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Synthesis of Aristoquinoline Enantiomers and Their Evaluation at the [alpha]3[beta]4 Nicotinic Acety
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Synthesis and Computational and Experimental Investigations of a para -Nicotinic Acid-Bridged Dirhenium(I) Dimer Complex
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Structural mechanism of muscle nicotinic receptor desensitization and block by curare
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The effects of allelochemical transfer on the dynamics of hosts, parasitoids, and competing hyperparasitoids
Allelochemicals produced by plants may be ingested by herbivorous insects and transferred to higher trophic levels with potentially deleterious effects. We develop a system of differential equations to investigate the effect of the transfer of allelochemicals, such as nicotine, on the population dynamics of a system of hosts, parasitoids, and two competing hyperparasitoids that attack different life stages of the parasitoids. We find both somewhat deleterious effects of nicotine on the larvae-attacking hyperparasitoids and increased attack rates for the pupae-attacking hyperparasitoids can promote coexistence. We also use an evolutionary game-theoretic approach to determine the optimal distribution of hyperparasitoid attacks among nicotine-producing and nicotine-free plants. With strong deleterious effects of nicotine and increased attack rates for the pupae-attacking hyperparasitoid, we find both species attack parasitoids on the nicotine-free plant but only pupae-attacking hyperparasitoids attack parasitoids on the nicotine-producing plant.
Rat bronchoalveolar lavage proteome changes following e-cigarette aerosol exposures
E-cigarette liquids are complex mixtures of chemicals consisting of humectants, such as propylene glycol (PG) and vegetable glycerin (VG), with nicotine or flavorings added. Published literature emphasizes the toxicity of e-cigarette aerosols with flavorings whereas much less attention has been given to the biologic effects of humectants. The purpose of the current study was to provide a comprehensive view of the acute biologic effects of e-cigarette aerosols on rat bronchoalveolar lavage (BAL) using mass spectrometry-based global proteomics. Sprague–Dawley rats were exposed to e-cigarette aerosol for 3 h/day for three consecutive days. Groups included: PG/VG alone, PG/VG + 2.5% nicotine (N), or PG/VG + N + 3.3% vanillin (V). Right lung lobes were lavaged for BAL and supernatants prepared for proteomics. Extracellular BAL S100A9 concentrations and BAL cell staining for citrullinated histone H3 (citH3) were also performed. From global proteomics, ~2,100 proteins were identified from rat BAL. Overall, the greatest change in number of BAL proteins occurred with PG/VG exposures alone compared with controls with biological pathways enriched for acute phase responses, extracellular trap formation, and coagulation. Extracellular BAL S100A9 concentrations and the number of citH3 + BAL cells also increased significantly in PG/VG and PG/VG + 2.5% N. In contrast to PG/VG or PG/VG + N, the addition of vanillin to PG/VG + N increased BAL neutrophilia and downregulated lipid transport proteins. In summary, global proteomics support e-cigarette aerosol exposures to PG/VG alone as having a significant biologic effect on the lung independent of nicotine or flavoring with increased markers of extracellular trap formation.
Polycyclic aromatic hydrocarbons and cannabinoids in secondhand cannabis smoke
The legalization of cannabis is exposing more people to secondhand smoke (SHS) generated during cannabis use. Given the serious health effects caused by tobacco SHS, there is a need to assess the potential health effects of exposure to cannabis SHS. As a step toward this, we measured the concentrations of cannabinoids, nicotine and polycyclic aromatic hydrocarbons (PAHs) in air samples collected in public places where cannabis was being consumed. These were compared with concentrations in exhaled aerosols from cannabis smoking and vaping, and in tobacco SHS. Tetrahydrocannabinol concentrations were 22 to 255 µg/m 3 in field samples, below the threshold for psychoactive effects. Nicotine concentrations in field samples did not exceed 1 µg/m 3 . The total PAH concentrations in field samples were from 3.2 to 80.5 ng/m 3 , depending on location type. By contrast, PAH levels averaged 72 ng/m 3 in tobacco SHS and 220 ng/m 3 in the more concentrated, exhaled cannabis aerosols. A total of 22 different PAHs were identified in field samples of cannabis aerosols, from which benz[a]anthracene (B[a]A) was present in the highest concentrations. The PAH profile of cannabis aerosols was different from that of tobacco SHS. A preliminary cancer risk evaluation showed that the dose associated with inhalation of cannabis SHS during an 8-h work shift exceeded the California No Significant Risk Level for B[a]A at all venues where cannabis was consumed primarily via smoking. In summary, the consumption of cannabis, by smoking and by vaporizing, can create aerosols that contain carcinogenic PAHs. Thus breathing secondhand cannabis aerosols increases exposure to carcinogens.
