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Experimental demonstrations of modified chemical structure and reactivity under strong light-matter coupling have spurred theoretical and computational efforts to uncover underlying mechanisms. Ab initio cavity quantum electrodynamics (QED) combines quantum chemistry with cavity QED to investigate these phenomena in detail. Unitary transformations of ab initio cavity QED Hamiltonians have been used to make them more computationally tractable. We analyze one such transformation, the coherent state transformation, using perturbation theory. Applying perturbation theory up to third order for ground state energies and potential energy surfaces of several molecular systems under electronic strong coupling, we show that the coherent state transformation yields better agreement with exact ground state energies. We examine one specific case using perturbation theory up to ninth order and find that coherent state transformation performs better up to fifth order but converges more slowly to the exact ground state energy at higher orders. In addition, we apply perturbation theory up to second order for cavity mode states under bilinear coupling, elucidating how the coherent state transformation accelerates the convergence of the photonic subspace toward the complete basis limit and renders molecular ion energies origin invariant. These findings contribute valuable insights into computational advantages of the coherent state transformation in the context of ab initio cavity quantum electrodynamics methods., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/).)

The emerging field of polaritonic chemistry explores the behavior of molecules under strong coupling with cavity modes. Despite recent developments in ab initio polaritonic methods for simulating polaritonic chemistry under electronic strong coupling, their capabilities are limited, especially in cases where the molecule also features strong electronic correlation. To bridge this gap, we have developed a novel method for cavity QED calculations utilizing the Density Matrix Renormalization Group (DMRG) algorithm in conjunction with the Pauli-Fierz Hamiltonian. Our approach is applied to investigate the effect of the cavity on the S 0 -S 1 transition of n -oligoacenes, with n ranging from 2 to 5, encompassing 22 fully correlated π orbitals in the largest pentacene molecule. Our findings indicate that the influence of the cavity intensifies with larger acenes. Additionally, we demonstrate that, unlike the full determinantal representation, DMRG efficiently optimizes and eliminates excess photonic degrees of freedom, resulting in an asymptotically constant computational cost as the photonic basis increases.

Molecules under strong or ultra-strong light-matter coupling present an intriguing route to modify chemical structure, properties, and reactivity. A rigorous theoretical treatment of such systems requires handling matter and photon degrees of freedom on an equal quantum mechanical footing. In the regime of molecular electronic strong or ultra-strong coupling to one or a few molecules, it is desirable to treat the molecular electronic degrees of freedom using the tools of ab initio quantum chemistry, yielding an approach referred to as ab initio cavity quantum electrodynamics (ai-QED), where the photon degrees of freedom are treated at the level of cavity QED. We analyze two complementary approaches to ai-QED: (1) a parameterized ai-QED, a two-step approach where the matter degrees of freedom are computed using existing electronic structure theories, enabling the construction of rigorous ai-QED Hamiltonians in a basis of many-electron eigenstates, and (2) self-consistent ai-QED, a one-step approach where electronic structure methods are generalized to include coupling between electronic and photon degrees of freedom. Although these approaches are equivalent in their exact limits, we identify a disparity between the projection of the two-body dipole self-energy operator that appears in the parameterized approach and its exact counterpart in the self-consistent approach. We provide a theoretical argument that this disparity resolves only under the limit of a complete orbital basis and a complete many-electron basis for the projection. We present numerical results highlighting this disparity and its resolution in a particularly simple molecular system of helium hydride cation, where it is possible to approach these two complete basis limits simultaneously. In this same helium hydride system, we examine and compare the practical issue of the computational cost required to converge each approach toward the complete orbital and many-electron bases limit. Finally, we assess the aspect of photonic convergence for polar and charged species, finding comparable behavior between parameterized and self-consistent approaches., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/).)

Polariton chemistry has attracted great attention as a potential route to modify chemical structure, properties, and reactivity through strong interactions among molecular electronic, vibrational, or rovibrational degrees of freedom. A rigorous theoretical treatment of molecular polaritons requires the treatment of matter and photon degrees of freedom on equal quantum mechanical footing. In the limit of molecular electronic strong or ultrastrong coupling to one or a few molecules, it is desirable to treat the molecular electronic degrees of freedom using the tools of ab initio quantum chemistry, yielding an approach we refer to as ab initio cavity quantum electrodynamics, where the photon degrees of freedom are treated at the level of cavity quantum electrodynamics. Here, we present an approach called Cavity Quantum Electrodynamics Complete Active Space Configuration Interaction theory to provide ground- and excited-state polaritonic surfaces with a balanced description of strong correlation effects among electronic and photonic degrees of freedom. This method provides a platform for ab initio cavity quantum electrodynamics when both strong electron correlation and strong light-matter coupling are important and is an important step toward computational approaches that yield multiple polaritonic potential energy surfaces and couplings that can be leveraged for ab initio molecular dynamics simulations of polariton chemistry.

