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  • Installing a Single Monomer within Acrylic Polymers Using Photoredox Catalysis
    Baker, Jared G.; Zhang, Richard; Figg, C. Adrian (American Chemical Society, 2023-12-21)
    Incorporating exactly one monomer at a defined position during a chain polymerization is exceptionally challenging due to the statistical nature of monomer addition. Herein, photoinduced electron/energy transfer (PET) enables the incorporation of exactly one vinyl ether into polyacrylates synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Near-quantitative addition (>96%) of a single vinyl ether is achieved while retaining >99% of the thiocarbonylthio chain ends. Kinetic studies reveal that performing the reactions at 2 °C limits unwanted chain breaking events. Finally, the syntheses of diblock copolymers are reported where molecular weights and dispersities are well-controlled on either side of the vinyl ether. Overall, this report introduces an approach to access acrylic copolymers containing exactly one chemical handle at a defined position, enabling novel macromolecular architectures to probe structure-function properties, introduce sites for de/reconstruction, store information, etc.
  • Spatially-Encoding Hydrogels With DNA to Control Cell Signaling
    Ramani, Namrata; Figg, C. Adrian; Anderson, Alex J.; Winegar, Peter H.; Oh, EunBi; Ebrahimi, Sasha B.; Samanta, Devleena; Mirkin, Chad A. (Wiley, 2023-09)
    Patterning biomolecules in synthetic hydrogels offers routes to visualize and learn how spatially-encoded cues modulate cell behavior (e.g., proliferation, differentiation, migration, and apoptosis). However, investigating the role of multiple, spatially defined biochemical cues within a single hydrogel matrix remains challenging because of the limited number of orthogonal bioconjugation reactions available for patterning. Herein, a method to pattern multiple oligonucleotide sequences in hydrogels using thiol-yne photochemistry is introduced. Rapid hydrogel photopatterning of hydrogels with micron resolution DNA features (≈1.5 µm) and control over DNA density are achieved over centimeter-scale areas using mask-free digital photolithography. Sequence-specific DNA interactions are then used to reversibly tether biomolecules to patterned regions, demonstrating chemical control over individual patterned domains. Last, localized cell signaling is shown using patterned protein-DNA conjugates to selectively activate cells on patterned areas. Overall, this work introduces a synthetic method to achieve multiplexed micron resolution patterns of biomolecules onto hydrogel scaffolds, providing a platform to study complex spatially-encoded cellular signaling environments.
  • Operando characterization and regulation of metal dissolution and redeposition dynamics near battery electrode surface
    Zhang, Yuxin; Hu, Anyang; Xia, Dawei; Hwang, Sooyeon; Sainio, Sami; Nordlund, Dennis; Michel, F. Marc; Moore, Robert B.; Li, Luxi; Lin, Feng (Nature Portfolio, 2023-07)
    Mn dissolution has been a long-standing, ubiquitous issue that negatively impacts the performance of Mn-based battery materials. Mn dissolution involves complex chemical and structural transformations at the electrode–electrolyte interface. The continuously evolving electrode–electrolyte interface has posed great challenges for characterizing the dynamic interfacial process and quantitatively establishing the correlation with battery performance. In this study, we visualize and quantify the temporally and spatially resolved Mn dissolution/redeposition (D/R) dynamics of electrochemically operating Mn-containing cathodes. The particle-level and electrode-level analyses reveal that the D/R dynamics is associated with distinct interfacial degradation mechanisms at different states of charge. Our results statistically differentiate the contributions of surface reconstruction and Jahn–Teller distortion to the Mn dissolution at different operating voltages. Introducing sulfonated polymers (Nafion) into composite electrodes can modulate the D/R dynamics by trapping the dissolved Mn species and rapidly establishing local Mn D/R equilibrium. This work represents an inaugural effort to pinpoint the chemical and structural transformations responsible for Mn dissolution via an operando synchrotron study and develops an effective method to regulate Mn interfacial dynamics for improving battery performance.