A simplified protocol for the automated production of 2‐[ 18 F]fluoro‐3‐[2‐((S)‐3‐pyrrolinyl)methoxy]pyridine ([ 18 F]nifene) on an IBA Synthera® module
The α4β2 nicotinic acetylcholine receptor (nAChR) ligand 2‐[18F]fluoro‐3‐[2‐((S)‐3‐pyrrolinyl)methoxy]pyridine ([18F]nifene) has been synthesized in 10% decay‐corrected radiochemical yield using the IBA Synthera® platform (IBA Cyclotron Solutions, Louvain‐la‐Neuve, Belgium) with an integrated fluidic processor (IFP). Boc‐nitronifene served as the precursor, and 20% trifluoroacetic acid (TFA) was used to deprotect the Boc‐group after radiolabeling. By omitting the solvent extraction step after radiolabeling, the process was simplified to a single step with no manual intervention. [18F]Nifene was obtained in decay‐corrected radiochemical yields of 10 ± 2% (n = 20) and radiochemical purity >99%. Typical specific radioactivities of 2700–4865 mCi/μmole (100–180 GBq/μmol) were measured at the end of synthesis; total synthesis times were about 1 h 40 min.
Chemical changes in thirdhand smoke associated with remediation using an ozone generator
Ozonation is a common remediation approach to eliminate odors from mold, tobacco and fire damage in buildings. Little information exists to: 1) assess its effectiveness; 2) provide guidance on operation conditions; and 3) identify potential risks associated with the presence of indoor ozone and ozonation byproducts. The goal of this study is to evaluate chemical changes in thirdhand smoke (THS) aerosols induced by high levels of ozone, in comparison with THS aerosols aged under similar conditions in the absence of ozone. Samples representing different stages of smoke aging in the absence of ozone, including freshly emitted secondhand smoke (SHS) and THS, were collected inside an 18-m 3 room-sized chamber over a period of 42 h after six cigarettes were consumed. The experiments involved collection and analysis of gas phase species including volatile organic compounds (VOCs), volatile carbonyls, semivolatile organic compounds (SVOCs), and particulate matter. VOC analysis was carried out by gas chromatography/mass spectrometry with a thermal desorption inlet (TD-GC/MS), and volatile carbonyls were analyzed by on-line derivatization with dinitrophenylhydrazine (DNPH), followed by liquid chromatography with UV/VIS detection. SVOCs were extracted from XAD-coated denuders and Teflon-coated fiberglass filters in the absence of ozone. In those extracts, tobacco-specific nitrosamines (TSNAs) and other SVOCs were analyzed by gas chromatography with positive chemical ionization-triple quadrupole mass spectrometric detection (GC/PCI-QQQ-MS), and polycyclic aromatic hydrocarbons (PAHs) were quantified by gas chromatography with ion trap mass spectrometric detection (GC/IT-MS) in selected ion monitoring mode. Particulate matter concentration was determined gravimetrically. In a second experiment, a 300 mg h -1 commercial ozone generator was operated during 1 h, one day after smoke was generated, to evaluate the remediation of THS by ozonation. VOCs and volatile carbonyls were analyzed before and after ozonation. Extracts from fabrics that were exposed in the chamber before and after ozonation as surrogates for indoor furnishings were analyzed by GC/IT-MS, and aerosol size distribution was studied with a scanning mobility particle sizer. Ozone concentration was measured with a photometric detector. An estimated 175 mg ozone reacted with THS after 1 h of treatment, corresponding to 58% of the total O 3 released during that period. Fabric-bound nicotine was depleted after ozonation, and the surface concentration of PAHs adsorbed to fabric specimens decreased by an order of magnitude due to reaction with ozone, reaching pre-smoking levels. These results suggest that ozonation has the potential to remove harmful THS chemicals from indoor surfaces. However, gas phase concentrations of volatile carbonyls, including formaldehyde, acetaldehyde and acetone were higher immediately after ozonation. Ultrafine particles (UFP, in most cases with size <60 nm) were a major ozonation byproduct. UFP number concentrations peaked shortly after ozonation ended, and remained at higher-than background levels for several hours. Based on these results, minimum re-entry times after ozone treatment were predicted for different indoor scenarios. Clearly defining re-entry times can serve as a practical measure to prevent acute exposures to ozone and harmful ozonation byproducts after treatment. This study evaluated potential benefits and risks associated with THS remediation using ozone, providing insights into this technology.
