fractal confinement could be combined with more effective paramagnetic chelates to develop multifunctional imaging probes, for example, for high-sensitivity 19F MRI combined with sensing.
Engineering Bacteria to Control Electron Transport Altering the Synthesis of Non-native Biopolymer
Authors: Bennett Mechelle , Jain Akhil , Kovacs Kaitalin , Hill Phil , Alexander Cameron , Rawson Frankie
Published: February 2022

The use of bacteria as catalysts for radical polymerizations of synthetic monomers has recently been established. However, the role of trans Plasma Membrane Electron Transport (tPMET) in modulating these processes is not well understood. We sort to study this by genetic engineering a part of the tPMET system NapC in E coli. We show that this engineering altered the rate of extracellular electron transfer coincided with an effect on cell-mediated polymerization using a model monomer. A plasmid with arabinose inducible PBAD promoters were shown to upregulate NapC protein upon induction at total arabinose concentrations of 0.0018% and 0.18%. These clones (E. coli (IP_0.0018%) and E. coli (IP_0.18%), respectively) were used in Iron-mediated atom transfer radical polymerization (Fe ATRP), affecting the nature of the polymerization, than cultures containing suppressed or empty plasmids (E. coli (IP_S) and E. coli(E), respectively). These results lead to the hypothesis that EET (Extracellular Electron Transfer) in part modulates cell instructed polymerizations.
Principal Component Analysis (PCA) and Statistical Tests Using Factoshiny and R Commander.
Authors: Borges Endler Marcel , Filgueiras Matheus Fernandes
Published: February 2022

Spreadsheets are commonly used for data handling. However, in huge data sets, spreadsheets cannot do statistical tests, such as one-way ANOVA, boxplot, plot of means, principal component analysis (PCA). Most of the students had never worked with programming software such as MATLAB, Phyton, Octave and R project. Hence, in this lab experiment, students analyzed large data sets using R Commander and Factoshiny plugins. Commander and Factoshiny are packages which gives graphical user interface (GUI). GUI plugins allows students with no programming knowledge to run statical tests quickly and easily without having to type a single command line. The class was divided into three parts. First, students analyzed a red wine data set (1599 samples, 11 physicochemical variables, and one qualitative variable) to find correlations between wine quality (qualitative variable) and its physicochemical variables (quantitative variable). Second, they analyzed a white wine data set (4898 samples, 11 physicochemical variables, and one qualitative variable) to find correlations between white wine quality and its physicochemical variables. Third, they analyzed a red wine and white wine data set and found correlations between wine's physicochemical variables and their quality and type. Statistical tests and PCA were carried out using R Commander and Factoshiny, respectively. Due to the graphical interface and simplicity of these two plugins, the class can be concluded in 200 min.
Concerted Cation–Electron Transfer Mechanism for CO2 Electroreduction
Authors: Shin Seung-Jae , Choi Hansol , Ringe Stefan , Won Da Hye , Choi Chang Hyuck , Kim Hyungjun
Published: February 2022

Converting carbon dioxide (CO2) into valuable products is one of the most important processes for a sustainable society. Especially, the electrochemical CO2 reduction reaction (CO2RR) offers an effective means, but its reaction mechanism is not yet fully understood. Here, we demonstrate that concerted cation–electron transfer (CCET) is a key catalytic step in the CO2RR to carbon monoxide. The first-principles-based multiscale simulation identifies a single cation that coordinates a CO2− intermediate adsorbed on Ag electrode. The CCET is experimentally verified by a collapse of the CO2RR polarization curves upon correcting for the thermodynamic activity of the cation. As further confirmation, a kinetic study shows that the CO2RR obeys first-order kinetics on the local cation concentration at the electric double layer (estimated by measuring the electrode surface charge). Finally, this work unveils the fundamental origin of different CO2RR activity depending on the species of alkali metal cation, and further highlights the importance of ion-pairing tendency of the cations for electrochemical interface design to achieve high-performance CO2 electrolysis.
Additive-free selective methylation of amines with formic acid over a Pd/In2O3 catalyst
Authors: Genre Caroline , Benaissa Idir , Godou Timothé , Pinault Mathieu , Cantat Thibault
Published: February 2022