  • Photoelectrochemical water oxidation by a MOF/semiconductor composite
    Gibbons, Bradley; Cairnie, Daniel R.; Thomas, Benjamin; Yang, Xiaozhou; Ilic, Stefan; Morris, Amanda J. (Royal Society of Chemistry, 2023-05)
    Artificial photosynthesis is one of the most promising forms of renewable fuel production, due to the abundance of water, carbon dioxide, and sunlight. However, the water oxidation reaction remains a significant bottleneck due to the high thermodynamic and kinetic requirements of the four-electron process. While significant work has been done on the development of catalysts for water splitting, many of the catalysts reported to date operate at high overpotentials or with the use of sacrificial oxidants to drive the reaction. Here, we present a catalyst embedded metal-organic framework (MOF)/ semiconductor composite that performs photoelectrochemical oxidation of water at a formal underpotential. Ru-UiO-67 (where Ru stands for the water oxidation catalyst [Ru(tpy)(dcbpy)OH2](2+) (tpy = 2,2':6',2''-terpyridine, dcbpy = 5,5-dicarboxy-2,2'-bipyridine)) has been previously shown to be active for water oxidation under both chemical and electrochemical conditions, but here we demonstrate, for the first time, incorporation of a light harvesting n-type semiconductor as a base photoelectrode. RuUiO-67/WO3 is active for photoelectrochemical water oxidation at a thermodynamic underpotential ( h approximate to 200 mV; E-onset = 600 mV vs. NHE), and incorporation of a molecular catalyst onto the oxide layer increases efficiency of charge transport and separation over bare WO3. The charge-separation process was evaluated with ultrafast transient absorption spectroscopy (ufTA) and photocurrent density measurements. These studies suggest that a key contributor to the photocatalytic process involves a hole transfer from excited WO* (3) to Ru-UiO-67. To our knowledge, this is the first report of a MOFbased catalyst active for water oxidation at a thermodynamic underpotential, a key step towards lightdriven water oxidation.
  • Uncorrelated Lithium-Ion Hopping in a Dynamic Solvent-Anion Network
    Yu, Deyang; Troya, Diego; Korovich, Andrew G.; Bostwick, Joshua E.; Colby, Ralph H.; Madsen, Louis A. (American Chemical Society, 2023-03)
    Lithium batteries rely crucially on fast charge and mass transport of Li+ in the electrolyte. For liquid and polymer electrolytes with added lithium salts, Li+ couples to the counter-anion to form ionic clusters that produce inefficient Li+ transport and lead to Li dendrite formation. Quantification of Li+ transport in glycerol-salt electrolytes via NMR experiments and MD simulations reveals a surprising Li+-hopping mechanism. The Li+ transference number, measured by ion-specific electrophoretic NMR, can reach 0.7, and Li+ diffusion does not correlate with nearby ion motions, even at high salt concentration. Glycerol's high density of hydroxyl groups increases ion dissociation and slows anion diffusion, while the close proximity of hydroxyls and anions lowers local energy barriers, facilitating Li+ hopping. This system represents a bridge between liquid and inorganic solid electrolytes, thus motivating new molecular designs for liquid and polymer electrolytes to enable the uncorrelated Li+-hopping transport needed for fast-charging and all-solid-state batteries.
  • SparseMaps-A systematic infrastructure for reduced-scaling electronic structure methods. VI. Linear-scaling explicitly correlated N-electron valence state perturbation theory with pair natural orbital
    Guo, Yang; Pavosevic, Fabijan; Sivalingam, Kantharuban; Becker, Ute; Valeev, Edward F. F.; Neese, Frank (AIP Publishing, 2023-03)
    In this work, a linear scaling explicitly correlated N-electron valence state perturbation theory (NEVPT2-F12) is presented. By using the idea of a domain-based local pair natural orbital (DLPNO), computational scaling of the conventional NEVPT2-F12 is reduced to near-linear scaling. For low-lying excited states of organic molecules, the excitation energies predicted by DLPNO-NEVPT2-F12 are as accurate as the exact NEVPT2-F12 results. Some cluster models of rhodopsin are studied using the new algorithm. Our new method is able to study systems with more than 3300 basis functions and an active space containing 12 p-electrons and 12 p-orbitals. However, even larger calculations or active spaces would still be feasible.