We calculate, using time-dependent density functional theory, absorption and circular dichroism (CD) spectra for a series of small helical gold nanorod structures with a width of 0.6 nm and length increasing from 0.7 nm for Au 24 to 1.9 nm for Au 56 . For a low-energy window, ranging from 1.7 to 4.1 eV, broadening the lines in the absorption spectra results in a low energy peak which previous studies have identified as the (localized) plasmon resonance. As expected, the absorption peak position of the plasmon resonance systematically redshifts as the length of the nanorod increases. However, trends in the CD and straightforwardly broadened CD spectra are more difficult to discern. We introduce the idea of an absolute value CD spectrum and show that broadening the lines results in a low energy peak that has not previously been reported. The peak position systematically redshifts as the length of the nanorod increases but over a significantly smaller range than that for the absorption spectrum., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

There is a growing demand for new fluorescent small molecule dyes for solid state applications in the photonics and optoelectronics industry. Thiazolo[5,4- d ]thiazole (TTz) is an organic heterocycle moiety which has previously shown remarkable properties as a conjugated polymer and in solution-based studies. For TTz-based small molecules to be incorporated in solid-state fluorescence-based optical devices, a thorough elucidation of their structure-photophysical properties needs to be established. Herein, we have studied four TTz-based materials functionalized with alkyl appendages of varying carbon chain lengths. We report the single crystal structures of the TTz derivatives, three of which were previously unknown. The packing modes of the crystals reveal that molecular arrangements are largely governed by a chorus of synergistic intermolecular non-covalent interactions. Three crystals packed in herringbone mode and one crystal packed in slipped stacks proving that alkyl appendages modulate structural organization in TTz-based materials. Steady state and time-resolved photophysical properties of these crystals were studied via diffuse-reflectance, micro-Raman, and photoluminescence spectroscopy. The crystals fluoresce from orange-red to blue spanning through the whole gamut of the visible spectrum. We have established that photophysical properties are a function of crystal packing in symmetrically substituted TTz-based materials. This correlation was then utilized to fabricate crystalline blends. We demonstrate, for the first time, that symmetrically substituted donor-acceptor-donor TTz-based materials can be used for phosphor-converted color-tuning and white-light emission. Given the cost effectiveness, ease of synthesis and now a structure-photophysics correlation, we present a compelling case for the adoption of TTz-based materials in solid-state photonic and fluorescence-based optical devices., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

We combine ab initio molecular electronic Hamiltonians with a cavity quantum electrodynamics model for dissipative photonic modes and apply mean-field theories to the ground- and excited-states of resulting polaritonic systems. In particular, we develop a non-Hermitian configuration interaction singles theory for mean-field ground- and excited-states of the molecular system strongly interacting with a photonic mode and apply these methods to elucidating the phenomenology of paradigmatic polaritonic systems. We leverage the Psi4Numpy framework to yield open-source and accessible reference implementations of these methods.

The influence of external dielectric environments is well understood for 2D semiconductor materials but overlooked for colloidally grown II-VI nanoplatelets (NPLs). In this work, we synthesize MX (M = Cd, Hg; X = Se, Te) NPLs of varying thicknesses and apply the Elliott model to extract exciton binding energies-reporting values in good agreement with prior methods and extending to less studied cadmium telluride and mercury chalcogenide NPLs. We find that the exciton binding energy is modulated both by the relative effect of internal vs external dielectric and by the thickness of the semiconductor material. An analytical model shows dielectric screening increases the exciton binding energy relative to the bulk by distorting the Coulombic potential across the NPL surface. We further confirm this effect by decreasing and recovering the exciton binding energy of HgTe NPLs through washing in polarizable solvents. Our results illustrate NPLs are colloidal analogues of van der Waals 2D semiconductors and point to surface modification as an approach to control photophysics and device properties.

We present a non-Hermitian formulation of the polaritonic structure of azobenzene strongly coupled to a photonic mode that explicitly accounts for the fleeting nature of the photon-molecule interaction. This formalism reveals that the polaritonic nonadiabatic couplings that facilitate cis-trans isomerization can be dramatically modified by photonic dissipation. We perform Fewest-Switches Surface Hopping dynamics on the surfaces that derive from our non-Hermitian formalism and find that the polaritonic isomerization yields are strongly suppressed for moderate dissipation rates and that cavity-free isomerization dynamics are recovered under large dissipation rates. These findings highlight the important role that the finite lifetime of photonic degrees of freedom play in polaritonic chemistry.

The efficiency of a thermophotovoltaic (TPV) system depends critically upon the spectral selectivity and stability of an emitter, which may operate most effectively at temperatures in excess of 1000 °C. We computationally design and experimentally demonstrate a novel selective emitter design based on multilayer nanostructures, robust to off-normal emission angles. A computational search of the material and temperature compatibility space of simple emitter designs motivates new material classes and identifies several promising multilayer nanostructure designs for both TPV absorber and emitter applications. One such structure, comprising a thin (<100 nm) tunable Ti x Al 1- x N (TiAlN) absorber and refractory oxide Bragg reflector is grown on W metal foil. In agreement with simulations, the emitter achieves record spectral efficiency (43.4%) and power density (3.6 W/cm 2 ) for an emitter with at least 1 h of high temperature (>800 °C) operation.

