Complexation of halide ions to tyrosine: role of non-covalent interactions evidenced by IRMPD spectroscopy.

The binding motifs in the halide adducts with tyrosine ([Tyr + X]-, X = Cl, Br, I) have been investigated and compared with the analogues with 3-nitrotyrosine (nitroTyr), a biomarker of protein nitration, in a solvent-free environment by mass-selected infrared multiple photon dissociation (IRMPD) spectroscopy over two IR frequency ranges, namely 950-1950 and 2800-3700 cm-1. Extensive quantum chemical calculations at B3LYP, B3LYP-D3 and MP2 levels of theory have been performed using the 6-311++G(d,p) basis set to determine the geometry, relative energy and vibrational properties of likely isomers and interpret the measured spectra. A diagnostic carbonyl stretching band at ∼1720 cm-1 from the intact carboxylic group characterizes the IRMPD spectra of both [Tyr + X]- and [nitroTyr + X]-, revealing that the canonical isomers (maintaining intact amino and carboxylic functions) are the prevalent structures. The spectroscopic evidence reveals the presence of multiple non-covalent forms. The halide complexes of tyrosine conform to a mixture of plane and phenol isomers. The contribution of phenol-bound isomers is sensitive to anion size, increasing from chloride to iodide, consistent with the decreasing basicity of the halide, with relative amounts depending on the relative energies of the respective structures. The stability of the most favorable phenol isomer with respect to the reference plane geometry is in fact 1.3, -2.1, -6.8 kJ mol-1, for X = Cl, Br, I, respectively. The change in π-acidity by ring nitration also stabilizes anion-π interactions yielding ring isomers for [nitroTyr + X]-, where the anion is placed above the face of the aromatic ring.

A Descriptive Study of a Spirituality Curriculum for General Psychiatry Residents.

OBJECTIVE: The study collected data on the attitudes of residents toward religion and spirituality in their practice after taking part in a 3-year curriculum on spirituality during their residency. METHODS: This is a descriptive, single-site study with psychiatry residents as subjects. A questionnaire was given to the residents at the end of their third year of residency (N = 12). RESULTS: The responses heavily endorsed the religiousness/spirituality curriculum to be helpful and meaningful. Residents consider addressing spiritual and religious needs of patients to be important (76.9%) and appropriate. For majority of the residents (69.2%), there is strong agreement in the management of addictions having spiritual dimensions. Residents also strongly agreed that treatment of suffering, depression, guilt, and complicated grief may require attention to spiritual concerns (92-100%). CONCLUSION: Regardless of cultural or religious background, the residents endorsed the curriculum as a worthwhile experience and increased their appreciation of the place of spirituality in the holistic care of patients with psychiatric conditions.

Mode-specific fragmentation of amino acid-containing clusters.

A combination of infrared multiple photon dissociation (IRMPD) spectroscopy and density functional theory calculations have been employed to study the structures and mode-specific dissociation pathways of the proton-bound dimer of 3-trifluoromethylphenylalanine (3-CF3-Phe) and trimethylamine (TMA). Three structural motifs are identified: canonical (charge-solvated), zwitterionic (charge-separated), and TMA-bridged. In the 1000-1350 cm(-1) region, similar spectra are observed in the TMA·H(+) and 3-CF3-Phe·H(+) product channels. At wavenumbers above 1350 cm(-1), infrared excitation of charge-solvated structures leads exclusively to production of protonated TMA, while excitation of zwitterionic or TMA-bridged structures results exclusively in production of protonated 3-CF3-Phe. The cluster potential energy landscape is topologically mapped and mechanisms for isomerization and mode-selective dissociation are proposed. In particular, cluster transparency as a result of IR-induced isomerization is implicated in deactivation of some IRMPD channels.

Structures and Energetics of Protonated Clusters of Methylamine with Phenylalanine Analogs, Characterized by Infrared Multiple Photon Dissociation Spectroscopy and Electronic Structure Calculations.