Probing Complex Chemical Processes at the Molecular Level with Vibrational Spectroscopy and X-ray Tools
Understanding the origins of structure and bonding at the molecular level in complex chemical systems spanning magnitudes in length and time is of paramount interest in physical chemistry. Here, we have coupled vibrational spectroscopy and X-ray based techniques with a series of microreactors and aerosol beams to tease out intricate and sometimes subtle interactions, such as hydrogen bonding, proton transfer, and noncovalent interactions. This allows for unraveling the self-assembly of arginine-oleic acid complexes in an aqueous solution and growth processes in a metal–organic framework. Terahertz and infrared spectroscopy provide an intimate view of the hydrogen-bond network and associated phase changes with temperature in neopentyl glycol. The hydrogen-bond network in aqueous glycerol aerosols and levels of protonation of nicotine in aqueous aerosols are visualized. Future directions in probing the hydrogen-bond networks in deep eutectic solvents and organic frameworks are described, and we suggest how X-ray scattering coupled to X-ray spectroscopy can offer insight into the reactivity of organic aerosols.
The Gas Phase Protonation Sites of Six Naturally Occurring Nicotinoids
We have determined the gas phase protonation sites of six naturally occurring nicotinoids, namely nicotine (NIC), nornicotine (NOR), anabasine (ANB), anatabine (ANT), cotinine (COT) and myosmine (MYO) from experimental cryogenic ion trap infrared spectroscopy and first principles electronic structure calculations. The structural motif of these compounds consists of a common Pyridine and a differing non-Pyridine rings. The protonation site on either of these two rings correlates with the nicotinoid’s biological activity (addiction). At room temperature NIC is a mixture of Pyridine and Pyrrolidine (non-Pyridene) protomers, NOR, ANB, ANT and COT are pure Pyridine protomers and finally MYO is mostly a Pyroline (non-Pyridine) protomer. Their biological activity (addiction) correlates with the protonation preference in the nonPyridine protomer, with the exception of MYO, which, although is protonated in the Pyroline (non-Pyridine) protomer, it is not addictive because of a conjugated p system that induces a flat structure that is not optimally interacting with the environment in the in the binding pocket of the human brain.
Synthetic antibodies against BRIL as universal fiducial marks for single-particle cryoEM structure determination of membrane proteins
We propose the concept of universal fiducials based on a set of pre-made semi-synthetic antibodies (sABs) generated by customized phage display selections against the fusion protein BRIL, an engineered variant of apocytochrome b562a. These sABs can bind to BRIL fused either into the loops or termini of different GPCRs, ion channels, receptors and transporters without disrupting their structure. A crystal structure of BRIL in complex with an affinity-matured sAB (BAG2) that bound to all systems tested delineates the footprint of interaction. Negative stain and cryoEM data of several examples of BRIL-membrane protein chimera highlight the effectiveness of the sABs as universal fiducial marks. Taken together with a cryoEM structure of sAB bound human nicotinic acetylcholine receptor, this work demonstrates that these anti-BRIL sABs can greatly enhance the particle properties leading to improved cryoEM outcomes, especially for challenging membrane proteins.
Pharmacological Profiling of a Brugia malayi Muscarinic Acetylcholine Receptor as a Putative Antiparasitic Target
The diversification of anthelmintic targets and mechanisms of action will help ensure the sustainable control of nematode infections in response to the growing threat of drug resistance. G protein-coupled receptors (GPCRs) are established drug targets in human medicine but remain unexploited as anthelmintic substrates despite their important roles in nematode neuromuscular and physiological processes. Bottlenecks in exploring the druggability of parasitic nematode GPCRs include a limited helminth genetic toolkit and difficulties establishing functional heterologous expression. In an effort to address some of these challenges, we profile the function and pharmacology of muscarinic acetylcholine receptors in the human parasite Brugia malayi, an etiological agent of human lymphatic filariasis. While acetylcholine-gated ion channels are intensely studied as targets of existing anthelmintics, comparatively little is known about metabotropic receptor contributions to parasite cholinergic signaling. Using multivariate phenotypic assays in microfilariae and adults, we show that nicotinic and muscarinic compounds disparately affect parasite fitness traits. We identify a putative G protein-linked acetylcholine receptor of B. malayi (Bma-GAR-3) that is highly expressed across intramammalian life stages and adapt spatial RNA in situ hybridization to map receptor transcripts to critical parasite tissues. Tissue-specific expression of Bma-gar-3 in Caenorhabditis elegans (body wall muscle, sensory neurons, and pharynx) enabled receptor deorphanization and pharmacological profiling in a nematode physiological context. Finally, we developed an image-based feeding assay as a reporter of pharyngeal activity to facilitate GPCR screening in parasitized strains. We expect that these receptor characterization approaches and improved knowledge of GARs as putative drug targets will further advance the study of GPCR biology across medically important nematodes.