Balancing gene expression is a fundamental challenge of all cell types. To properly regulate transcription on a genome-wide level, there are myriad mechanisms employed by the cell. One layer to this regulation is through spatial positioning, with particular chromosomal loci exerting an influence on transcription throughout a region. Many coregulated gene families utilize spatial positioning to coordinate transcription, with functionally related genes clustering together which can allow coordinated expression via adjacent gene coregulation. The mechanisms underlying this process have not been elucidated, though there are many coregulated gene families that exhibit this genomic distribution. In the present study, we tested for a role for the enhancer-promoter (EP) hypothesis, which demonstrates that regulatory elements can exert transcriptional effects over a broad distance, in coordinating transcriptional coregulation using budding yeast, Saccharomyces cerevisiae We empirically validated the EP model, finding that the genomic distance a promoter can affect varies by locus, which can profoundly affect levels of transcription, phenotype, and the extent of transcriptional disruption throughout a genomic region. Using the nitrogen metabolism, ribosomal protein, toxin response, and heat shock gene families as our test case, we report functionally clustered genes localize to genomic loci that are more conducive to transcriptional regulation at a distance compared to the unpaired members of the same families. Furthermore, we report that the coregulation of functional clusters is dependent, in part, on chromatin maintenance and remodeling, providing one mechanism underlying adjacent gene coregulation. IMPORTANCE The two-dimensional, physical positioning of genes along a chromosome can impact proper transcriptional regulation throughout a genomic region. The transcription of neighboring genes is correlated in a genome-wide manner, which is a characteristic of eukaryotes. Many coregulated gene families can be found clustered with another member of the same set-which can result in adjacent gene coregulation of the pair. Due to the myriad gene families that exhibit a nonrandom genomic distribution, there are likely multiple mechanisms working in concert to properly regulate transcriptional coordination of functionally clustered genes. In this study, we utilized budding yeast in an attempt to elucidate mechanisms that underlie this coregulation: testing and empirically validating the enhancer-promoter hypothesis in this species and reporting that functionally related genes cluster to genomic regions that are more conducive to transcriptional regulation at a distance. These clusters rely, in part, on chromatin maintenance and remodelers to maintain proper transcriptional coordination. Our work provides insight into the mechanisms underlying adjacent gene coregulation., (Copyright © 2019 Cera et al.)

It is essential that cells orchestrate gene expression for the specific niche that they occupy, and this often requires coordination of the expression of large sets of genes. There are multiple regulatory systems that exist for modulation of gene expression, including the adjacent-gene coregulation of the rRNA and ribosome biogenesis and ribosomal protein families. Both gene families exhibit a nonrandom genomic distribution, often clustered directly adjacent to another member of the same family, which results in a tighter transcriptional coordination among adjacent paired genes than that of the unpaired genes within each regulon and can result in a shared promoter that coordinates expression of the pairs. This nonrandom genomic distribution has been seen in a few functionally related gene families, and many of these functional pairings are conserved across divergent fungal lineages. To date, the significance of these observations has not been extended in a systematic way to characterize how prevalent the role of adjacent-gene coregulation is in transcriptional regulation. In the present study, we systematically analyzed the transcriptional coherence of the functional pairs compared to the singletons within all gene families defined by the Gene Ontology Slim designation, using Saccharomyces cerevisiae as a model system, finding that clusters exhibit a tighter transcriptional correlation under specific contexts. We found that the longer a functional pairing is conserved the tighter its response to broad stress and nutritional responses, that roughly 25% of gene families exhibit a nonrandom genomic distribution, and that many of these clusters are conserved. This suggests that adjacent-gene coregulation is a widespread, yet underappreciated, transcriptional mechanism. IMPORTANCE The spatial positioning of genes throughout the genome arrangement can alter their expression in many eukaryotic organisms. Often this results in a genomic context-specific effect on transcription. One example of this is through the clustering of functionally related genes, which results in adjacent-gene coregulation in the budding yeast Saccharomyces cerevisiae In the present study, we set out to systematically characterize the prevalence of this phenomenon, finding the genomic organization of functionally related genes into clusters is a characteristic of myriad gene families. These arrangements are found in many evolutionarily divergent fungi and thus represent a widespread, yet underappreciated, layer of transcriptional regulation., (Copyright © 2018 Eldabagh et al.)