Gas-phase clusters of protonated methylamine and phenylalanine (Phe) derivatives have been studied using infrared multiple photon dissociation (IRMPD) spectroscopy in combination with electronic structure calculations at the MP2/aug-cc-pVTZ//B3LYP/6-311+G(d,p) level of theory. Experiments were performed on several Phe derivatives including 4-chloro-l-phenylalanine (4Chloro-Phe), 4-nitro-l-phenylalanine (4Nitro-Phe), 3-cyano-l-phenylalanine (3Cyano-Phe), and 3-trifluoromethyl-l-phenylalanine (3CF3-Phe). Through comparisons between experimental IRMPD spectra and stimulated spectra obtained by electronic structure calculations, charge-solvated structures were found to be prevalent in both 4Chloro-Phe and 4Nitro-Phe, whereas 3Cyano-Phe favored zwitterionic structures and 3-CF3-Phe likely have both zwitterionic and charge-solvated structures present.

Insight into the gas-phase structure of a copper(II) L-histidine complex, the agent used to treat Menkes disease.

Copper(II) L-histidine is used in the treatment of a rare neurological disease called Menkes disease. An infrared multiple photon dissociation (IRMPD) vibrational spectrum of the gas-phase copper(II) L-histidine complex has been obtained. This spectrum was compared to lowest-energy computational spectra obtained at the B3LYP/6-311+G** level of theory. Two species, CuHis1 and CuHis2, are very close in Gibbs free energy, and both have computed vibrational spectra in good agreement with the experimentally observed IRMPD spectrum. The first structure exhibits four histidine-copper interactions in the same plane and a fifth out-of-plane interaction. The second structure exhibits four histidine-copper interactions in the same plane. The fact that the experimental and computational spectra are found to be in good agreement adds considerable insight into the gas-phase structure of the copper(II) L-histidine complex.

Assessing the impact of anion-π effects on phenylalanine ion structures using IRMPD spectroscopy.

The gas-phase structures of two halide-bound phenylalanine anions (PheX(-), X = Cl(-) or Br(-)) and five fluorinated derivatives have been identified using infrared multiple photon dissociation (IRMPD) spectroscopy. The addition of electron-withdrawing groups to the aromatic ring creates a π-acidic system that additionally stabilizes the halide above the ring face. Detailed ion structures were determined by comparing the IRMPD spectra with harmonic and anharmonic infrared spectra computed using B3LYP/6-311++G(d,p) as well as with 298 K enthalpies and Gibbs energies determined by the MP2(full)/6-311++G(2d,2p)//B3LYP/6-311++G(d,p) and MP2(full)/aug-cc-pVTZ//B3LYP/6-311++G(d,p) methods. PheX(-) structures were found to be dependent on both the nature of the anion and the extent of ring fluorination. Canonical isomers were established to be the dominant structures in every case, but halide addition significantly narrowed the energy gap with zwitterionic potential energy surfaces. This enabled zwitterions to appear as minor contributors to the gas-phase populations of Phe35F2Cl(-) and PheF5Br(-).

Gas-phase solvation of protonated amino acids by methanol.

The enthalpy and entropy changes for the formation of the 1:1 complexes of methanol with various gaseous protonated amino acids have been measured using pulsed-ionization high-pressure mass spectrometry. The enthalpy changes for formation of the clusters Gly(MeOH)H(+), Ala(MeOH)H(+), Val(MeOH)H(+), Leu(MeOH)H(+), Ile(MeOH)H(+), and Pro(MeOH)H(+) have been determined to be -92.0, -83.3, -82.4, -79.5, -78.7, and -73.6 kJ mol(-1), respectively. These values agree very well with the energetic values computed at the MP2(full)/6-311++G(2d,2p)//B3LYP/6-311+G(d,p) level of theory for the lowest energy adducts in each system. Both experimental observations and computational determinations of the potential energy surface for the glycine system suggest that a mixture of low-lying isomers may be present for each of the cluster systems examined. The primary structural motif for these clusters is the coordination of the methanol molecule to the ammonium group of the protonated amino acid via a strong ionic hydrogen bond. For the amino acids studied here, computational results reveal that one methanol molecule does not sufficiently stabilize any zwitterionic structure such that no appreciable extent of proton transfer from the amino acid to methanol was observed.

