The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16176. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

A Small Contribution to a Large System: The Leptin Receptor Complex.

Obesity is a classified epidemic, increasing the risk of secondary diseases such as diabetes, inflammation, cardiovascular disease, and cancer. The pleiotropic hormone leptin is the proposed link for the gut-brain axis controlling nutritional status and energy expenditure. Research into leptin signaling provides great promise toward discovering therapeutics for obesity and its related diseases targeting leptin and its cognate leptin receptor (LEP-R). The molecular basis underlying the human leptin receptor complex assembly remains obscure, due to the lack of structural information regarding the biologically active complex. In this work, we investigate the proposed receptor binding sites in human leptin utilizing designed antagonist proteins combined with AlphaFold predictions. Our results show that binding site I has a more intricate role in the active signaling complex than previously described. We hypothesize that the hydrophobic patch in this region engages a third receptor forming a higher-order complex, or a new LEP-R binding site inducing allosteric rearrangement.

Impact of COVID-19 anxiety on functional foods consuming intention: role of electronic word of mouth.

Purpose: The COVID-19 pandemic, which involving mass quarantines in many nations, has affected consumer health consciousness behaviors, including food consumption. This study aimed to investigate the impact of COVID-19 anxiety on functional food consumption within the framework of changes in health concerns and electronic word-of-mouth communication through digital platforms, paying special attention to the moderating effect of trust on eWOM information. Design: /methodology/approach: This cross-sectional study included 527 participants. The data were analyzed using a structural equation modeling approach. Mediating moderating effects were tested using bootstrapping and multigroup methods. Findings: Anxiety about the COVID-19 virus has a great impact on individuals' health concerns, word-of-mouth information seeking, and functional food consumption intention. Mediating effects of health consciousness and eWOM on functional food consumption intention were also observed. The anxiety about the COVID-19 virus and health consciousness triggers eWOM communication, and is a strong driver of intention to purchase functional foods if people trust the eWOM information source. Originality/value: While scholars have demonstrated the impact of COVID-19 on human behavior, a largely uninvestigated issue is the effect of COVID-19 virus anxiety on health product consumption. This is one of the first studies to examine the interrelationships among COVID-19 anxiety, health consciousness, eWOM, and functional food consumption intention.This study provides valuable insights into consumer behavior during the COVID-19 pandemic. Future research should consider the effect of COVID-19 virus anxiety on health-related issues and nutritional behavioral consequences. Based on the results, implications for managers and researchers are proposed.

U(VI) binding onto electrospun polymers functionalized with phosphonate surfactants.

We previously observed that phosphonate functionalized electrospun nanofibers can uptake U(VI), making them promising materials for sensing and water treatment applications. Here, we investigate the optimal fabrication of these materials and their mechanism of U(VI) binding under the influence of environmentally relevant ions (e.g., Ca2+ and CO 3 2 - ). We found that U(VI) uptake was greatest on polyacrylonitrile (PAN) functionalized with longer-chain phosphonate surfactants (e.g., hexa- and octadecyl phosphonate; HDPA and ODPA, respectively), which were better retained in the nanofiber after surface segregation. Subsequent uptake experiments to better understand specific solid-liquid interfacial interactions were carried out using 5 mg of HDPA-functionalized PAN mats with 10 µM U at pH 6.8 in four systems with different combinations of solutions containing 5 mM calcium (Ca2+) and 5 mM bicarbonate ( HCO 3 - ). U uptake was similar in control solutions containing no Ca2+ and HCO 3 - (resulting in 19 ± 3% U uptake), and in those containing only 5 mM Ca2+ (resulting in 20 ± 3% U uptake). A decrease in U uptake (10 ± 4% U uptake) was observed in experiments with HCO 3 - , indicating that UO2-CO3 complexes may increase uranium solubility. Results from shell-by-shell EXAFS fitting, aqueous extractions, and surface-enhanced Raman scattering (SERS) indicate that U is bound to phosphonate as a monodentate inner sphere surface complex to one of the hydroxyls in the phosphonate functional groups. New knowledge derived from this study on material fabrication and solid-liquid interfacial interactions will help to advance technologies for use in the in-situ detection and treatment of U in water.

A naturally occurring membrane-anchored Gαs variant, XLαs, activates phospholipase Cß4.