Revefenacin (TD-4208) is a novel, long-acting, and lung-selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pK I  = 8.2-9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4-10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM 3 ( t 1/2  = 82 minutes) compared to the hM 2 ( t 1/2  = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin-mediated antagonism of acetylcholine (ACh)-evoked calcium mobilization responses were reversed less rapidly at hM 3 compared to the hM 2 mAChR. In isolated tracheal tissues from rat and guinea pig and isolated bronchial tissues from humans, revefenacin potently antagonized mAChR-mediated contractile responses. Furthermore, the antagonistic effects of revefenacin in rat, guinea pig, and human airway tissues were slowly reversible ( t 1/2 of 13.3, >16, and >10 hours, respectively). These data demonstrate that revefenacin is a potent, high affinity, and selective functional mAChR antagonist with kinetic selectivity for the hM 3 receptor and produces potent and long-lasting antagonism of mAChR-mediated contractile responses in rat, guinea pig, and human airway tissue. These data suggest that revefenacin has the potential to be a potent once-daily dosed inhaled bronchodilator in COPD patients.

Neutropenia is a common consequence of radiation and chemotherapy in cancer patients. The resulting immunocompromised patients become highly susceptible to potentially life-threatening infections. Granulocyte colony-stimulating factor (G-CSF) is known to stimulate neutrophil production and is widely used as a treatment of chemotherapy-induced neutropenia. A small-molecule G-CSF secretagogue without a requirement for refrigerated supply chain would offer a more convenient and cost-effective treatment of chemotherapy-induced neutropenia. Bacterial lipopeptides activate innate immune responses through Toll-like receptor 2 (TLR2) and induce the release of cytokines, including G-CSF, from macrophages, monocytes, and endothelial. Pam 2 CSK 4 is a synthetic lipopeptide that effectively mimics bacterial lipoproteins known to activate TLR2 receptor signaling through the TLR2/6 heterodimer. Substrate-based drug design led to the discovery of GSK3277329, which stimulated the release of G-CSF in activated THP-1 cells, peripheral blood mononuclear cells, and human umbilical vein endothelial cells. When administered subcutaneously to cynomolgus monkeys ( Macaca fasciculari s), GSK3277329 caused systemic elevation of G-CSF and interleukin-6 (IL-6), but not IL-1β or tumor necrosis factor α, indicating a selective cytokine-stimulation profile. Repeat daily injections of GSK3277329 in healthy monkeys also raised circulating neutrophils above the normal range over a 1-week treatment period. More importantly, repeated daily injections of GSK3277329 over a 2-week period restored neutrophil loss in monkeys given chemotherapy treatment (cyclophosphamide, Cytoxan). These data demonstrate preclinical in vivo proof of concept that TLR2 agonism can drive both G-CSF induction and subsequent neutrophil elevation in the cynomolgus monkey and could be a therapeutic strategy for the treatment of chemotherapy-induced neutropenia., Competing Interests: Conflict-of-interest disclosure: The authors are employees of GlaxoSmithKline PLC.

We report on a nanoinfrared (IR) imaging study of ultraconfined plasmonic hotspots inside graphene nanobubbles formed in graphene/hexagonal boron nitride (hBN) heterostructures. The volume of these plasmonic hotspots is more than one-million-times smaller than what could be achieved by free-space IR photons, and their real-space distributions are controlled by the sizes and shapes of the nanobubbles. Theoretical analysis indicates that the observed plasmonic hotspots are formed due to a significant increase of the local plasmon wavelength in the nanobubble regions. Such an increase is attributed to the high sensitivity of graphene plasmons to its dielectric environment. Our work presents a novel scheme for plasmonic hotspot formation and sheds light on future applications of graphene nanobubbles for plasmon-enhanced IR spectroscopy.

We report a class of thermophotovoltaic emitter structures built upon planar films that support resonant modes, known as perfectly-absorbing modes, that facilitate an exceptional optical response for selective emission. These planar structures have several key advantages over previously-proposed designs for TPV applications: they are simple to fabricate, are stable across a range of temperatures and conditions, and are capable of achieving some of the highest spectral efficiencies reported of any class of emitter structure. Utilization of these emitters leads to exceptionally high device efficiencies under low operating temperature conditions, which should open new opportunities for waste heat management. We present a theoretical framework for understanding this performance, and show that this framework can be leveraged as a search algorithm for promising candidate structures. In addition to providing an efficient theoretical methodology for identifying high-performance emitter structures, our methodology provides new insight into underlying design principles and should pave way for future design of structures that are simple to fabricate, temperature stable, and possess exceptional optical properties.