Persistent Intramolecular C-H···X (X = O or S) Hydrogen-Bonding in Benzyl Meldrum's Acid Derivatives.

C-H···X (where X = O or S) intramolecular hydrogen bonding is investigated in three benzyl Meldrum's acid derivatives using a combination of solution phase NMR spectroscopy, gas phase infrared multiple photon dissociation spectroscopy, and density functional theory calculations. In one compound, an abnormally large C-H···S hydrogen bond energy of 30.4 kJ mol-1 is calculated with a natural bond orbital analysis. Intramolecular C-H···O hydrogen bonding is found to persist in the gas phase. Gibbs energy decomposition pathways are calculated.

Proton-bound 3-cyanophenylalanine trimethylamine clusters: isomer-specific fragmentation pathways and evidence of gas-phase zwitterions.

The structures and dissociation pathways of the proton-bound 3-cyanophenylalanine·trimethylamine cluster have been studied using a combination of infrared multiple photon dissociation (IRMPD) spectroscopy and density functional theory calculations. Three isomer motifs are identified: charge-solvated, zwitterionic, and trimethylamine (TMA)-bridged. While the TMA-bridged structures fragment to yield protonated TMA (channel 1) and protonated 3-cyanophenylalanine (channel 2), charge-solvated species exclusively fragment via channel 1 and zwitterionic species exclusively fragment via channel 2. Mechanisms are proposed.

Weak ion-molecule interactions in the gas phase: a high-pressure mass spectrometry and computational study of chloride-alkane interactions.

High-pressure mass spectrometric equilibrium experiments and electronic structure calculations have been carried out to investigate the energetics of the interactions of chloride ion with a series of normal alkanes and cycloalkanes in the gas phase. The structures of the complexes obtained from the electronic structure calculations provide considerable insight into the nature of the interaction between the negatively charged ion and the alkanes, which has the character of a purely ion-induced dipole interaction. The structural information also shows how the charged species affect the confirmation of the normal alkanes.

Tridentate ionic hydrogen-bonding interactions of the 5-fluorocytosine cationic dimer and other 5-fluorocytosine analogues characterized by IRMPD spectroscopy and electronic structure calculations.

Ionic hydrogen-bonding interactions have been found in several clusters formed by 5-fluorocytosine (5-FC). The chloride and trimethylammonium cluster ions, along with the cationic (proton-bound) dimer have been characterized by infrared multiple-photon dissociation (IRMPD) spectroscopy and electronic structure calculations performed at the B2PLYP/aug-cc-pVTZ//B3LYP/6-311+G(d,p) level of theory. IRMPD action spectra, in combination with calculated spectra and relative energetics, indicate that it is most probable that predominantly a single isomer exists in each experiment. For the 5-FC-trimethylammonium cluster specifically, the calculated spectrum of the lowest-energy isomer convincingly matches the experimental spectrum. Interestingly, the cationic dimer of 5-FC was found to have a single energetically relevant isomer (Cationic-IV) involving a tridentate ionic hydrogen-bonding interaction. The three sites of intermolecular ionic hydrogen bonds in this isomer interact very efficiently, leading to a significant calculated binding energy of 180 kJ/mol. The magnitude of the calculated binding energy for this species, in combination with the strong correlation between the simulated and IRMPD spectra, suggests that a tridentate-proton-bound dimer was observed predominantly in the experiments. Comparison of the calculated relative Gibbs free energies (298 K) for this species and several of the other isomers considered also supports the likelihood of the dominant protonated dimer existing as Cationic-IV.

Dealing with mass death in disasters and pandemics: Some key differences but many similarities.