Formic acid is used as the sole carbon and hydrogen source in the methylation of aromatic and aliphatic amines to methylamines. The reaction proceeds via a formylation/transfer hydrogenation pathway over a solid Pd/In2O3 catalyst without the need for any additive.
Exploring the Effects of Methylation on the CID of Lysine: A Combined Experimental and Computational Approach
Authors: Lucas Kenneth , Chen Amy , Schubmehl Megan , Kolonko Kristopher J. , Barnes George L.
Published: February 2022

We report the results of both experiments, simulations, and DFT calculations that focus on describing the reaction dynamics observed within the collision-induced dissociation of L-lysine and its side-chain methylated analogues, $N_\epsilon$-Methyl-L-lysine (\methylLys{1}), $N_\epsilon$,$N_\epsilon$-Dimethyl-L-lysine (\methylLys{2}), and $N_\epsilon$,$N_\epsilon$,$N_\epsilon$-Trimethyl-L-lysine (\methylLys{3}). There is good qualitative agreement between simulations and experiments. The major pathways observed in the experimental measurements were {\it m/z} 130 and 84, with the former dominant at low collision energies and the latter at intermediate to high collision energies. The {\it m/z} peak corresponds to loss of H$_2$CO$_2$ while {\it m/z} 84 has the additional loss of N(CH$_3$)$_n$H$_{3-n}$. Within the time frame of the direct dynamics simulations, {\it m/z} 130 and 101 were the most populous peaks, with the latter identified as an intermediate to {\it m/z} 84. The simulations allowed for the determination of several reaction pathways that result in these products, and a graph theory analysis enabled the elucidation of the major structures that compose each peak. Methylation results in an increase in the preferential loss of the side-chain amide group and a reduced occurrence of cyclic structures within the population of the {\it m/z} 84 peak in simulations.
On the Utility of Coated POSS-Polyimides for Vehicles in Very Low Earth Orbit (VLEO)
Authors: Minton Timothy , Schwartzentruber Thomas , Xu Chenbiao
Published: February 2022

The environment encountered by space vehicles in very low Earth orbit (VLEO, 180 – 350 km altitude) contains predominantly atomic oxygen (AO) and molecular nitrogen (N2), which collide with ram surfaces at relative velocities of ~7.5 km s-1. Structural, thermal-control, and coating materials containing organic polymers are particularly susceptible to AO attack at these high velocities, resulting in erosion, roughening, and degradation of function. Copolymerization or blending of a polymer with polyhedral oligomeric silsesquioxane (POSS) yields a material that can resist AO attack through the formation of a passivating silicon-oxide layer. Still, these hybrid organic/inorganic polymers become rough through AO reactions as the passivating layer is forming. Surface roughness may enhance satellite drag because it promotes energy transfer and scattering angle randomization during gas-surface collisions. As potential low-drag and AO-resistant materials, we have investigated POSS-containing films of clear and Kapton-like polyimides that have an atomically smooth AO-resistant coating of Al2O3 that is grown by atomic layer deposition (ALD). Coated and uncoated films were exposed to hyperthermal molecular beams containing atomic and molecular oxygen to investigate their AO resistance, and molecular beam-surface scattering studies were conducted to characterize the gas-surface scattering dynamics on pristine and AO-exposed surfaces to inform drag predictions. The AO erosion yield of Al2O3 ALD-coated films is essentially zero. Simulations of drag on a representative satellite structure that are based on the observed scattering dynamics suggest that the use of the Al2O3 ALD-coated POSS-polyimides on external satellite surfaces have the potential to reduce drag to less than half that predicted for diffuse scattering surfaces. These smooth and AO-resistant polymer films thus show promise for use in the extreme oxidizing and high-drag environment in VLEO.
Atomistically Resolved Structure of Layered Covalent Organic Frameworks
Authors: Zhang Yingying , Položij Miroslav , Heine Thomas
Published: February 2022

