Evaluation of Force-Field Calculations of Lattice Energies on a Large Public Dataset, Assessment of Pharmaceutical Relevance, and Comparison to Density Functional Theory.

Crystal lattice energy is a key property affecting the ease of processing pharmaceutical materials during manufacturing, as well as product performance. We present an extensive comparison of 324 force-field protocols for calculating the lattice energies of single component, organic molecular crystals (further restricted to Z' less than or equal to one), corresponding to a wide variety of force-fields (DREIDING, Universal, CVFF, PCFF, COMPASS, COMPASSII), optimization routines, and other variations, which could be implemented as part of an automated workflow using the industry standard Materials Studio software. All calculations were validated using a large new dataset (SUB-BIG), which we make publicly available. This dataset comprises public domain sublimation data, from which estimated experimental lattice energies were derived, linked to 235 molecular crystals. Analysis of pharmaceutical relevance was performed according to two distinct methods based upon (A) public and (B) proprietary data. These identified overlapping subsets of SUB-BIG comprising (A) 172 and (B) 63 crystals, of putative pharmaceutical relevance, respectively. We recommend a protocol based on the COMPASSII force field for lattice energy calculations of general organic or pharmaceutically relevant molecular crystals. This protocol was the most highly ranked prior to subsetting and was either the top ranking or amongst the top 15 protocols (top 5%) following subsetting of the dataset according to putative pharmaceutical relevance. Further analysis identified scenarios where the lattice energies calculated using the recommended force-field protocol should either be disregarded (values greater than or equal to zero and/or the messages generated by the automated workflow indicate extraneous atoms were added to the unit cell) or treated cautiously (values less than or equal to -249 kJ/mol), as they are likely to be inaccurate. Application of the recommended force-field protocol, coupled with these heuristic filtering criteria, achieved an root mean-squared error (RMSE) around 17 kJ/mol (mean absolute deviation (MAD) around 11 kJ/mol, Spearman's rank correlation coefficient of 0.88) across all 226 SUB-BIG structures retained after removing calculation failures and applying the filtering criteria. Across these 226 structures, the estimated experimental lattice energies ranged from -60 to -269 kJ/mol, with a standard deviation around 29 kJ/mol. The performance of the recommended protocol on pharmaceutically relevant crystals could be somewhat reduced, with an RMSE around 20 kJ/mol (MAD around 13 kJ/mol, Spearman's rank correlation coefficient of 0.76) obtained on 62 structures retained following filtering according to pharmaceutical relevance method B, for which the distribution of experimental values was similar. For a diverse set of 17 SUB-BIG entries, deemed pharmaceutically relevant according to method B, this recommended force-field protocol was compared to dispersion corrected density functional theory (DFT) calculations (PBE + TS). These calculations suggest that the recommended force-field protocol (RMSE around 15 kJ/mol) outperforms PBE + TS (RMSE around 37 kJ/mol), although it may not outperform more sophisticated DFT protocols and future studies should investigate this. Finally, further work is required to compare our recommended protocol to other lattice energy calculation protocols reported in the literature, as comparisons based upon previously reported smaller datasets indicated this protocol was outperformed by a number of other methods. The SUB-BIG dataset provides a basis for these future studies and could support protocol refinement.

A Perfluorinated Carboxylic Sulfuric Anhydride: Microwave and Computational Studies of CF3COOSO2OH.

Trifluoroacetic sulfuric anhydride (CF3COOSO2OH, TFASA) and its deuterated isotopologue have been observed by pulsed-nozzle Fourier transform microwave spectroscopy. TFASA was generated in situ in a supersonic expansion from the reaction of CF3COOH or CF3COOD with SO3. The spectrum, which was notably weaker than those of previously studied carboxylic sulfuric anhydrides, is that of a simple asymmetric rotor with no evidence of internal rotation of the CF3 group. Calculations at the M06-2X/6-311++G(3df,3pd) level indicate that the title compound is produced via a mechanism involving a concerted cycloaddition, analogous to that found for other carboxylic sulfuric anhydrides. The calculations further show that the equilibrium orientation of CF3 relative to the C═O bond changes upon formation of the anhydride, indicating that any path connecting the equilibrium structures of CF3COOH and CF3COOSO2OH necessarily includes both cycloaddition and internal rotation. CCSD(T)/complete basis set with double and triple extrapolation [CBS(D-T)] single-point energy calculations at key points on the potential surface indicate that the barrier to form TFASA from a putative CF3COOH···SO3 complex is about 1.2 kcal/mol after zero-point energy corrections. This value is significantly larger than the near-zero or slightly negative barriers previously reported for the reactions of SO3 with nonfluorinated carboxylic acids and likely accounts, at least in part, for the reduced spectral intensity. Thus, TFASA is a somewhat unique addition to the series of carboxylic sulfuric anhydrides studied to date. Theoretical values of certain structural parameters, atomic charges, and vibrational frequencies also support this point of view. Despite the differences, however, this work clearly demonstrates that the reaction RCOOH + SO3 → RCOOSO2OH readily occurs in the gas phase and is not restricted to acids with hydrocarbon R groups.