Light-Induced Al Plating on Si for Fabrication of an Ag-Free All-Al Solar Cell
Light-induced electroplating of Al as the front electrode on the n-type emitter of Si solar cells is proposed as a substitute for screen-printed Ag. The advantages and disadvantages of Al over Cu as the front electrode are discussed. The power of a green laser used for patterning of the SiN x antireflection coating is optimized. Conditions for removal of laser damage and contamination on the laser-patterned surface are identified. The effect of plating temperature and post-annealing temperature on Al morphology and resistivity are investigated. Several plating additives are explored to improve the morphology and resistivity of the Al film. Nicotinic acid produces the lowest resistivity of 3.1 μ Ω-cm. However, the lowest contact resistivity between light-induced Al and Si is 69 mΩ-cm 2 due to laser-induced damage to the emitter. The Al film spikes through the thin n-type emitter when annealed at 500 °C causing cell failure. The process reproducibility is also poor due to atmospheric moisture.
Global transcriptome profile of the developmental principles of in vitro iPSC-to-motor neuron differentiation
Abstract Background Human induced pluripotent stem cells (iPSC) have opened new avenues for regenerative medicine. Consequently, iPSC-derived motor neurons have emerged as potentially viable therapies for spinal cord injuries and neurodegenerative disorders including Amyotrophic Lateral Sclerosis. However, direct clinical application of iPSC bears in itself the risk of tumorigenesis and other unforeseeable genetic or epigenetic abnormalities. Results Employing RNA-seq technology, we identified and characterized gene regulatory networks triggered by in vitro chemical reprogramming of iPSC into cells with the molecular features of motor neurons (MNs) whose function in vivo is to innervate effector organs. We present meta-transcriptome signatures of 5 cell types: iPSCs, neural stem cells, motor neuron progenitors, early motor neurons, and mature motor neurons. In strict response to the chemical stimuli, along the MN differentiation axis we observed temporal downregulation of tumor growth factor-β signaling pathway and consistent activation of sonic hedgehog, Wnt/β-catenin, and Notch signaling. Together with gene networks defining neuronal differentiation (neurogenin 2, microtubule-associated protein 2, Pax6, and neuropilin-1), we observed steady accumulation of motor neuron-specific regulatory genes, including Islet-1 and homeobox protein HB9. Interestingly, transcriptome profiling of the differentiation process showed that Ca 2+ signaling through cAMP and LPC was downregulated during the conversion of the iPSC to neural stem cells and key regulatory gene activity of the pathway remained inhibited until later stages of motor neuron formation. Pathways shaping the neuronal development and function were well-represented in the early motor neuron cells including, neuroactive ligand-receptor interactions, axon guidance, and the cholinergic synapse formation. A notable hallmark of our in vitro motor neuron maturation in monoculture was the activation of genes encoding G-coupled muscarinic acetylcholine receptors and downregulation of the ionotropic nicotinic acetylcholine receptors expression. We observed the formation of functional neuronal networks as spontaneous oscillations in the extracellular action potentials recorded on multi-electrode array chip after 20 days of differentiation. Conclusions Detailed transcriptome profile of each developmental step from iPSC to motor neuron driven by chemical induction provides the guidelines to novel therapeutic approaches in the re-construction efforts of muscle innervation.
Tobacco-specific nitrosamine 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal (NNA) causes DNA damage and impaired replication/transcription in human lung cells
Thirdhand smoke (THS) is a newly described health hazard composed of toxicants, mutagens and carcinogens, including nicotine-derived tobacco specific nitrosamines (TSNAs), one of which is 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal (NNA). Although TSNAs are generally potent carcinogens, the risk of NNA, which is specific to THS, is poorly understood. We recently reported that THS exposure-induced adverse impact on DNA replication and transcription with implications in the development of cancer and other diseases. Here, we investigated the role of NNA in THS exposure-induced harmful effects on fundamental cellular processes. We exposed cultured human lung epithelial BEAS-2B cells to NNA. The formation of DNA base damages was assessed by Long Amplicon QPCR (LA-QPCR); DNA double-strand breaks (DSBs) and NNA effects on replication and transcription by immunofluorescence (IF); and genomic instability by micronuclei (MN) formation. We found increased accumulation of oxidative DNA damage and DSBs as well as activation of DNA damage response pathway, after exposure of cells to NNA. Impaired S phase progression was also evident. Consistent with these results, we found increased MN formation, a marker of genomic instability, in NNA-exposed cells. Furthermore, ongoing RNA synthesis was significantly reduced by NNA exposure, however, RNA synthesis resumed fully after a 24h recovery period only in wild-type cells but not in those deficient in transcription-coupled nucleotide excision repair (TC-NER). Importantly, these cellular effects are common with the THS-exposure induced effects. Our findings suggest that NNA in THS could be a contributing factor for THS exposure-induced adverse health effect.