  • Polyethylene Glycol 20k. Does It Fluoresce?
    Laatsch, Bethany F.; Brandt, Michael; Finke, Brianna; Fossum, Carl J.; Wackett, Miles J.; Lowater, Harrison R.; Narkiewicz-Jodko, Alex; Le, Christine N.; Yang, Thao; Glogowski, Elizabeth M.; Bailey-Hartsel, Scott C.; Bhattacharyya, Sudeep; Hati, Sanchita (American Chemical Society, 2023-04)
    Polyethylene glycol (PEG) is a polyether compound commonly used in biological research and medicine because it is biologically inert. This simple polymer exists in variable chain lengths (and molecular weights). As they are devoid of any contiguous pi-system, PEGs are expected to lack fluorescence properties. However, recent studies suggested the occurrence of fluorescence properties in non-traditional fluorophores like PEGs. Herein, a thorough investigation has been conducted to explore if PEG 20k fluoresces. Results of this combined experimental and computational study suggested that although PEG 20k could exhibit "through-space" delocalization of lone pairs of electrons in aggregates/clusters, formed via intermolecular and intramolecular interactions, the actual contributor of fluorescence between 300 and 400 nm is the stabilizer molecule, i.e., 3-tert-butyl-4-hydroxyanisole present in the commercially available PEG 20k. Therefore, the reported fluorescence properties of PEG should be taken with a grain of salt, warranting further investigation.
  • Enzyme-Triggered Chemodynamic Therapy via a Peptide-H2S Donor Conjugate with Complexed Fe2+
    Zhu, Yumeng; Archer, William R.; Morales, Katlyn F.; Schulz, Michael D.; Wang, Yin; Matson, John B. (Wiley-V C H Verlag, 2023-04)
    Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe2+, CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H2S donor conjugate, complexed with Fe2+, termed AAN-PTC-Fe2+. The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H2S, an inhibitor of catalase, an enzyme that detoxifies H2O2. Fe2+ and H2S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe2+, the AAN sequence, or the ability to generate H2S. AAN-PTC-Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H2S-amplified, enzyme-responsive platform for synergistic cancer treatment.
  • Supramolecular Peptide Nanostructures Regulate Catalytic Efficiency and Selectivity
    Li, Zhao; Joshi, Soumil Y.; Wang, Yin; Deshmukh, Sanket A.; Matson, John B. (Wiley-V C H, 2023-05)
    We report three constitutionally isomeric tetrapeptides, each comprising one glutamic acid (E) residue, one histidine (H) residue, and two lysine (K-S) residues functionalized with side-chain hydrophobic S-aroylthiooxime (SATO) groups. Depending on the order of amino acids, these amphiphilic peptides self-assembled in aqueous solution into different nanostructures:nanoribbons, a mixture of nanotoroids and nanoribbons, or nanocoils. Each nanostructure catalyzed hydrolysis of a model substrate, with the nanocoils exhibiting the greatest rate enhancement and the highest enzymatic efficiency. Coarse-grained molecular dynamics simulations, analyzed with unsupervised machine learning, revealed clusters of H residues in hydrophobic pockets along the outer edge of the nanocoils, providing insight for the observed catalytic rate enhancement. Finally, all three supramolecular nanostructures catalyzed hydrolysis of the l-substrate only when a pair of enantiomeric Boc-l/d-Phe-ONp substrates were tested. This study highlights how subtle molecular-level changes can influence supramolecular nanostructures, and ultimately affect catalytic efficiency.