Hydration of an Acid Anhydride: The Water Complex of Acetic Sulfuric Anhydride.

The complex formed from acetic sulfuric anhydride (CH3COOSO2OH, ASA) and water has been observed by pulsed nozzle Fourier transform microwave spectroscopy. ASA was formed in situ in the supersonic jet via the reaction of SO3 and CH3COOH, and subsequently complexed with water using a concentric, dual injection needle that allows reagents to be introduced at different points along the expansion axis. Spectroscopic constants for the parent, fully deuterated, and CH313COOSO2OH species are reported. Both A and E internal rotor states have been observed and analyzed. The fitted internal rotation barrier of the methyl group is 219.598(21) cm-1 for the parent species, indicating that complexation with water lowers the internal rotation barrier of the methyl group by 9% relative to that of the free ASA. M06-2X/6-311++G(3df,3pd) calculations predict at least two distinct isomeric forms of ASA···H20. Spectroscopic constants for the observed species agree with those for the lower energy isomer in which the water inserts into the intramolecular hydrogen bond of the ASA monomer. CCSD(T)/CBS(D-T) calculations place the binding energy of this isomer at 13.3 kcal/mol below that of the isolated ASA and H2O monomers. The calculations further indicate that the doubly hydrogen bonded complex CH3COOH···H2SO4, which contains the hydrolysis products of ASA, lies even lower in energy, but this species was not observed in this study. This system represents the first stage of microsolvation of an acid anhydride, and the results indicate that a single water molecule does not induce spontaneous hydrolysis in a cold molecular cluster.

Observation of Two Conformers of Acrylic Sulfuric Anhydride by Microwave Spectroscopy.

The rotational spectrum of acrylic sulfuric anhydride (CH2═CHCOOSO2OH, AcrSA) has been observed using pulsed-nozzle Fourier transform microwave spectroscopy. The species was produced from the reaction between acrylic acid and sulfur trioxide in a supersonic jet. Spectroscopic constants are reported for both the s-cis- and s-trans-AcrSA conformers of the parent and monodeuterated (OD) isotopologues. Geometries were optimized for both conformers using M06-2X/6-311++G(3df,3pd) methods. Single-point energy calculations at the M06-2X geometries were calculated using the CCSD(T)/complete basis set method with double and triple extrapolation [CBS(D-T)]. Further calculations indicate that the anhydride results from a π2 + π2 + σ2 cycloaddition reaction within the acrylic acid-SO3 complex. Because the C═O double bond of the acrylic acid migrates from one of the COOH oxygens to the other during the reaction, the s-cis form of acrylic acid leads to the s-trans form of the anhydride and vice versa. With zero-point energy corrections applied to the CCSD(T) energies, the s-cis and s-trans forms of CH2═CHCOOSO2OH are 19.0 and 18.8 kcal/mol lower in energy than that of SO3 + their corresponding CH2═CHCOOH precursor conformation. The zero-point-corrected transition state energies for formation of the s-trans and s-cis anhydrides are 0.22 and 0.33 kcal/mol lower than those of the complexes of SO3 with s-cis and s-trans acrylic acid, respectively, indicating that the reaction is essentially barrierless. This system adds to a growing body of examples demonstrating that carboxylic acids readily add to SO3 in the gas phase to produce the corresponding carboxylic sulfuric anhydride.

Facile Formation of Acetic Sulfuric Anhydride: Microwave Spectrum, Internal Rotation, and Theoretical Calculations.