Opiate Sensitivity in Fruit Flies
Substance use disorder is a debilitating clinical condition in which behavioral dependence results from biological, environmental, genetic, and psychosocial factors. An epidemic surrounding the use and abuse of opioids is ravaging the world. While considerable efforts have explored the social drivers of addiction, a deeper understanding of biological causes and genetic vulnerabilities, preventative interventions, and effective treatments, have all proven elusive. This perspective article aims to remind readers that addictive natural compounds such as cocaine, nicotine, cathinone, or morphine, evolved as defensive metabolites to deter insect herbivory. The molecular mechanisms underlying motivational seeking and learning/reward show remarkable conservation since their early emergence in bilateral metazoans. An extended coevolutionary arms race subsequently weaponized these compounds into disruptors of learning, motivation, and incentivized attention. When plant chemical defenses attack insect physiology, humans are rendered susceptible due to strong conservation in the underlying molecular machinery. This perspective addresses the paradox that opiates were shaped to target insect neuropharmacology, even though this taxon appears to lack the recognized opioid receptor clade of mammals. We argue that the link is to be found in the allatostatin receptor, a basal ortholog of opioid receptors. Moreover, preliminary evidence indicates that morphine reduces Drosophila feeding and locomotion, concordant with a purported role as a defensive compound reducing herbivory. An implementation via allatostatin-mediated mechanisms is likely. This research argues for a broader heuristic perspective of substance abuse and a recognition of the evolutionary constraints that have likely shaped the biological drivers of opioid sensitivity and of its behavioral targets.
Genomics, Exometabolomics, and Metabolic Probing Reveal Conserved Proteolytic Metabolism of Thermoflexus hugenholtzii and Three Candidate Species From China and Japan
Thermoflexus hugenholtzii JAD2 T , the only cultured representative of the Chloroflexota order Thermoflexales, is abundant in Great Boiling Spring (GBS), NV, United States, and close relatives inhabit geothermal systems globally. However, no defined medium exists for T. hugenholtzii JAD2 T and no single carbon source is known to support its growth, leaving key knowledge gaps in its metabolism and nutritional needs. Here, we report comparative genomic analysis of the draft genome of T. hugenholtzii JAD2 T and eight closely related metagenome-assembled genomes (MAGs) from geothermal sites in China, Japan, and the United States, representing “Candidatus Thermoflexus japonica,” “Candidatus Thermoflexus tengchongensis,” and “Candidatus Thermoflexus sinensis.” Genomics was integrated with targeted exometabolomics and 13 C metabolic probing of T. hugenholtzii. The Thermoflexus genomes each code for complete central carbon metabolic pathways and an unusually high abundance and diversity of peptidases, particularly Metallo- and Serine peptidase families, along with ABC transporters for peptides and some amino acids. The T. hugenholtzii JAD2 T exometabolome provided evidence of extracellular proteolytic activity based on the accumulation of free amino acids. However, several neutral and polar amino acids appear not to be utilized, based on their accumulation in the medium and the lack of annotated transporters. Adenine and adenosine were scavenged, and thymine and nicotinic acid were released, suggesting interdependency with other organisms in situ. Metabolic probing of T. hugenholtzii JAD2 T using 13 C-labeled compounds provided evidence of oxidation of glucose, pyruvate, cysteine, and citrate, and functioning glycolytic, tricarboxylic acid (TCA), and oxidative pentose-phosphate pathways (PPPs). However, differential use of position-specific 13 C-labeled compounds showed that glycolysis and the TCA cycle were uncoupled. Thus, despite the high abundance of Thermoflexus in sediments of some geothermal systems, they appear to be highly focused on chemoorganotrophy, particularly protein degradation, and may interact extensively with other microorganisms in situ.