Covalent organic frameworks (COFs) are among the fast-est growing classes of materials with an almost unlimited number of achievable structures, topologies, and func-tionalities. Their exact structure remains, however, un-known to date as reflected by the significant mismatch between experimental powder X-ray diffraction pattern (PXRD) and predicted geometries. We attribute these discrepancies to an overlooked, inherent disorder in the stacking of layered COFs, invalidating standard theoretical 3D models. We have built models of COF-1, COF-5 and ZnPc-pz by stacking layers following the Maxwell-Boltzmann energy distribution of their stacking modes. Simulated PXRD patterns of these model structures are close experiments, featuring an agreement in peak intensi-ty, width and asymmetry that has never been obtained before. The rarely considered ABC stacking mode plays an important role in layered COFs, and solvent molecules have a major effect on the stacking. As our model holds for two main layered COF lattice types (honey-comb/kagome and square), generalization is expected for all layered COFs and MOFs.
Mechanism and Origin of Remote Stereocontrol in the Organocatalytic C(sp2)-H Alkylation using Nitroalkanes as Alkylating Agents
Authors: Mallojjala Sharath Chandra , Sakar Rahul , Karugu Rachael W. , Manna Madhu Sudan , Mukherjee Santanu , Hirschi Jennifer S.
Published: February 2022

ABSTRACT: Experimental 13C kinetic isotope effects (KIEs) and DFT calculations are used to evaluate the mecha-nism and the origin of enantioselectivity in the C(sp2)‒H alkylative desymmetrization of cyclopentene-1,3-diones using nitroalkanes as the alkylating agent. An unusual combination of an inverse (~0.980) and a normal (~1.030) KIE is observed on the bond-forming carbon atoms of the cyclopentene-1,3-dione and nitroalkane, respectively. These data provide strong support for a mechanism involving reversible carbon-carbon bond-formation followed by rate- and enantioselectivity-determining nitro-group elimination. The theoretical free energy profile and predicted KIEs indicate that this elimination event occurs via an E1cB pathway. The origin of remote stereocontrol is evaluated by distortion-interaction and SAPT0 analyses of the enantiomeric E1cB transition states.
Extended Mechanism and Rate-Limiting Step of the Plasminogen Activator Staphylokinase Revealed by Global Kinetic Analysis
Authors: Toul Martin , Nikitin Dmitri , Marek Martin , Damborsky Jiri , Prokop Zbynek
Published: February 2022

The plasminogen activator staphylokinase is a fibrin-specific thrombolytic biomolecule and an attractive target for the development of effective myocardial infarction and stroke therapy. To engineer the protein rationally, a detailed understanding of the biochemical mechanism and limiting steps is essential. Conventional fitting to equations derived based on simplifying approximations may be inaccurate for complex mechanisms like that of staphylokinase. We employed a modern numerical approach of global kinetic data analysis whereby steady-state kinetics and binding affinity datasets were analyzed in parallel. Our approach provided an extended, revised understanding of the staphylokinase mechanism without simplifying approximations and determined the value of turnover number kcat of 117 s-1 that was 10,000-fold higher than that reported in the literature. The model further showed that the rate-limiting step of the catalytic cycle is the binding of staphylokinase to plasmin molecules, which occurs via an induced-fit mechanism. The overall staphylokinase effectivity is further influenced by the formation of an inactive staphylokinase.plasminogen complex. Here, we describe a quick and simplified guide for obtaining reliable estimates of key parameters whose determination is critical to fully understand the staphylokinase catalytic functionality and define rational strategies for its engineering. Our study provides an interesting example of how global numerical analysis of kinetic data can be used to better understand the mechanism and limiting factors of complex biochemical processes.
Targeted Activation in Localized Protein Environments via Deep Red Photoredox Catalysis
Authors: Tay Nicholas , Ryu Keun Ah , Weber John , Olow Aleksandra , Reichman David , Oslund Rob , Fadeyi Olugbeminiyi , Rovis Tomislav
Published: February 2022