  • The Utilisation of Hydrogels for iPSC-Cardiomyocyte Research
    Patel, Leena; Worch, Joshua C.; Dove, Andrew P.; Gehmlich, Katja (MDPI, 2023-06-10)
    Cardiac fibroblasts’ (FBs) and cardiomyocytes’ (CMs) behaviour and morphology are influenced by their environment such as remodelling of the myocardium, thus highlighting the importance of biomaterial substrates in cell culture. Biomaterials have emerged as important tools for the development of physiological models, due to the range of adaptable properties of these materials, such as degradability and biocompatibility. Biomaterial hydrogels can act as alternative substrates for cellular studies, which have been particularly key to the progression of the cardiovascular field. This review will focus on the role of hydrogels in cardiac research, specifically the use of natural and synthetic biomaterials such as hyaluronic acid, polydimethylsiloxane and polyethylene glycol for culturing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The ability to fine-tune mechanical properties such as stiffness and the versatility of biomaterials is assessed, alongside applications of hydrogels with iPSC-CMs. Natural hydrogels often display higher biocompatibility with iPSC-CMs but often degrade quicker, whereas synthetic hydrogels can be modified to facilitate cell attachment and decrease degradation rates. iPSC-CM structure and electrophysiology can be assessed on natural and synthetic hydrogels, often resolving issues such as immaturity of iPSC-CMs. Biomaterial hydrogels can thus provide a more physiological model of the cardiac extracellular matrix compared to traditional 2D models, with the cardiac field expansively utilising hydrogels to recapitulate disease conditions such as stiffness, encourage alignment of iPSC-CMs and facilitate further model development such as engineered heart tissues (EHTs).
  • Spatiotemporal Visualization and Chemical Identification of the Metal Diffusion Layer at the Electrochemical Interface
    Zhang, Yuxin; Hu, Anyang; Maxey, Evan; Li, Luxi; Lin, Feng (Electrochemical Society, 2022-10)
    The diffusion layer created by transition metal (TM) dissolution is ubiquitous at the electrochemical solid-liquid interface and plays a key role in determining electrochemical performance. Tracking the spatiotemporal dynamics of the diffusion layer has remained an unresolved challenge. With spatially resolved synchrotron X-ray fluorescence microscopy and micro-X-ray absorption spectroscopy, we demonstrate the in situ visualization and chemical identification of the dynamic diffusion layer near the electrode surface under electrochemical operating conditions. Our method allows for direct mapping of the reactive electrochemical interface and provides insights into engineering the diffusion layer for improving electrochemical performance.
  • Fluorescent detection of hydrogen sulfide (H2S) through the formation of pyrene excimers enhances H2S quantification in biochemical systems
    Pose, Manuela; Dillon, Kearsley M.; Denicola, Ana; Alvarez, Beatriz; Matson, John B.; Moeller, Matias N.; Cuevasanta, Ernesto (Elsevier, 2022-10)
    Hydrogen sulfide (H2S) is produced endogenously by several enzymatic pathways and modulates physiological functions in mammals. Quantification of H2S in biochemical systems re-mains challenging because of the presence of interferents with similar reactivity, particularly thiols. Herein, we present a new quantification method based on the formation of pyrene exci-mers in solution. We synthesized the probe 2-(maleimido)ethyl 4-pyrenylbutanoate (MEPB) and determined that MEPB reacted with H2S in a two-step reaction to yield the thioether-linked dimer (MEPB)2S, which formed excimers upon excita-tion, with a broad peak of fluorescence emission centered at 480 nm. In contrast, we found that the products formed with thiols showed peaks at 378 and 398 nm. The difference in emission between the products prevented the interference. Furthermore, we showed that the excimer fluorescence signal yielded a linear response to H2S, with a limit of detection of 54 nM in a fluorometer. Our quantification method with MEPB was successfully applied to follow the reaction of H2S with glutathione disulfide and to quantify the production of H2S from cysteine by Escherichia coli. In conclusion, this method represents an addition to the toolkit of biochemists to quantify H2S specifically and sensitively in biochemical systems.