PURPOSE: There are many differences in how authorities handle the dead during mass death incidents involving disasters and pandemics. These differences would suggest that planning for a disaster death and planning for a pandemic death should be done separately. This may be true to some extent, however, there are many similarities between the two that this article will seeks to examine. The main objective of this study is to show that planning for both disasters and pandemics should either be done by a single entity that coordinates both types of responses, or by agencies that communicate closely and frequently. DESIGN/METHODOLOGY/APPROACH: This study compared mass death incidents predominantly within the Canadian historical record, including disasters and pandemics. It took a specific look at the influenza pandemic of 1918 in North America and how the dead were handled. FINDINGS: Both disasters and pandemics offer unique challenges in handling the dead and documenting the incident. In a pandemic the cause of death is usually clear, while in a disaster it is not always understood. However, the similarities they hold in common must not be overlooked. They will involve immense and complicated amounts of paperwork, cause a shortage of supplies (be it medical, food or otherwise) and create the need for assistance. ORIGINALITY/VALUE: The research finds that though disasters and pandemics are often handled differently by the various agencies involved, they should be treated alike and dealt with in the same manner.

The Use of Clonidine in the Treatment of Debilitating Obsessive-Compulsive Behaviors Comorbid With Depression and Post-Traumatic Stress Disorder: A Case Report.

Clonidine is an alpha-2 agonist traditionally used as an antihypertensive, and more recently in the treatment of psychiatric disorders such as attention-deficit hyperactive disorder (ADHD), tic disorders such as Tourette's syndrome, and post-traumatic stress disorder (PTSD). However, there are scarce data in the literature about the use of clonidine in the treatment of obsessive-compulsive disorder (OCD). In this report, we present the case of a 16-year-old female suffering from OCD. The first-line treatment with sertraline was not very efficacious in improving her symptoms and even led to worsening of the same. However, subsequent treatment with clonidine resulted in rapid and significant improvement in her condition. We postulate that further research is required to gain more insight into the therapeutic potential of clonidine in OCD patients.

Benzodiazepine Misuse: An Epidemic Within a Pandemic.

Coronavirus disease 2019 (COVID-19) had deleterious effects on patients with mental health problems and several studies have shown a spike in the rates of depression, insomnia, and post-traumatic stress disorder. Anxiety and insomnia rates have also increased among both the general public and health care professionals. Benzodiazepines are some of the most commonly used drugs in the treatment of anxiety and insomnia. However, benzodiazepines are also misused, abused alone, or abused in combination with other drugs. Lockdowns and social distancing have also had negative consequences on patients with mental health problems. We assessed the extent of benzodiazepine use during the pandemic and interpreted its effects in the future. We conducted a literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol and eight articles reviewed specifically reported worrying fluctuations in benzodiazepine use during the pandemic. We observed varied trends in the usage of benzodiazepines in various parts of the world. Some studies showed an increase in the consumption of benzodiazepine while others demonstrated a decrease in the prescription refills of benzodiazepine, which may be a result of gaps in mental health care. At this time, we can conclude that the current trend with benzodiazepine use is fluctuating and mental health professionals must continue to exercise caution before prescribing benzodiazepines. Future research is also warranted to be aware of the changing patterns and to avoid misuse and/or abuse at an epidemic level.

Structures, energetics, and dynamics of gas phase ions studied by FTICR and HPMS.

Both Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and high-pressure mass spectrometry (HPMS) are very powerful tools in the field of gas phase ion chemistry. Many experimental method developments based on FTICR-MS and HPMS are summarized, including the coupling of a high-pressure external ion source to a FTICR mass spectrometer, blackbody infrared radiative dissociation (BIRD), coupling laser desorption ionization with HPMS, infrared multiple photon dissociation (IRMPD), radiative association and bimolecular routes to gas phase cluster ion formation. An abundance of thermochemical data, such as proton affinities, gas phase acidities, methyl cation affinities and metal cation affinities, have been obtained. Some of these data are the basis of the standard data listed in the NIST thermochemical databases. Ion-molecule interactions, energetics, reactivities, and structures of molecules have been extensively investigated using the methods developed based on HPMS and FTICR mass spectrometric techniques.