Extra-large stimulatory Gα (XLαs) is a large variant of G protein αs subunit (Gαs) that uses an alternative promoter and thus differs from Gαs at the first exon. XLαs activation by G protein-coupled receptors mediates cAMP generation, similarly to Gαs; however, Gαs and XLαs have been shown to have distinct cellular and physiological functions. For example, previous work suggests that XLαs can stimulate inositol phosphate production in renal proximal tubules and thereby regulate serum phosphate levels. In this study, we show that XLαs directly and specifically stimulates a specific isoform of phospholipase Cß (PLCß), PLCß4, both in transfected cells and with purified protein components. We demonstrate that neither the ability of XLαs to activate cAMP generation nor the canonical G protein switch II regions are required for PLCß stimulation. Furthermore, this activation is nucleotide independent but is inhibited by Gßγ, suggesting a mechanism of activation that relies on Gßγ subunit dissociation. Surprisingly, our results indicate that enhanced membrane targeting of XLαs relative to Gαs confers the ability to activate PLCß4. We also show that PLCß4 is required for isoproterenol-induced inositol phosphate accumulation in osteocyte-like Ocy454 cells. Taken together, we demonstrate a novel mechanism for activation of phosphoinositide turnover downstream of Gs-coupled receptors that may have a critical role in endocrine physiology.

Quantitative Surface-Enhanced Spectroscopy.

Surface-enhanced Raman scattering (SERS), a powerful technique for trace molecular detection, depends on chemical and electromagnetic enhancements. While recent advances in instrumentation and substrate design have expanded the utility, reproducibility, and quantitative capabilities of SERS, some challenges persist. In this review, advances in quantitative SERS detection are discussed as they relate to intermolecular interactions, surface selection rules, and target molecule solubility and accessibility. After a brief introduction to Raman scattering and SERS, impacts of surface selection rules and enhancement mechanisms are discussed as they relate to the observation of activation and deactivation of normal Raman modes in SERS. Next, experimental conditions that can be used to tune molecular affinity to and density near SERS substrates are summarized and considered while tuning these parameters is conveyed. Finally, successful examples of quantitative SERS detection are discussed, and future opportunities are outlined.

Uveal melanoma-associated mutations in PLCß4 are constitutively activating and promote melanocyte proliferation and tumorigenesis.

Activating mutations in Gαq/11 proteins are frequent in uveal melanoma, the most common eye cancer arising from the uveal tract. A small proportion of uveal melanomas have a D630Y mutation in phospholipase C ß4 (PLCß4), an effector of Gαq/11. Here, we found that the D630Y mutation in PLCß4 results in a high level of constitutive PLCß4 activity. Mutations at the corresponding position in other PLC isoforms also resulted in constitutive activity, revealing an unrecognized mechanism underlying PLC activation. In cultured human uveal melanoma cell lines, inhibition of PLC suppressed proliferation in Gαq/11-dependent cells. Furthermore, we found that PLCß4(D630Y) mediated proliferation in cutaneous melanocytes and the growth of melanomas in mice. These results are consistent with PLCß4(D630Y) driving oncogenic signaling downstream of Gαq/11.

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Introduction and Other Protein Targets.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15537. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Tuning gold nanostar morphology for the SERS detection of uranyl.

The impact of tunable morphologies and plasmonic properties of gold nanostars are evaluated for the surface enhanced Raman scattering (SERS) detection of uranyl. To do so, gold nanostars are synthesized with varying concentrations of the Good's buffer reagent, 2-[4-(2-hydroxyethyl)-1-piperazinyl]propanesulfonic acid (EPPS). EPPS plays three roles including as a reducing agent for nanostar nucleation and growth, as a nanostar-stabilizing agent for solution phase stability, and as a coordinating ligand for the capture of uranyl. The resulting nanostructures exhibit localized surface plasmon resonance (LSPR) spectra that contain two visible and one near-infrared plasmonic modes. All three optical features arise from synergistic coupling between the nanostar core and branches. The tunability of these optical resonances are correlated with nanostar morphology through careful transmission electron microscopy (TEM) analysis. As the EPPS concentration used during synthesis increases, both the length and aspect ratio of the branches increase. This causes the two lower energy extinction features to grow in magnitude and become ideal for the SERS detection of uranyl. Finally, uranyl binds to the gold nanostar surface directly and via sulfonate coordination. Changes in the uranyl signal are directly correlated to the plasmonic properties associated with the nanostar branches. Overall, this work highlights the synergistic importance of nanostar morphology and plasmonic properties for the SERS detection of small molecules.

Highly Strained 1,8-Naphthalene-Bridged Cyclic Oligophenylenes and Their Open-Shell Diradical Dications.