Acetic sulfuric anhydride, CH3COOSO2OH, was produced by the reaction of SO3 and CH3COOH in a supersonic jet. Four isotopologues were observed by microwave spectroscopy. Spectra of both A and E internal rotor states were observed and analyzed, yielding a value of 241.093(30) cm-1 for the methyl group internal rotation barrier of the parent species. Similar values were obtained for the other isotopologues studied. M06-2X/6-311++G(3df,3pd) calculations indicate that the formation of the anhydride proceeds via a π2 + π2 + σ2 cycloaddition reaction within the CH3COOH-SO3 complex. The equilibrium orientation of the methyl group relative to the O═C-C plane is different in the anhydride and in the CH3COOH-SO3 complex, indicating that the -CH3 internal rotation accompanies the cycloaddition reaction. The energies of key points on the potential energy surface were calculated using CCSD(T)/complete basis set with double and triple extrapolation [CBS/(D-T)], and the transformation from the CH3COOH-SO3 complex to CH3COOSO2OH is shown to be nearly barrierless regardless of the orientation of the methyl group. This study provides the second experimental observation of the reaction between a carboxylic acid and SO3 to form a carboxylic sulfuric anhydride in the gas phase. Possible connections to atmospheric aerosol formation are discussed.

Multidimensional Large Amplitude Dynamics in the Pyridine-Water Complex.

Aqueous pyridine plays an important role in a variety of catalytic processes aimed at harnessing solar energy. In this work, the pyridine-water interaction is studied by microwave spectroscopy and density functional theory calculations. Water forms a hydrogen bond to the nitrogen with the oxygen tilted slightly toward either of the ortho-hydrogens of the pyridine, and a tunneling motion involving in-plane rocking of the water interconverts the resulting equivalent structures. A pair of tunneling states with severely perturbed rotational spectra is identified and their energy separation, ΔE, is inferred from the perturbations and confirmed by direct measurement. Curiously, values of ΔE are 10404.45 and 13566.94 MHz for the H2O and D2O complexes, respectively, revealing an inverted isotope effect upon deuteration. Small splittings in some transitions suggest an additional internal motion making this complex an interesting challenge for theoretical treatments of large amplitude motion. The results underscore the significant effect of the ortho-hydrogens on the intermolecular interaction of pyridine.

Absolute protein quantification of the yeast chaperome under conditions of heat shock.

Chaperones are fundamental to regulating the heat shock response, mediating protein recovery from thermal-induced misfolding and aggregation. Using the QconCAT strategy and selected reaction monitoring (SRM) for absolute protein quantification, we have determined copy per cell values for 49 key chaperones in Saccharomyces cerevisiae under conditions of normal growth and heat shock. This work extends a previous chemostat quantification study by including up to five Q-peptides per protein to improve confidence in protein quantification. In contrast to the global proteome profile of S. cerevisiae in response to heat shock, which remains largely unchanged as determined by label-free quantification, many of the chaperones are upregulated with an average two-fold increase in protein abundance. Interestingly, eight of the significantly upregulated chaperones are direct gene targets of heat shock transcription factor-1. By performing absolute quantification of chaperones under heat stress for the first time, we were able to evaluate the individual protein-level response. Furthermore, this SRM data was used to calibrate label-free quantification values for the proteome in absolute terms, thus improving relative quantification between the two conditions. This study significantly enhances the largely transcriptomic data available in the field and illustrates a more nuanced response at the protein level.

The Trimethylamine-Formic Acid Complex: Microwave Characterization of a Prototype for Potential Precursors to Atmospheric Aerosol.

The reactions of amines and carboxylic acids have recently received attention for their possible role in the formation of atmospheric aerosol. Here, we report a microwave study of the trimethylamine-formic acid hydrogen-bonded complex, a simple prototype in which to study amine-carboxylic acid interactions. Spectra of three isotopologues of the system have been observed using a tandem cavity and chirped-pulse Fourier transform microwave spectrometer. The complex has a plane of symmetry, with the acidic proton of the formic acid directed toward the lone pair of the nitrogen. The zero-point-averaged hydrogen bond length is 1.702 Å, and the O-H···N angle is 177°. (14)N nuclear quadrupole hyperfine structure has been used to assess the degree of proton transfer from the formic acid to the trimethylamine. Experimental results are supplemented with density functional theory calculations. M06-2X/6-311++G(3df,3pd) calculations indicate a binding energy of 16.8 kcal/mol with counterpoise correction (17.4 kcal/mol without counterpoise correction).