Switchable surface redox chemistry is demonstrated in gold@iron/iron oxide core-shell nanoparticles with ambient oxidation and plasmon-mediated reduction to modulate the oxidation state of shell layers. The iron shell can be oxidized to iron oxide through ambient oxidation, leading to an enhancement and red-shift of the gold surface plasmon resonance (SPR). This enhanced gold SPR can drive reduction of the iron oxide shell under broadband illumination to reversibly blue-shift and significantly dampen gold SPR absorption. The observed phenomena provide a unique mechanism for controlling the plasmonic properties and surface chemistry of small metal nanoparticles., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Synthesis of nanoparticle dimers made of asymmetric compositions is very challenging because of the difficulty in manipulating the nanoparticles' surface chemistries in order to control the assembly and/or growth of different nanoparticles. In this Letter, we report a seed-mediated, surface-confined epitaxial overgrowth strategy that enables the synthesis of high-quality interfaced Au-Ag heterodimers in the quantum size regime (diameters <10 nm). Au and Ag share a common face-centered cubic lattice and have nearly identical lattice constants, which facilitates epitaxial overgrowth and allows direct contact between the Au and Ag domains. Quantum size effects, formation of the Au/Ag interfaces, and chemical interactions with surfactant molecules strongly influence the optical properties of the dimers and lead to the observation of unique surface plasmon resonances. In particular, we find an unusual enhancement of the characteristic Au surface plasmon resonance and the emergence of a charge transfer plasmon across the Au/Ag domains, which together lead to broad-band absorption spanning visible to near-infrared wavelengths. A model that captures the changes in optical behavior due to chemical interactions and quantum size effects is used to calculate the absorption spectra of the interfaced heterodimers, resulting in good agreement with experimental measurements.

Recent experiments show that the cage isomer of the water hexamer is lower in energy than the prism isomer near 0 K, and yet state-of-the-art electronic structure calculations predict the prism to be lower in energy than the cage at 0 K. Here, we study the relative energies of the water hexamers from the parametric two-electron reduced density matrix (2-RDM) method in which the 2-RDM rather than the wave function is the basic variable of the calculations. In agreement with experiment and in contrast with traditional wave function methods, the 2-RDM calculations predict the cage to be more stable than the prism after vibrational zero-point correction. Multiple configurations from the hydrogen bonding are captured by the method. More generally, the results are consistent with our previous 2-RDM applications in that they reveal how multireference correlation in molecular systems is important for resolving small energy differences from hydrogen bonding as well as other types of intermolecular forces, even in systems that are not conventionally considered strongly correlated.

The objective of this study was to evaluate pharmacist use of a Regional Poison Information Center (RPIC), identify potential barriers to utilization, and provide strategies to overcome these barriers. All calls placed to a RPIC by a pharmacist, physician, or nurse over a 5-year period were retrieved. These data were analyzed to assess the pharmacist utilization of the RPIC and the variation of call types. Additionally, a survey, designed to assess the past and future use of the RPIC by pharmacists, was distributed to pharmacists in the region. Of the 37,799 calls made to the RPIC, 26,367 (69.8%) were from nurses, 8096 (21.4%) were from physicians, and 3336 (8.8%) were from pharmacists. Among calls initiated by pharmacists, the majority involved medication identification (n = 2391, 71.7%). The survey had a 38.9% response rate (n = 715) and revealed a trend toward less RPIC utilization by pharmacists with more formal training but less practice experience. The utilization of the RPIC was lowest among pharmacists as compared to other health care professionals. This may be due to pharmacists' unfamiliarity with the poison center's scope of services and resources. Therefore, it is important that pharmacists are educated on the benefit of utilizing poison centers in clinical situations.

Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half-life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 μg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 μg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases.

Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Rationale: A number of cancer chemotherapeutic agents have been associated with a loss of memory in breast cancer patients although little is known of the causality of this effect., Objectives: To assess the potential cognitive effects of repeated exposure to chemotherapeutic agents, we administered the selective estrogen receptor modulator tamoxifen or the antimetabolite chemotherapy, methotrexate, and 5-fluorouracil, alone and in combination to mice and tested them in a learning and memory assay., Methods: Swiss-Webster male mice were injected with saline, 32 mg/kg tamoxifen, 3.2 or 32 mg/kg methotrexate, 75 mg/kg 5-fluorouracil, 3.2 or 32 mg/kg methotrexate in combination with 75 mg/kg 5-fluorouracil once per week for 3 weeks. On days 23 and 24, mice were tested for acquisition and retention of a nose-poke response in a learning procedure called autoshaping. In addition, the acute effects of tamoxifen were assessed in additional mice in a similar procedure., Results: The chemotherapeutic agents alone and in combination reduced body weight relative to saline treatment over the course of 4 weeks. Repeated treatment with tamoxifen produced both acquisition and retention effects relative to the saline-treated group although acute tamoxifen was without effect except at a behaviorally toxic dose. Repeated treatment with methotrexate in combination with 5-fluorouracil produced effects on retention, but the magnitude of these changes depended on the methotrexate dose., Conclusions: These data demonstrate that repeated administration of tamoxifen or certain combination of methotrexate and 5-fluorouracil may produce deficits in the acquisition or retention of learned responses which suggest potential strategies for prevention or remediation might be considered in vulnerable patient populations.