State-of-the art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high energy light (λ < 500 nm) for substrate or photocatalyst sensitization can lead to background activation of photoactive small molecule probes and reduce its efficacy in complex biological environments. Here we describe the development of targeted aryl azide activation via deep red light (λ = 660 nm) photoredox catalysis and its use in photocatalyzed proximity labeling. We demonstrate that aryl azides are converted to triplet nitrenes via a novel redox-centric mechanism and show that its spatially localized-formation requires both red light and a photocatalyst-targeting modality. This technology was applied in different colon cancer cell systems for targeted protein environment labeling of epithelial cell adhesion molecule (EpCAM). We identified a small subset of proteins with previously known and unknown association to EpCAM, including CDH3, a clinically relevant protein that shares high tumor selective expression with EpCAM.
QM/MM Study of the Reactivity of Zeolite Bound Methoxy and Carbene Groups
Authors: Nastase Stefan A. F. , Logsdail Andrew , Catlow Richard
Published: February 2022

The conversion of methanol-to-hydrocarbons (MTH) is known to occur via an autocatalytic process in zeolites, where framework-bound methoxy species play a pivotal role, especially during catalyst induction. Recent NMR and FT-IR experimental studies suggest that methoxylated zeolites are able to produce hydrocarbons by a mechanism involving carbene migration and association. In order to understand these observations, we have performed QM/MM computational investigations on a range of reaction mechanisms for the reaction of zeolite bound methoxy and carbene groups, which are proposed to initiate hydrocarbon formation in the MTH process. Our simulations demonstrate that it is kinetically unfavourable for methyl species to form on the framework away from the zeolite acid site, and both kinetically and thermodynamically unfavourable for methyl groups to migrate through the framework and aggregate around an acid site. Formation of carbene moieties was considered as an alternative pathway to the formation of C-C bonds; however, the reaction energy for conversion of a methyl to a carbene is unfavourable. Metadynamics simulations help confirm further that methyl species at the framework acid sites would be more reactive towards formed C2+ species, rather than inter-framework migration and that the role of carbenes in the formation of the first –C bond will be via a concerted type of mechanism rather than stepwise.
Synthetic Studies of Maleimide Derivatives for Bioconjugates Polymers by RAFT polymerization.
Authors: GONDI SUDERSHAN
Published: February 2022

An efficient method for the synthesis of maleimides derivatives in toluene in presence of PTSA is described. The method features a broad substrate scope of utility in both simple and complex setting and provide access to valuable derivatives without any column chromatography purification is described.
From Fragment to Lead: A Structure-Guided Approach Towards a Selective FGFR2 Inhibitor
Authors: Turner Lewis , Trinh Chi , Hubball Ryan , Orritt Kyle , Lin Chi-Chuan , Burns Julie , Knowles Margaret , Fishwick Colin
Published: February 2022

Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials for FGFR-implicated malignancies. Pan-FGFR inhibitors often cause toxic side-effects via off-target inhibition and very few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach towards the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series that exhibited moderate sub-micromolar activity against FGFRs 1–3. Subsequent synthesis, biological evaluation, and iterative rounds of SBDD led to an inhibitor with nM potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. Subsequent X-ray crystallographic studies revealed significant morphological differences in the P-loop flanking the ATP-binding pocket which appeared to be determined by which inhibitor was bound. It was posited that this dynamic phenomenon was fundamental to the selectivity of these compounds and complementary to current theories surrounding sub-type FGFR2 selectivity. In addition, several derivatives exhibited low µM potency against FGFR1/2-activated cell lines and underlined the potential of these compounds for development into medicines for the treatment of FGFR-driven cancers.
Enhancement of DNA Droplet Formation Ability in Liquid–Liquid Phase Separation by Introduction of Artificial Nucleobase
Authors: Tashiro Ryu , Kitagawa Tomohiro , Ito Yuta
Published: February 2022

Controlling liquid–liquid phase separation (LLPS) of biomolecules is a challenge for understanding its biological phenomena and developing drugs for LLPS associated diseases. We found that substitution of DNA bases with 5-nitroindoles, known as universal bases, considerably improves the droplet formation ability of DNA. Our findings show the feasibility of introducing an artificial DNA nucleobase with a superior droplet formation ability, paving the way for the development of novel control systems for LLPS.