The synthesis and characterization of two 1,8-naphthalene-bridged cyclic oligo-para-phenylenes with four or eight phenylene units are reported. Both molecules exhibit a highly strained structure with two nearly face-to-face arranged p,p'-biphenylylene/p,p'-quaterphenylylene chains. Their dications were obtained by chemical oxidation with NO·SbF6, and both showed open-shell singlet diradical character with a small singlet-triplet energy gap.

Gold Nanostar Spatial Distribution Impacts the Surface-Enhanced Raman Scattering Detection of Uranyl on Amidoximated Polymers.

The plasmonic properties of carboxylated gold nanostars distributed on amidoximated polyacrylonitrile (AO PAN) electrospun polymer films scale with surface-enhanced Raman scattering (SERS) intensities for coordinated uranium(VI) oxide (uranyl) species. This two-step plasmonic sensor first isolates uranyl from solution using functionalized polymers; then carboxylated gold nanostars are subsequently deposited for SERS. Spatially resolved localized surface plasmon resonance (LSPR) and SERS facilitate correlated nanostar optical density and uranyl quantification. To reduce sampling bias, gold nanostars are deposited in an inverted drop-coating geometry and measurements are conducted inside resulting nanoparticle coffee rings that form on the polymer substrates. This approach naturally preserves the plasmonic properties of gold nanostars while reducing the deposition of nanoparticle aggregates in active sensing regions, thereby maximizing both the accuracy and the precision of SERS measurements. Several advances are made. First, second-derivative analysis of LSPR spectra facilitates the quantification of local nanostar density across large regions of the sensor substrate by reducing background variations caused by the polymeric and gold materials. Second, local nanostar densities ranging from 140 to 200 pM·cm are shown to result in uranyl signals that are independent of nanostar concentration. Third, the Gibbs free energy of uranyl adsorption to carboxylated nanostars is estimated at 8.4 ± 0.2 kcal/mol. Finally, a linear dynamic range from ∼0.3 to 3.4 µg U/mg polymer is demonstrated. Signals vary by 10% or less. As such, the uniformity of the plasmonic activity of distributed gold nanostars and the employment of spatially resolved spectroscopic measurements on the composite nanomaterial sensor interface facilitate the quantitative detection of uranyl while also reducing the dependence on user expertise and the selected sampling region. These important advances are critical for the development of a user-friendly SERS-based sensor for uranyl.

A new skink of the genus emSubdoluseps/em Freitas, Datta-Roy, Karanth, Grismer amp; Siler, 2019 (Squamata: Scincidae) from southern Vietnam.

We describe a new species of the genus Subdoluseps Freitas, Datta-Roy, Karanth, Grismer Siler from a coastal area in southern Vietnam. Subdoluseps vietnamensis sp. nov. is characterized by the following morphological characters: medium size in adults (snout-vent length up to 48.7 mm); tail length/snout-vent length ratio 1.04; toes not reaching finger when limbs adpressed; 27-30 midbody scale rows, smooth; 55-57 paravertebral scales; 55-62 ventral scale rows; 64-74 subcaudal scales; frontoparietal scale single; four supraoculars; prefrontals not in contact with one another; two loreal scales; seven supralabials; ear-opening with two lobules on the anterior border; smooth lamellae beneath finger III 9 or 10 and toe IV 12-15; six enlarged precloacal scales; and four distinct black stripes on dorsum. The new species differs genetically from its closest congeners, S. bowringii (Günther) and S. frontoparietale (Taylor), by uncorrected p-distances of 10.0% and 9.5%, respectively in ND1 sequences, and clusters into the same matriline with these two congeners on the phylogenetic trees.

A Stable [4,3]Peri-acene Diradicaloid: Synthesis, Structure, and Electronic Properties.

The synthesis of peri-fused acenes (peri-acenes) with two or more rows is challenging due to their intrinsic open-shell diradical character. Herein, we report the isolation of a derivative (4) of [4,3]peri-acene in crystalline form. The parent [4,3]peri-acene, containing three rows of tetracene, has a large diradical character (y0 =94.8 %) originating from aromatic stabilization. Due to kinetic blocking, 4 showed a reasonable stability with a half-life time of ≈157 h under ambient conditions. Its structure was determined by X-ray crystallographic analysis, and bond-length analysis revealed eight localized Clar's sextets. 4 exhibited an open-shell singlet ground state with a narrow electrochemical energy gap (1.13 eV) and a small singlet-triplet energy gap (-0.57 kcal mol-1 from SQUID measurements). Its electronic properties are compared with previously reported peri-tetracene and teranthene derivatives.