Intramolecular competition between n-pair and π-pair hydrogen bonding: Microwave spectrum and internal dynamics of the pyridine-acetylene hydrogen-bonded complex.

a-type rotational spectra of the hydrogen-bonded complex formed from pyridine and acetylene are reported. Rotational and (14)N hyperfine constants indicate that the complex is planar with an acetylenic hydrogen directed toward the nitrogen. However, unlike the complexes of pyridine with HCl and HBr, the acetylene moiety in HCCH-NC5H5 does not lie along the symmetry axis of the nitrogen lone pair, but rather, forms an average angle of 46° with the C2 axis of the pyridine. The a-type spectra of HCCH-NC5H5 and DCCD-NC5H5 are doubled, suggesting the existence of a low lying pair of tunneling states. This doubling persists in the spectra of HCCD-NC5H5, DCCH-NC5H5, indicating that the underlying motion does not involve interchange of the two hydrogens of the acetylene. Single (13)C substitution in either the ortho- or meta-position of the pyridine eliminates the doubling and gives rise to separate sets of spectra that are well predicted by a bent geometry with the (13)C on either the same side ("inner") or the opposite side ("outer") as the acetylene. High level ab initio calculations are presented which indicate a binding energy of 1.2 kcal/mol and a potential energy barrier of 44 cm(-1) in the C2v configuration. Taken together, these results reveal a complex with a bent hydrogen bond and large amplitude rocking of the acetylene moiety. It is likely that the bent equilibrium structure arises from a competition between a weak hydrogen bond to the nitrogen (an n-pair hydrogen bond) and a secondary interaction between the ortho-hydrogens of the pyridine and the π electron density of the acetylene.

The formic acid-nitric acid complex: microwave spectrum, structure, and proton transfer.

Rotational spectra are reported for seven isotopologues of the complex HCOOH-HNO3 in a supersonic jet. The system is planar and bound by a pair of hydrogen bonds, much like the more widely studied carboxylic acid dimers. Double proton exchange interconverts the system between a pair of equivalent structures, as revealed by a splitting of the a-type spectrum that disappears when one of the hydrogen bonding protons is replaced by deuterium. The observation of relative intensities that are consistent with nuclear spin statistics in a symmetric and antisymmetric pair of tunneling states provides additional evidence for such a motion. The observed splittings in the pure rotational spectrum are 1-2 orders of magnitude smaller than those recently reported in the pure rotational spectra of several related carboxylic acid dimers. This is a curious difference, although we note that because the observed spectra do not cross the tunneling doublet, the splittings are a measure of the difference in effective rotational constants for the two states, not the tunneling frequency itself. The observed rotational constants have been used to determine an accurate vibrationally averaged structure for the complex. The two hydrogen bond lengths, 1.686(17) Å and 1.813(10) Å for the hydrogen bonds involving the HNO3 and HCOOH protons, respectively, differ by 0.127(27) Å. Likewise, the associated oxygen-oxygen distances determined for the parent species, 2.631 and 2.794 Å, differ by 0.163 Å. These results suggest that the double proton transfer is necessarily accompanied by substantial motion of the heavy atom frame, and thus this system, in principle, provides an excellent prototype for multidimensional tunneling processes. Ab initio calculations of the binding energy and the barrier height are presented. Excellent agreement between the calculated equilibrium structure and the experimental, vibrationally averaged structure suggests that the vibrational wave function is not highly delocalized in the region between the equivalent potential wells. (14)N nuclear quadrupole hyperfine structure is interpreted in terms of the degree to which the HNO3 releases its proton in either of the equivalent potential energy minima.

Effects of a remote binding partner on the electric field and electric field gradient at an atom in a weakly bound trimer.

Microwave spectra are reported for the C3v symmetric complexes Kr-SO3 and Kr-SO3-CO. The S-C distance in the trimer, 2.871(9) Å, is the same as that previously determined for SO3-CO to within the estimated uncertainties. The Kr-S distances are 3.438(3) Å and 3.488(6) Å in Kr-SO3 and Kr-SO3-CO, respectively, indicating that the addition of CO to Kr-SO3 increases the Kr-S distance by 0.050(9) Å. Measurements of the (83)Kr nuclear quadrupole coupling constants provide direct probes of the electric field gradient at the Kr nucleus, and a comparison between the two systems reflects the degree to which the CO influences the electronic structure of the krypton atom. Although the Kr and CO in the trimer are on opposite sides of the SO3 and thus are not in direct contact, the addition of CO to Kr-SO3 reduces the electric field gradient at the Kr nucleus by 18%. Calculations using the block localized wavefunction decomposition method are performed to understand the physical origins of this change. While the magnitudes of both the electric field and the electric field gradient at the Kr nucleus decrease upon addition of the CO to Kr-SO3, the changes are shown to arise from rather complex combinations of geometrical distortion, electrostatic, polarization, and electron transfer effects. For the electric field, the electrostatic term accounts for the largest portion of the reduction, while for the electric field gradient, polarization and structural change of the Kr-SO3 moiety make the primary contributions. Despite significant changes in the electronic environment at the Kr nucleus, calculated binding energies indicate that the interactions are largely additive, with the binding energy of the trimer very nearly equal to the sum of the Kr-SO3 and SO3-CO binding energies.