  • Terminology for chain polymerization (IUPAC Recommendations 2021)
    Fellows, Christopher M.; Jones, Richard G.; Keddie, Daniel J.; Luscombe, Christine K.; Matson, John B.; Matyjaszewski, Krzysztof; Merna, Jan; Moad, Graeme; Nakano, Tamaki; Penczek, Stanislaw; Russell, Gregory T.; Topham, Paul D. (Walter De Gruyter, 2022-09)
    Chain polymerizations are defined as chain reactions where the propagation steps occur by reaction between monomer(s) and active site(s) on the polymer chains with regeneration of the active site(s) at each step. Many forms of chain polymerization can be distinguished according to the mechanism of the propagation step (e.g., cyclopolymerization - when rings are formed, condensative chain polymerization - when propagation is a condensation reaction, group-transfer polymerization, polyinsertion, ring-opening polymerization - when rings are opened), whether they involve a termination step or not (e.g., living polymerization - when termination is absent, reversible-deactivation polymerization), whether a transfer step is involved (e.g., degenerative-transfer polymerization), and the type of chain carrier or active site (e.g., radical, ion, electrophile, nucleophile, coordination complex). The objective of this document is to provide a language for describing chain polymerizations that is both readily understandable and self-consistent, and which covers recent developments in this rapidly evolving field.
  • Discovery of Two Inhibitors of the Type IV Pilus Assembly ATPase PilB as Potential Antivirulence Compounds
    Dye, Keane J.; Vogelaar, Nancy J.; O'Hara, Megan; Sobrado, Pablo; Santos, Webster; Carlier, Paul R.; Yang, Zhaomin (American Society for Microbiology, 2022-12)
    Many bacterial pathogens use their type IV pilus (T4P) to facilitate and maintain an infection in a human host. Small-molecule inhibitors of the production or assembly of the T4P are promising for the treatment and prevention of infections by these bacteria, especially in our fight against antibiotic-resistant pathogens. With the pressing antibiotic resistance pandemic, antivirulence has been increasingly explored as an alternative strategy against bacterial infections. The bacterial type IV pilus (T4P) is a well-documented virulence factor and an attractive target for small molecules for antivirulence purposes. The PilB ATPase is essential for T4P biogenesis because it catalyzes the assembly of monomeric pilins into the polymeric pilus filament. Here, we describe the identification of two PilB inhibitors by a high-throughput screen (HTS) in vitro and their validation as effective inhibitors of T4P assembly in vivo. We used Chloracidobacterium thermophilum PilB as a model enzyme to optimize an ATPase assay for the HTS. From a library of 2,320 compounds, benserazide and levodopa, two approved drugs for Parkinson's disease, were identified and confirmed biochemically to be PilB inhibitors. We demonstrate that both compounds inhibited the T4P-dependent motility of the bacteria Myxoccocus xanthus and Acinetobacter nosocomialis. Additionally, benserazide and levodopa were shown to inhibit A. nosocomialis biofilm formation, a T4P-dependent process. Using M. xanthus as a model, we showed that both compounds inhibited T4P assembly in a dose-dependent manner. These results suggest that these two compounds are effective against the PilB protein in vivo. The potency of benserazide and levodopa as PilB inhibitors both in vitro and in vivo demonstrate potentials of the HTS and its two hits here for the development of anti-T4P chemotherapeutics.IMPORTANCE Many bacterial pathogens use their type IV pilus (T4P) to facilitate and maintain an infection in a human host. Small-molecule inhibitors of the production or assembly of the T4P are promising for the treatment and prevention of infections by these bacteria, especially in our fight against antibiotic-resistant pathogens. Here, we report the development and implementation of a method to identify anti-T4P chemicals from compound libraries by high-throughput screen. This led to the identification and validation of two T4P inhibitors both in the test tubes and in bacteria. The discovery and validation pipeline reported here as well as the confirmation of two anti-T4P inhibitors provide new venues and leads for the development of chemotherapeutics against antibiotic-resistant infections.