Microporous silica membranes promote plasmonic nanoparticle stability for SERS detection of uranyl.

Silica membrane stabilized gold coated silver (Ag@Au) (i.e., internally etched silica coated Ag@Au (IE Ag@Au@SiO2)) nanoparticles promote surface-enhanced Raman scattering (SERS) activity and detection of uranium(vi) oxide (uranyl) under harsh solution phase conditions including at pH 3-7, with ionic strengths up to 150 mM, and temperatures up to 37 °C for at least 10 hours. These materials overcome traditional solution-phase plasmonic nanomaterial limitations including signal variability and/or degradation arising from nanoparticle aggregation, dissolution, and/or surface chemistry changes. Quantitative uranyl detection occurs via coordination to 3-mercaptopropionate (MPA), a result confirmed through changes in correlated SERS intensities for uranyl and COOH/COO- vibrational modes. Quantification is demonstrated down to 110 nM, a concentration below toxic levels. As pH varies from 3 to 7, the plasmonic properties of the nanoparticles are unchanged, and the uranyl signal depends on both the protonation state of MPA as well as uranyl solubility. High ionic strengths (up to 150 mM) and incubation at 37 °C for at least 10 hours do not impact the SERS activity of uranyl even though slight silica dissolution is observed during thermal treatment. All in all, microporous silica membranes effectively protect the nanoparticles against variations in solution conditions thus illustrating robust tunability for uranyl detection using SERS.

Understanding Time-Dependent Surface-Enhanced Raman Scattering from Gold Nanosphere Aggregates Using Collision Theory.

Aggregates or clusters of primary metal nanoparticles in solution are one of the most widely used platforms for surface-enhanced Raman scattering (SERS) measurements because these nanostructures induce strong electric fields or hot spots between nanoparticles and as a result, SERS signals. While SERS signals are observed to vary with time, the impact of cluster formation mechanisms on SERS activity has been less studied. Herein, variations in time-dependent SERS signals from gold nanosphere clusters and aggregates are considered both experimentally and theoretically. An excess of the Raman reporter molecule, 2-naphthalenethiol, is added to induce rapid monolayer formation on the nanoparticles. In this diffusion-limited regime, clusters form as loosely packed fractals and the ligands help control nanoparticle separation distances once clusters form. By systematically varying gold nanosphere concentration and diameter, the reaction kinetics and dynamics associated with cluster formation can be studied. Dynamic light scattering (DLS), localized surface plasmon resonance (LSPR) spectroscopy, and SERS reveal that aggregates form reproducibly in the diffusion-limited regime and follow a self-limiting cluster size model. The rate of cluster formation during this same reaction window is explained using interaction pair potential calculations and collision theory. Diffusion-limited reaction conditions are limited by sedimentation only if sedimentation velocities exceed diffusion velocities of the clusters or via plasmon damping through radiation or scattering losses. These radiative loses are only significant when the extinction magnitude near the excitation wavelength exceeds 1.5. By evaluating these responses as a function of both nanosphere radius and concentration, time-dependent SERS signals are revealed to follow collision theory and be predictable when both nanosphere concentration and size are considered.

S-shaped para-Quinodimethane-Embedded Double [6]Helicene and Its Charged Species Showing Open-Shell Diradical Character.

Helicenes and extended helical π-conjugated compounds have been widely studied, but most of the systems contain only aromatic benzene or heterocyclic rings, showing local aromatic character. Herein, new S-shaped double [6]helicene 1, which has two embedded para-quinodimethane (p-QDM) units, is reported. Due to the existence of a proaromatic quinoidal substructure, it has open-shell diradical character. Its model compound, C-shaped single [6]helicene 2 containing one p-QDM unit, was also synthesized and compared. Their ground-state structures and electronic properties were systematically studied by a combination of various experimental methods assisted by theoretical calculations. Compound 1 has a double-helical structure in the crystal, with the two terminal [6]helicene units bent in opposite directions (i.e., anti form). However, an anti/syn isomerization process with a moderate interconversion energy barrier was observed on the NMR timescale. Compound 1 shows amphoteric redox behavior. It also exhibits open-shell diradical character (y0 =12.1 %) and a small singlet-triplet gap. On the other hand, compound 2 has a typical closed-shell nature. The dication and dianion of 1 also show open-shell diradical character. The dianion of 2 and the tetraanion of 1 exhibit similar electronic structures to their respective isoelectronic structures, that is, [6]helicene and a double [6]helicene. This work provides some insights into the design and synthesis of stable helical π systems with open-shell diradical character and magnetic activity.