Infrared vibrational spectra as a structural probe of gaseous ions formed by caffeine and theophylline.

Ionic hydrogen bond (IHB) interactions, resulting from the association of ammonia and the two protonated methylxanthine derivatives, caffeine and theophylline, have been characterized using infrared multiphoton dissociation (IRMPD) spectroscopy and electronic structure calculations at the MP2/aug-cc-pVTZ//B3LYP/6-311+G(d,p) level of theory. The proton-bound dimer (PBD) of caffeine and ammonia exhibits a low binding energy and was found to be elusive under the experimental conditions due, most probably, to collision-induced dissociation of the complex with helium buffer gas before IRMPD irradiation. The IRMPD spectrum of a PBD of theophylline and ammonia was obtained and revealed bidentate IHB formation within the complex, which greatly increased the binding energy relative to the most stable isomer of the PBD of caffeine and ammonia. The IRMPD spectra of the protonated forms of caffeine and theophylline have also been obtained. The spectrum of protonated caffeine showed dominant protonation at the N(9) site, whereas the spectrum of protonated theophylline showed a mixture of two isomers. The first protonated isomer of theophylline exhibits protonation at the N(9) site and the second isomer demonstrated protonation at the C(6) carbonyl oxygen. The protonated carbonyl isomer of theophylline cannot be produced as a result of direct protonation and is thus suggested to be a consequence of proton-transport catalysis (PTC) initiated by the electrostatic interaction between water and N(9) protonated theophylline. Calculated anharmonic spectra have been simulated at the B3LYP/6-311+G(d,p) level of theory. It is shown that calculated anharmonic frequencies significantly outperform calculated harmonic frequencies in providing simulated IRMPD spectra in all cases.

Energetics and structural elucidation of mechanisms for gas phase H/D exchange of protonated peptides.

Hydrogen/deuterium exchange reactions involving protonated triglycine and deuterated ammonia (ND(3)) have been examined in the gas phase using a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. Ab initio and density functional theory (DFT) calculations have been carried out to model the exchanges and to obtain energetics and vibrational frequencies for molecules involved in the proposed exchange mechanisms. Structural optimization and frequency calculations have been performed at the B3LYP level of theory with the 6-311+G(d,p) basis set. Transition states have been calculated at the same level of theory and basis set as above using the QST2 and QST3 methods. Single-point energy calculations have been performed at the MP2/6-311+G(d,p) level. Six labile sites of protonated triglycine were found to undergo H/D exchange. Of these six labile hydrogens, two are amide, three are ammonium, and one is carboxyl. Detailed mechanisms for each of these transfers are proposed. Qualitative onium ion and tautomer mechanisms for the exchanges of ammonium and amide hydrogens, respectively, using semiempirical calculations were suggested in previous studies by Beauchamp et al. As shown by the current ab initio and DFT calculations completed during this study, the mechanisms proposed in that study are notionally correct; however, the tautomer mechanisms are shown here to be the result of the fact that a second stable isomer of protonated triglycine exists in which the amide1 carbonyl oxygen is protonated. The exchange of the carboxyl hydrogen is found to proceed via a transition state resembling an ammonium ion interacting with a carboxylate moiety via two hydrogen bonds. The current work thus provides significant mechanistic and structural detail for a considerably more in-depth understanding of the processes involved in gas phase H/D exchange of peptides.

Protonation sites and conformations of peptides of glycine (Gly(1-5)H(+)) by IRMPD spectroscopy.