Photoexcited radical reactions are critical to processes in both nature and materials, and yet they can be challenging for electronic structure methods due to the presence of strong electron correlation. Reduced-density-matrix (RDM) methods, based on solving the anti-Hermitian contracted Schrödinger equation (ACSE) for the two-electron RDM (2-RDM), are examined for studying the strongly correlated mechanisms of these reactions with application to the electrocyclic interconversion of allyl and cyclopropyl radicals. We combine recent extensions of the ACSE to excited states [G. Gidofalvi and D. A. Mazziotti, Phys. Rev. A 80, 022507 (2009)] and arbitrary spin states [A. E. Rothman, J. J. Foley IV, and D. A. Mazziotti, Phys. Rev. A 80, 052508 (2009)]. The ACSE predicts that the ground-state ring closure of the allyl radical has a high 52.5 kcal/mol activation energy that is consistent with experimental data, while the closure of an excited allyl radical can occur by disrotatory and conrotatory pathways whose transition states are essentially barrierless. Comparisons are made with multireference second- and third-order perturbation theories and multireference configuration interaction. While predicted energy differences do not vary greatly between methods, the ACSE appears to improve these differences when they involve a strongly and a weakly correlated radical by capturing a greater share of single-reference correlation that increases the stability of the weakly correlated radicals. For example, the ACSE predicts a -39.6 kcal/mol conversion of the excited allyl radical to the ground-state cyclopropyl radical in comparison to the -32.6 to -37.3 kcal/mol conversions predicted by multireference methods. In addition, the ACSE reduces the computational scaling with the number of strongly correlated orbitals from exponential (traditional multireference methods) to quadratic. Computed ground- and excited-state 2-RDMs are nearly N-representable.

Biaryl amides were discovered as novel and subtype selective M(1) muscarinic acetylcholine receptor agonists. The identification, synthesis, and initial structure-activity relationships that led to compounds 3j and 4c, possessing good M(1) agonist potency and intrinsic activity, and subtype selectivity for M(1) over M(2-5), are described., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A conical intersection in triplet excited states of methylene is computed through the direct calculation of two-electron reduced density matrices (2-RDMs) from solutions of the anti-Hermitian contracted Schrodinger equation (ACSE). The study synthesizes recent extensions of the ACSE method for the treatment of excited states [G. Gidofalvi and D. A. Mazziotti, Phys. Rev. A 80, 022507 (2009)] and arbitrary-spin states [A. E. Rothman, J. J. Foley, and D. A. Mazziotti, Phys. Rev. A 80, 052508 (2009)]. We compute absolute energies of the 1 (3)B(1), 1 (3)A(2), and 2 (3)B(1) states of methylene (CH(2)) and the location of the conical intersection along the 1 (3)A(2)-2 (3)B(1) potential-energy surfaces. To treat multireference correlation, we seed the ACSE with an initial 2-RDM from a multiconfiguration self-consistent field (MCSCF) calculation. The ACSE produces energies that significantly improve upon those from MCSCF and second-order multireference many-body perturbation theory, and the 2-RDMs from the ACSE nearly satisfy necessary N-representability conditions. Comparison of the results from augmented double-zeta and triple-zeta basis sets demonstrates the importance of augmented (or diffuse) functions for determining the location of the conical intersection.

Although the neurotransmitter, 5-hydroxytryptamine (serotonin, 5-HT), has been implicated as a mediator of learning and memory, the specific role of 5-HT receptors in rodents requires further delineation. In this study, 5-HT2C receptor ligands of varying relative intrinsic efficacies were tested in a mouse learning and memory model called autoshaping-operant. On day 1, mice were placed in experimental chambers and presented with a tone on a variable interval schedule. The tone remained on for 6 s or until a nose-poke response occurred to produce a dipper with Ensure solution. Mice were then injected with saline, MK212 (full agonist), m-chlorophenylpiperazine (partial agonist), mianserin, and SB206 553 (inverse agonists), and methysergide and (+)-2-bromo lysergic acid diethylamide (+)-hydrogen tartrate (neutral antagonists). Each compound was injected after either 1 or 2-h acquisition sessions on day 1 to investigate the role of acquisition session length on consolidation. Day 1 injection of the 5-HT2C inverse agonist mianserin produced greater retrieval impairments of the autoshaped operant response on day 2 than any other agent tested. Furthermore, decreasing the length of the acquisition session to 1h significantly increased the difficulty of the autoshaping task further modulating the consolidation effects produced by the 5-HT2C ligands tested.

Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery.

We describe here two strategies to produce biologically active chemokines with authentic N-terminal amino acid residues. The first involves producing the target chemokine with an N-terminal 6xHis-SUMO tag in Escherichia coli as inclusion bodies. The fusion protein is solubilized and purified with Ni-NTA-agarose in denaturing reagents. This is further followed by tag removal and refolding in a redox refolding buffer. The second approach involves expressing the target chemokine with an N-terminal 6xHis-Trx-SUMO tag in an engineered E. coli strain that facilitates formation of disulfide bonds in the cytoplasm. Following purification of the fusion protein via Ni-NTA and tag removal, the target chemokine is refolded without redox buffer and purified by reverse phase chromatography. Using the procedures, we have produced more than 15 biologically active chemokines, with a yield of up to 15 mg/L.