Efficient self-assembly of heterometallic triangular necklace with strong antibacterial activity.

Sophisticated mechanically interlocked molecules (MIMs) with interesting structures, properties and applications have attracted great interest in the field of supramolecular chemistry. We herein report a highly efficient self-assembly of heterometallic triangular necklace 1 containing Cu and Pt metals with strong antibacterial activity. Single-crystal X-ray analysis shows that the finely arranged triangular necklace 1 has two racemic enantiomers in its solid state with intriguing packing motif. The superior antibacterial activity of necklace 1 against both standard and clinically drug-resistant pathogens implies that the presence of Cu(I) center and platinum(II) significantly enhance the bacterium-binding/damaging activity, which is mainly attributed to the highly positively charged nature, the possible synergistic effect of heterometals in the necklace, and the improved stability in culture media. This work clearly discloses the structure-property relationships that the existence of two different metal centers not only facilitates successful construction of heterometallic triangular necklace but also endows it with superior nuclease properties and antibacterial activities.

Stable Olympicenyl Radicals and Their π-Dimers.

An olympicenyl radical, a spin 1/2 hydrocarbon radical with C2v symmetry and uneven spin distribution, remains elusive despite the considerable theoretical research interest. Herein, we report syntheses of two air-stable olympicenyl radical derivatives, OR1 and OR2, with half-life times (τ1/2) in air-saturated solution of 7 days and 34 days. The high stability was ascribed to kinetic blocking of reactive sites with high spin densities. X-ray crystallographic analysis revealed unique 20-center-2-electron head-to-tail π-dimer structures with intermolecular distances shorter than the sum of van der Waals radius of carbon. The ground state of the π-dimers was found to be singlet, with singlet-triplet energy gaps estimated to be -2.34 kcal/mol and -3.28 kcal/mol for OR1 and OR2, respectively, by variable-temperature electron spin resonance (ESR) spectroscopy. The monomeric radical species were in equilibrium with the π-dimer in solution, and the optical and electrochemical properties of the monomers and π-dimers in solution were investigated by UV-vis-NIR spectroscopy and cyclic voltammetry, revealing a concentration-dependent nature. Theoretical calculations illustrated that upon formation of a π-dimer the local aromaticity of each monomer was enhanced, and spatial ring current between the monomers was present, which resulted in an increment of aromaticity of the interior of the π-dimer.

Benzidine/Quinoidal-Benzidine-Linked, Superbenzene-Based π-Conjugated Chiral Macrocycles and Cyclophanes.

Synthesis of fully conjugated cyclophanes containing large-size polycyclic aromatics is challenging. Now, three benzidine-linked, hexa-peri-hexabenzocoronene (superbenzene)-based ortho-, para-, and meta-cyclophanes are synthesized through intermolecular Yamamoto coupling reaction of structurally pre-organized precursors. Subsequent oxidative dehydrogenation gave the corresponding quinoidal benzidine-linked cyclophanes. Their geometries were confirmed by X-ray crystallographic analysis and their electronic properties were investigated by electronic absorption, cyclic voltammetry, and DFT calculations. The quinoidal benzidine-linked cyclophanes show thermally populated paramagnetic activity with a relatively large singlet-triplet energy gap. Two enantiomers for the ortho-cyclophanes (1-NH and 1-N) were isolated and their chiral figure-of-eight macrocyclic structures were identified. The cage-like cyclophanes 2-NH and 3-NH with concave surface can selectively encapsulate fullerene C70 .

3D global aromaticity in a fully conjugated diradicaloid cage at different oxidation states.

Aromaticity is a vital concept that governs the electronic properties of π-conjugated organic molecules and has long been restricted to 2D systems. The aromaticity in 3D π-conjugated molecules has been rarely studied. Here we report a fully conjugated diradicaloid molecular cage and its global aromaticity at different oxidation states. The neutral compound has an open-shell singlet ground state with a dominant 38π monocyclic conjugation pathway and follows the [4n + 2] Hückel aromaticity rule; the dication has a triplet ground state with a dominant 36π monocyclic conjugation pathway and satisfies [4n] Baird aromaticity; the tetracation is an open-shell singlet with 52 π-electrons that are delocalized along the 3D rigid framework, showing 3D global antiaromaticity; and the hexacation possesses D3 symmetry with 50 globally delocalized π-electrons, showing [6n + 2] 3D global aromaticity. Different types of aromaticity were therefore accessed in one molecular cage platform, depending on the symmetry, number of π-electrons and spin state.