  • Is Nonflammability of Electrolyte Overrated in the Overall Safety Performance of Lithium Ion Batteries? A Sobering Revelation from a Completely Nonflammable Electrolyte
    Jia, Hao; Yang, Zhijie; Xu, Yaobin; Gao, Peiyuan; Zhong, Lirong; Kautz, David J. J.; Wu, Dengguo; Fliegler, Ben; Engelhard, Mark H. H.; Matthews, Bethany E. E.; Broekhuis, Benjamin; Cao, Xia; Fan, Jiang; Wang, Chongmin; Lin, Feng; Xu, Wu (Wiley-VCH, 2023-01)
    It has been widely assumed that the flammability of the liquid electrolyte is one of the most influential factors that determine the safety of lithium-ion batteries (LIBs). Following this consideration, a completely nonflammable electrolyte is designed and adopted for graphite||LiFePO4 (Gr||LFP) batteries. Contrary to the conventional understanding, the completely nonflammable electrolyte with phosphorus-containing solvents exhibits inferior safety performance in commercial Gr||LFP batteries, in comparison to the flammable conventional LiPF6-organocarbonate electrolyte. Mechanistic studies identify the exothermic reactions between the electrolyte (especially the salt LiFSI) and the charged electrodes as the "culprit" behind this counterintuitive phenomenon. The discovery emphasizes the importance of reducing the electrolyte reactivity when designing safe electrolytes, as well as the necessity of evaluating safety performance of electrolytes on a battery level.
  • Encapsulation of PI3K Inhibitor LY294002 within Polymer Nanoparticles Using Ion Pairing Flash Nanoprecipitation
    Fergusson, Austin D.; Zhang, Rui; Riffle, Judy S.; Davis, Richey M. (MDPI, 2023-04-06)
    Flash nanoprecipitation (FNP) is a turbulent mixing process capable of reproducibly producing polymer nanoparticles loaded with active pharmaceutical ingredients (APIs). The nanoparticles produced with this method consist of a hydrophobic core surrounded by a hydrophilic corona. FNP produces nanoparticles with very high loading levels of nonionic hydrophobic APIs. However, hydrophobic compounds with ionizable groups are not as efficiently incorporated. To overcome this, ion pairing agents (IPs) can be incorporated into the FNP formulation to produce highly hydrophobic drug salts that efficiently precipitate during mixing. We demonstrate the encapsulation of the PI3K inhibitor, LY294002, within poly(ethylene glycol)-b-poly(D,L lactic acid) nanoparticles. We investigated how incorporating two hydrophobic IPs (palmitic acid (PA) and hexadecylphosphonic acid (HDPA)) during the FNP process affected the LY294002 loading and size of the resulting nanoparticles. The effect of organic solvent choice on the synthesis process was also examined. While the presence of either hydrophobic IP effectively increased the encapsulation of LY294002 during FNP, HDPA resulted in well-defined colloidally stable particles, while the PA resulted in ill-defined aggregates. The incorporation of hydrophobic IPs with FNP opens the door for the intravenous administration of APIs that were previously deemed unusable due to their hydrophobic nature.
  • SPICE, A Dataset of Drug-like Molecules and Peptides for Training Machine Learning Potentials
    Eastman, Peter; Behara, Pavan Kumar; Dotson, David L.; Galvelis, Raimondas; Herr, John E.; Horton, Josh T.; Mao, Yuezhi; Chodera, John D.; Pritchard, Benjamin P.; Wang, Yuanqing; De Fabritiis, Gianni; Markland, Thomas E. (Nature Portfolio, 2023-01-04)
    Machine learning potentials are an important tool for molecular simulation, but their development is held back by a shortage of high quality datasets to train them on. We describe the SPICE dataset, a new quantum chemistry dataset for training potentials relevant to simulating drug-like small molecules interacting with proteins. It contains over 1.1 million conformations for a diverse set of small molecules, dimers, dipeptides, and solvated amino acids. It includes 15 elements, charged and uncharged molecules, and a wide range of covalent and non-covalent interactions. It provides both forces and energies calculated at the omega B97M-D3(BJ)/def2-TZVPPD level of theory, along with other useful quantities such as multipole moments and bond orders. We train a set of machine learning potentials on it and demonstrate that they can achieve chemical accuracy across a broad region of chemical space. It can serve as a valuable resource for the creation of transferable, ready to use potential functions for use in molecular simulations.