The hydrogen [1,3]-sigmatropic shift in propene is predicted by the Woodward-Hoffman rules to occur by an antarafacial pathway, yet the lack of experimental evidence suggests that this pathway is not favorable. Two natural questions arise: (i) can the [1,3]-shift be made more favorable by a symmetry-forbidden multistep pathway, and (ii) can the energetics be influenced by a substituent on propene? As in many chemical reactions, describing the energetics of these reactions requires a balanced treatment of both single-reference and multireference electron correlations, and yet traditional wave function methods often excel in treating only one kind of correlation. An equitable description of correlation effects, however, can be achieved, at a cost similar to efficient single-reference methods, by computing the two-electron reduced density matrix (2-RDM) from the anti-Hermitian part of the contracted Schrödinger equation (ACSE) [D. A. Mazziotti, Phys. Rev. Lett. 97, 143002 (2006)]. As with the contracted Schrödinger equation, the indeterminacy of the ACSE is removed without the many-electron wave function by reconstructing the 3-RDM from the 2-RDM via cumulant theory [D. A. Mazziotti, Chem. Phys. Lett. 289, 419 (1998)]. In this paper we apply the ACSE to study sigmatropic shifts in both propene and acetone enolate while extending its formalism to treat doublet spin states. In the 6-311G(**) basis set the ACSE predicts the activation energy of the trimethylene-to-propene rearrangement to be 8.8 kcal/mol while multireference perturbation theory yields a smaller barrier of 2.2 kcal/mol and coupled cluster singles-doubles predicts a negative barrier. We further find that the [1,3]-shift in acetone enolate is more favorable by approximately 30 kcal/mol than the [1,3]-shift in propene, which is consistent with a prior theoretical investigation as well as experimental observations of these shifts in 2-butanone enolate.

A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M(3) receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M(3) antagonist with a very long in vivo duration of bronchoprotection.

Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.

A series of N-arylpiperazine camphor sulfonamides was discovered as novel CXCR3 antagonists. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent and selective CXCR3 antagonists are described.

SAR exploration of multiple regions of a tyrosine urea template led to the identification of very potent muscarinic acetylcholine receptor antagonists such as 10b with good subtype selectivity for M(3) over M(1). The structure-activity relationships (SAR) and optimization of the tyrosine urea series are described.

A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.

Rationale: The concern that adjuvant cancer chemotherapy agents cause cognitive impairment in a significant number of patients has been expressed by patients and healthcare providers, but clinical studies have yielded conflicting results to date., Objective: We directly tested two commonly used chemotherapeutic agents in a mouse model of learning and memory., Materials and Methods: In the present study, mice were conditioned to respond for a liquid reinforcer (Ensure solution) in the presence of an audible tone on day 1 as a measure of acquisition and were then required to perform the same response on day 2 as a measure of retrieval and retention. Methotrexate and 5-fluorouracil were administered prior to the day 1 session., Results: Methotrexate (1.0-32 mg/kg) alone failed to alter mean latency acquisition, retrieval, or reinforced response rates. Similar to scopolamine, a known amnesic in this assay, 5-fluorouracil (3-75 mg/kg) failed to alter response rates or acquisition latency on day 1 but significantly altered latency to retrieve a previously learned response on day 2. In combination, 3.2 mg/kg methotrexate plus 75 mg/kg 5-fluorouracil significantly increased day 1 and day 2 acquisition and retrieval latencies without altering response rates or motivation to respond as measured by progressive ratio responding., Conclusion: Taken together, these data demonstrate that 5-fluorouracil causes increased latencies for retrieval of previously learned behavioral responses and that combination of chemotherapeutic agents may produce greater delays than either agent alone, including when neither agent alone does so.

High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.

SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl benzamide series led to the identification of very potent human urotensin-II receptor antagonists such as 1a with a K(i) of 4 nM. The synthesis and structure-activity relationships (SAR) of N-cyclic azaalkyl benzamides are described.

In the course of our research program to develop novel muscarinic receptor antagonists for the treatment of COPD, new tropane carbamate derivatives were identified as potent anti-muscarinic agents. The synthesis, structure-activity relationships and pharmacological evaluation that led to the identification of compound 5o, are described.

A series of 3-arylamino-2H-1,2,4-benzothiadiazin-5-ol 1,1-dioxides were prepared and shown to be novel and selective antagonists of the CXCR2 receptor. Synthesis, structure and activity relationships, selectivity, and some developability properties are described.

N,N'-diarylsquaramides were prepared and evaluated as antagonists of CXCR2. The compounds were found to be potent and selective antagonists of CXCR2. Significant differences in SAR was observed relative to the previously described N,N'-diarylurea series. As was the case in the N,N'-diarylurea series, placing sulfonamide substituent adjacent to the acidic phenol significantly reduced the clearance in rat pharmacokinetic studies.

High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.

A series of N-(2-hydroxy-3-sulfonamidobenzene)-N'-arylcyanoguanidines was prepared. In general, these compounds proved to be potent antagonists of CXCR2 while the selectivity versus CXCR1 ranged from non-selective to >200-fold.