The protonation sites and conformations of protonated glycine and its peptides (Gly(1-5)) have been investigated using infrared multiple photon dossociation (IRMPD) spectroscopy in combination with theoretical calculations. For small peptides, protonation is generally presumed to occur at the amine nitrogen of the N-terminus or a nitrogen of a basic side chain. However, for triglycine, the experimental and calculated results indicate that one of the main species is an isomer in which the proton is bound to an amide oxygen. The amide II vibrational mode is found to be very sensitive to the protonation site. When the protonation site is at the amine nitrogen, the amide II mode appears around 1540 cm(-1) for diglycine, tetraglycine, pentaglycine, and one of the main isomers of triglycine (GGGH02). When the proton is bound to an amide oxygen, the amide II mode is blue-shifted to 1590 cm(-1), as seen in GGGH01. IR spectra have been obtained to provide direct evidence that an amide oxygen may serve as the protonation site in a peptide. An analogous result is found for the tripeptide of alanine. In the progression from glycine to pentaglycine, the corresponding conformations of the most stable isomers vary from linear to cyclic structures. Both glycine and diglycine are linear structures, while the most stable isomers of the tetra- and pentapeptides are both cyclic structures. For triglycine, the linear and cyclic isomers are found to coexist. The carbonyl stretches also directly reflect the conformational changes. For the linear isomers of the di- and tripeptides of glycine, two well-separated bands are observed. The amide I modes appear slightly above 1700 cm(-1), but as a result of the fact that the C horizontal lineO bond in the carboxylic acid moiety is stronger than those of the amide carbonyls, the corresponding band appears near 1800 cm(-1). However, for the cyclic isomers of the tri-, tetra-, and pentapeptides, the carbonyl oxygen in the carboxylic acid group acts as a proton acceptor to form a very strong intramolecular hydrogen bond with the protonated amine terminus. This results in a weakening of the C horizontal lineO bond, such that the amide I modes are nearly identical in frequency to the carbonyl stretch of the carboxylic acid group.

Investigations of strong hydrogen bonding in (ROH)n...FHF- (n = 1, 2 and R = H, CH3, C2H5) clusters via high-pressure mass spectrometry and quantum calculations.

An examination of strong hydrogen bonds found in (ROH)(n)...FHF(-) clusters (n = 1 and 2; R = H, CH(3), C(2)H(5)) is presented. Excellent agreement is observed between thermochemical values obtained from high-pressure mass spectrometric measurements and those predicted from MP2(full)/6-311++G(d,p)//B3LYP/6-311++G(d,p) calculations. Calculated structures are examined, and insight into the geometric nature of the bonding for these systems is obtained. In the case of water binding to FHF(-), it was found that the large entropic advantage of one particular structure, which was not the most enthalpically favored, was significant enough to make it the predominant species within the ion source. In the case of methanol solvation, no evidence of secondary interaction of the methyl group and any other moiety could be found. The structural details revealed from calculations of the ethanol-solvated clusters indicate that secondary interactions between the terminal methyl group and FHF(-) have an impact on the length of the FHF and OHF bonds.

Transcriptional profiling and inhibition of cholesterol biosynthesis in human T lymphocyte cells by the marine toxin azaspiracid.

Azaspiracid-1 (AZA-1) is a marine biotoxin reported to accumulate in shellfish from several countries, including eastern Canada, Morocco, and much of western Europe, and is frequently associated with severe gastrointestinal human intoxication. As the mechanism of action of AZA-1 is currently unknown, human DNA microarrays and qPCR were used to profile gene expression patterns in human T lymphocyte cells following AZA-1 exposure. Some of the early (1 h) responding genes consisted of transcription factors, membrane proteins, receptors, and inflammatory genes. Four- and 24-h responding genes were dominated by genes involved in de novo lipid biosynthesis of which 17 of 18 involved in cholesterol biosynthesis were significantly up regulated. The up regulation of synthesis genes was likely in response to the ca. 50% reduction in cellular cholesterol, which correlated with up regulated protein expression levels of the low-density lipoprotein receptor. These data collectively detail the inhibition of de novo cholesterol synthesis, which is the likely cause of cytotoxicity and potentially a target pathway of the toxin.