  • Quantum self-consistent equation-of-motion method for computing molecular excitation energies, ionization potentials, and electron affinities on a quantum computer
    Asthana, Ayush; Kumar, Ashutosh; Abraham, Vibin; Grimsley, Harper; Zhang, Yu; Cincio, Lukasz; Tretiak, Sergei; Dub, Pavel A.; Economou, Sophia E.; Barnes, Edwin; Mayhall, Nicholas J. (Royal Society Chemistry, 2023-01-27)
    Near-term quantum computers are expected to facilitate material and chemical research through accurate molecular simulations. Several developments have already shown that accurate ground-state energies for small molecules can be evaluated on present-day quantum devices. Although electronically excited states play a vital role in chemical processes and applications, the search for a reliable and practical approach for routine excited-state calculations on near-term quantum devices is ongoing. Inspired by excited-state methods developed for the unitary coupled-cluster theory in quantum chemistry, we present an equation-of-motion-based method to compute excitation energies following the variational quantum eigensolver algorithm for ground-state calculations on a quantum computer. We perform numerical simulations on H-2, H-4, H2O, and LiH molecules to test our quantum self-consistent equation-of-motion (q-sc-EOM) method and compare it to other current state-of-the-art methods. q-sc-EOM makes use of self-consistent operators to satisfy the vacuum annihilation condition, a critical property for accurate calculations. It provides real and size-intensive energy differences corresponding to vertical excitation energies, ionization potentials and electron affinities. We also find that q-sc-EOM is more suitable for implementation on NISQ devices as it is expected to be more resilient to noise compared with the currently available methods.
  • Targeting negative energy balance with calorie restriction and mitochondrial uncoupling in db/db mice
    Chen, Sing -Young; Beretta, Martina; Olzomer, Ellen M.; Shah, Divya P.; Wong, Derek Y. H.; Alexopoulos, Stephanie J.; Aleksovska, Isabella; Salamoun, Joseph M.; Garcia, Christopher J.; Cochran, Blake J.; Rye, Kerry-Anne; Smith, Greg C.; Byrne, Frances L.; Morris, Margaret J.; Santos, Webster L.; Cantley, James; Hoehn, Kyle L. (Elsevier, 2023-01)
    Objective: Calorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver. Methods: Male db/db mice were treated with w50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR. Results: Calorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis. Conclusions: BAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice. However, mice fed BAM15 had superior effects on glucose control compared to the calorie restricted group that consumed half as much food. Submaximal dosing with BAM15 demonstrated that its beneficial effects on glucose control are independent of weight loss. These data highlight the potential for mitochondrial uncoupler pharmacotherapies in the treatment of metabolic disease. (c) 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • Sphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analogues
    Pashikanti, Srinath; Foster, Daniel J.; Kharel, Yugesh; Brown, Anne M.; Bevan, David R.; Lynch, Kevin R.; Santos, Webster L. (American Chemical Society, 2022-10-19)
    Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with five native G-protein coupled receptors (S1P1-5) to regulate cell growth, survival, and proliferation. S1P has been implicated in a variety of pathologies including cancer, kidney fibrosis, and multiple sclerosis. As key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmacologic intervention. In this report, we describe the design, synthesis, and biological evaluation of sphingosine kinase 2 (SphK2) inhibitors with a focus on systematically introducing rigid structures in the aliphatic lipid tail present in existing SphK2 inhibitors. Experimental as well as molecular modeling studies suggest that conformationally restricted "lipophilic tail" analogues bearing a bulky terminal moiety or an internal phenyl ring are useful to complement the "J"-shaped sphingosine binding pocket of SphK2. We identified 14c (SLP9101555) as a potent SphK2 inhibitor (Ki= 90 nM) with 200-fold selectivity over SphK1. Molecular docking studies indicated key interactions: the cyclohexyl ring binding in the cleft deep in the pocket, a trifluoromethyl group fitting in a small side cavity, and a hydrogen bond between the guanidino group and Asp308 (amino acid numbering refers to human SphK2 (isoform c) orthologue). In vitro studies using U937 human histiocytic lymphoma cells showed marked decreases in extracellular S1P levels in response to our SphK2 inhibitors. Administration of 14c (dose: 5 mg/kg) to mice resulted in a sustained increase of circulating S1P levels, suggesting target engagement.