Several peptidic urotensin-II (UT) receptor antagonists exert 'paradoxical' agonist activity in recombinant cell- and tissue-based bioassay systems, likely the result of differential urotensin-II receptor (UT receptor) signal transduction/coupling efficiency between assays. The present study has examined this phenomenon in mammalian arteries and recombinant UT-HEK (human embryonic kidney) cells.BacMam-mediated recombinant UT receptor upregulation in HEK cells augmented agonist activity for all four peptidic UT ligands studied. The nominal rank order of relative intrinsic efficacy was U-II>urantide ([Pen(5)-DTrp(7)-Orn(8)]hU-II(4-11))>SB-710411 (Cpa-c[DCys-Pal-DTrp-Lys-Val-Cys]-Cpa-amide)>>GSK248451 (Cin-c[DCys-Pal-DTrp-Orn-Val-Cys]-His-amide) (the relative coupling efficiency of recombinant HEK cells was cat>human>>rat UT receptor). The present study further demonstrated that the use of high signal transduction/coupling efficiency isolated blood vessel assays (primate>cat arteries) is required in order to characterize UT receptor antagonism thoroughly. This cannot be attained simply by using the rat isolated aorta, an artery with low signal transduction/coupling efficiency in which low-efficacy agonists appear to function as antagonists. In contrast to the 'low-efficacy agonists' urantide and SB-710411, GSK248451 functioned as a potent UT receptor antagonist in all native isolated tissues studied (UT receptor selectivity was confirmed in the rat aorta). Further, GSK248451 exhibited an extremely low level of relative intrinsic activity in recombinant HEK cells (4-5-fold less than seen with urantide). Since GSK248451 (1 mg kg(-1), i.v.) blocked the systemic pressor actions of exogenous U-II in the anaesthetized cat, it represents a suitable peptidic tool antagonist for delineating the role of U-II in the aetiology of mammalian cardiometabolic diseases.

High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (1a), are described.

1. SB-706375 potently inhibited [(125)I]hU-II binding to both mammalian recombinant and 'native' UT receptors (K(i) 4.7+/-1.5 to 20.7+/-3.6 nM at rodent, feline and primate recombinant UT receptors and K(i) 5.4+/-0.4 nM at the endogenous UT receptor in SJRH30 cells). 2. Prior exposure to SB-706375 (1 microM, 30 min) did not alter [(125)I]hU-II binding affinity or density in recombinant cells (K(D) 3.1+/-0.4 vs 5.8+/-0.9 nM and B(max) 3.1+/-1.0 vs 2.8+/-0.8 pmol mg(-1)) consistent with a reversible mode of action. 3. The novel, nonpeptidic radioligand [(3)H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (K(D) 2.6+/-0.4 nM, B(max) 0.86+/-0.12 pmol mg(-1)) in a manner that was inhibited by both U-II isopeptides and SB-706375 (K(i) 4.6+/-1.4 to 17.6+/-5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT receptor binding domain. 4. SB-706375 was a potent, competitive hU-II antagonist across species with pK(b) 7.29-8.00 in HEK293-UT receptor cells (inhibition of [Ca(2+)](i)-mobilization) and pK(b) 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (K(app) approximately 20 nM). 5. SB-706375 was a selective U-II antagonist with >/=100-fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (K(i)/IC(50)>1 microM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 microM). 6. In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals.

Urotensin-II (U-II), acting through its G-protein-coupled receptor, UT, is a possible contributor to hypertension. Variable functional responses to U-II, both within and between species studied to date, complicate the characterization of UT antagonists. In the cat, however, U-II causes systemic hypertension and constricts arterial segments isolated from several vascular beds. The purpose of this study was to clone and pharmacologically characterize cat recombinant UT to determine whether this system represents a model for characterizing UT antagonists. Cloned cat UT displayed 74% identity to primate UT, and 77% identity to rodent UT. [(125)I] hU-II bound in a saturable manner to a single site on recombinant cat UT with high affinity (K(D) 288+/-13pM) and high density (B(max) 747+/-66fmol/mg protein). U-II isopeptides displayed equipotent, high affinity binding to cat UT (K(i) 1.8-5.3nM). Cat UT was coupled to intracellular [Ca(2+)] release (EC(50) 0.6+/-0.2nM) and total inositol phosphate (IP) formation (EC(50) 0.4+/-0.1nM). Protein kinase C activation desensitized cat, but not human, UT-mediated IP formation. UT mRNA expression was detected in cat blood vessels, trachea, lung, and kidney, where the medulla (K(D) 815+/-34) and cortex and (K(D) 316+/-39pM) displayed high affinity binding for human U-II (hU-II). The cat urotensin-II receptor represents a suitable in vitro model to examine the role of the U-II/UT system in the etiology of hypertension, assisting in the evaluation of the UT antagonists to help treat cardiovascular disease.