TRAFFICVIS: Visualizing Organized Activity and Spatio-Temporal Patterns for Detecting and Labeling Human Trafficking.

Law enforcement and domain experts can detect human trafficking (HT) in online escort websites by analyzing suspicious clusters of connected ads. How can we explain clustering results intuitively and interactively, visualizing potential evidence for experts to analyze? We present TRAFFICVIS, the first interface for cluster-level HT detection and labeling. Developed through months of participatory design with domain experts, TRAFFICVIS provides coordinated views in conjunction with carefully chosen backend algorithms to effectively show spatio-temporal and text patterns to a wide variety of anti-HT stakeholders. We build upon state-of-the-art text clustering algorithms by incorporating shared metadata as a signal of connected and possibly suspicious activity, then visualize the results. Domain experts can use TRAFFICVIS to label clusters as HT, or other, suspicious, but non-HT activity such as spam and scam, quickly creating labeled datasets to enable further HT research. Through domain expert feedback and a usage scenario, we demonstrate TRAFFICVIS's efficacy. The feedback was overwhelmingly positive, with repeated high praises for the usability and explainability of our tool, the latter being vital for indicting possible criminals.

Development and Feasibility of a Porcine Model of Amlodipine Toxicity.

INTRODUCTION: Toxicity related to calcium-channel blockers remains a significant cause of morbidity and mortality. Amlodipine-induced shock is unique in that its mechanism of action is thought to occur in part via the release of nitric oxide (NO) in the peripheral vasculature. Specific therapeutic interventions, including methylene blue (an NO scavenger), have been suggested, but efficacy studies are severely limited. To facilitate a larger porcine study into the effect of various interventions on amlodipine toxicity, we undertook this model development and feasibility study. METHODS: Intravenous amlodipine was prepared by dissolving commercially obtained amlodipine tablets in dimethylsulfoxide. The concentration of the drug was verified using ultraviolet spectroscopy. We administered this solution to three animals in order to determine a toxic dose, capable of facilitating a two-arm study of amlodipine toxicity. RESULTS: The first pig died rapidly after the bolus infusion. The second pig developed mild toxicity, but the dissolution of the plastic tubing by the solvent and subsequent leakage limited the interpretability of the result. The third animal developed expected toxicity with an infusion rate between 2.0  and 5.5 mg/kg/h. CONCLUSION: This study demonstrates a potentially repeatable model of amlodipine-induced toxic shock using intravenous administration of amlodipine and several methodological considerations for researchers undertaking similar work.

Involving medical students in service improvement: evaluation of a student-led, extracurricular, multidisciplinary quality improvement initiative.

BACKGROUND: Quality improvement (QI) is considered a duty of every doctor and, as such, it is fundamental that medical schools nurture QI skills of medical students. At a London medical school, a novel initiative was designed to involve medical students in QI. Such novel aspects include its student leadership, multidisciplinary approach and extra-curricular nature. The aim of this study is to evaluate the effectiveness of the initiative, and thus add to the experiences of existing medical student QI programs, as well as provide guidance to other institutions wishing to involve medical students in QI. METHODS: The key features of the initiative's design is described. Its effectiveness was evaluated by the collection of retrospective data on the quality of the initiative's QI projects (QIPs), including the proportion which: 1) reached completion; 2) resulted in a significant improvement in their primary outcome; 3) had sustained results at follow-up; 4) achieved publication; and 5) contributed towards a prize or conference presentation. RESULTS: There were 109 students involved throughout 10 projects from 14 different undergraduate and postgraduate courses from 2015-2019. 50% of the initiative's projects achieved a significant improvement in their primary outcome, and the proportion of projects which sustained these improvements at follow-up was 100%. Furthermore, 20% of projects were published, and 60% contributed towards a prize or conference presentation. CONCLUSION: The results of this study show that the initiative was effective at involving medical students in QI. As such, other groups establishing medical student QI programs may benefit from replicating positive elements of its design and operation.

The difficulty of predicting clinical outcome after intended submaximal resection of large vestibular Schwannomas.

INTRODUCTION: Intended subtotal resection of large vestibular schwannomas (T4a and b according to the Hannover classification system) has been shown to be safe and, in combination with stereotactic radiosurgery, might enable sufficient tumor control. However, risk factors for postoperative neurological deterioration in these surgically challenging lesions are largely unknown. METHODS: Pre- and postoperative symptoms, clinical and radiological data of patients who underwent intended subtotal resection for vestibular schwannoma in our department between 2010 and 2014 were reviewed. Risk factors for postoperative neurological deterioration were analyzed in uni- and multivariate analyses. RESULTS: 63 patients harboring T4a (N = 33, 52%) or T4b (N = 30, 48%) tumors were included. At time of discharge, facial nerve and hearing function had deteriorated from a serviceable to a non-serviceable level (H&B grades I + II vs. >II) in 24% (N = 15/63) and 21% (N = 6/29), respectively. Deterioration of vertigo was more common after near (N = 3/9, 33% vs. 2/38, 5%) than after subtotal resection (<.25 ccm vs. ≥ .25 ccm tumor remnant on the initial postoperative MRI; p = .042). No further correlation with patient age, sex, neurofibromatosis, resection extent and tumor volume, or -cyst volume was found. Patients were reevaluated after a median of 3 months after surgery. At that time, facial nerve function and hearing had both decreased from a preoperative serviceable to a non-serviceable level in 5%. In univariate analyses, risk of deterioration of facial nerve function increased with preoperative tumor volume (p = .037). CONCLUSION: Intended submaximal resection provides satisfactory neurological outcome for patients with large VS. Risk factors for postoperative neurological deterioration remain unclear.

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties.

Articular cartilage undergoes matrix degradation and loss of mechanical properties when stimulated with proinflammatory cytokines such as interleukin-1 (IL-1). Aggrecanases and matrix metalloproteinases (MMPs) are thought to be principal downstream effectors of cytokine-induced matrix catabolism, and aggrecanase- or MMP-selective inhibitors reduce or block matrix destruction in several model systems. The objective of this study was to use metalloproteinase inhibitors to perturb IL-1-induced matrix catabolism in bovine cartilage explants and examine their effects on changes in tissue compression and shear properties. Explanted tissue was stimulated with IL-1 for up to 24 days in the absence or presence of inhibitors that were aggrecanase-selective, MMP-selective, or non-selective. Analysis of conditioned media and explant digests revealed that aggrecanase-mediated aggrecanolysis was delayed to varying extents with all inhibitor treatments, but that aggrecan release persisted. Collagen degradation was abrogated by MMP- and non-selective inhibitors and reduced by the aggrecanase inhibitor. The inhibitors delayed but did not reduce loss of the equilibrium compression modulus, whereas the losses of dynamic compression and shear moduli were delayed and reduced. The data suggest that non-metalloproteinase mechanisms participate in IL-1-induced matrix degradation and loss of tissue material properties.

SULFUR CHEMISTRY. Gas phase observation and microwave spectroscopic characterization of formic sulfuric anhydride.

We report the observation of a covalently bound species, formic sulfuric anhydride (FSA), that is produced from formic acid and sulfur trioxide under supersonic jet conditions. FSA has been structurally characterized by means of microwave spectroscopy and further investigated by using density functional theory and ab initio calculations. Theory indicates that a π2 + π2 + σ2 cycloaddition reaction between SO3 and HCOOH is a plausible pathway to FSA formation and that such a mechanism would be effectively barrierless. We speculate on the possible role that FSA may play in the Earth's atmosphere.

3D-printed slit nozzles for Fourier transform microwave spectroscopy.

3D printing is a new technology whose applications are only beginning to be explored. In this report, we describe the application of 3D printing to the design and construction of supersonic nozzles. Nozzles can be created for $0.50 or less, and the ease and low cost can facilitate the optimization of nozzle performance for the needs of any particular experiment. The efficacy of a variety of designs is assessed by examining rotational spectra of OCS (carbonyl sulfide) and Ar-OCS using a Fourier transform microwave spectrometer with tandem cavity and chirped-pulse capabilities. A slit geometry which, to the best of our knowledge has not been used in conjunction with Fourier transform microwave spectrometers, was found to increase the signal-to-noise ratio for the J = 1←0 transition of OCS, by a factor of three to four compared with that obtained using our standard circular nozzle. Corresponding gains for the Ar-OCS complex were marginal, at best, but further optimization of nozzle geometry should be possible. The spectrometer itself is designed to allow rapid switching between cavity and chirped-pulse modes of operation without the need to break vacuum. This feature, as well as the newly incorporated chirped-pulse capability, is described in detail.