Coaxial Dielectric Spectroscopy as an In-Line Process Analytical Technique for Reaction Monitoring.

The suitability of broadband dielectric spectroscopy (DS) as a tool for in-line (in situ) reaction monitoring is demonstrated. Using the esterification of 4-nitrophenol as a test-case, we show that multivariate analysis of time-resolved DS data-collected across a wide frequency range with a coaxial dip-probe-allows reaction progress to be measured with both high precision and high accuracy. In addition to the workflows for data collection and analysis, we also establish a convenient method for rapidly assessing the applicability of DS to previously untested reactions or processes. We envisage that, given its orthogonality to other spectroscopic methods, its low cost, and its ease of implementation, DS will be a valuable addition to the process chemist's analytical toolbox.

HO2 + NO2: Kinetics, Thermochemistry, and Evidence for a Bimolecular Product Channel.

A master equation (ME) analysis of available experimental data has been carried out on the reaction HO2 + NO2 + M ⇋ HO2NO2 + M (1a)/(-1a). The analysis, based on the ME code MESMER, uses both the association and dissociation kinetic data from the literature, and provides improved thermochemistry on reaction 1a. Our preferred model assigns two low-frequency vibrations of HO2NO2 as hindered rotors and couples these to the external rotations. This model gives ΔrH°0(1a) = -93.9 ± 1.0 kJ mol-1, which implies that ΔfH°0 HO2NO2 = -42.0 ± 1.0 kJ mol-1 (uncertainties are 2σ). A significant contributor to the uncertainty derives from modeling the interaction between the internal and external rotors. Using this improved kinetics for reaction 1a/-1a, data at elevated temperatures, 353-423 K, which show no evidence of the expected equilibration, have been reanalyzed, indicating that an additional reaction is occurring that masks the equilibration. Based on a published ab initio study, this additional channel is assigned to the bimolecular reaction HO2 + NO2 → H-NO2 + O2 (1b); H-NO2 is nitryl hydride and has not previously been directly observed in experiments. The output of the master equation analysis has been parametrized and Troe expressions are provided for an improved description of k1a(p,T) and k-1a(p,T).

An Exploratory Investigation of Pupillometry As a Measure of Tinnitus Intrusiveness on a Test of Auditory Short-Term Memory.

OBJECTIVES: The purpose of the current study was to investigate the potential of pupillometry to provide an objective measure of competition between tinnitus and external sounds during a test of auditory short-term memory. DESIGN: Twelve participants with chronic tinnitus and twelve control participants without tinnitus took part in the study. Pretest sessions used an adaptive method to estimate listeners' frequency discrimination threshold on a test of delayed pitch discrimination for pure tones. Target and probe tones were presented at 72 dB SPL and centered on 750 Hz±2 semitones with an additional jitter of 5 to 20 Hz. Test sessions recorded baseline pupil diameter and task-related pupillary responses (TEPRs) during three blocks of delayed pitch discrimination trials. The difference between target and probe tones was set to the individual's frequency detection threshold for 80% response-accuracy. Listeners with tinnitus also completed the Tinnitus Handicap Inventory (THI). Linear mixed effects procedures were applied to examine changes in baseline pupil diameter and TEPRs associated with group (tinnitus versus control), block (1 to 3) and their interaction. The association between THI scores and maximum TEPRs was assessed using simple linear regression. RESULTS: Patterns of baseline pupil dilation across trials diverged in listeners with tinnitus and controls. For controls, baseline pupil dilation remained constant across blocks. For listeners with tinnitus, baseline pupil dilation increased on blocks 2 and 3 compared with block 1. TEPR amplitudes were also larger in listeners with tinnitus than controls. Linear mixed effects models yielded a significant group by block interaction for baseline pupil diameter and a significant main effect of group on maximum TEPR amplitudes. Regression analyses yielded a significant association between THI scores and TEPR amplitude in listeners with tinnitus. CONCLUSIONS: Our data indicate measures of baseline pupil diameter, and TEPRs are sensitive to competition between tinnitus and external sounds during a test of auditory short-term memory. This result suggests pupillometry can provide an objective measure of intrusion in tinnitus. Future research will be required to establish whether our findings generalize to listeners across a full range of tinnitus severity.

Global Master Equation Analysis of Rate Data for the Reaction C2H4 + H ⇄ C2H5: ΔfH0⊖C2H5.

While forward and reverse rate constants are frequently used to determine enthalpies of reaction and formation, this process is more difficult for pressure-dependent association/dissociation reactions, especially since the forward and reverse reactions are usually studied at very different temperatures. The problems can be overcome by using a data-fitting procedure based on a master equation model. This approach has been applied to existing experimental pressure-dependent forward and reverse rate coefficients for the reaction C2H4 + H ⇄ C2H5 (k1, k-1) using the MESMER code to determine ΔfH0⊖C2H5 from the enthalpy of the reaction. New measurements of k1, k-1 were included in analysis. They are based on laser flash photolysis with direct observation of H atom time profiles by vacuum ultraviolet laser-induced fluorescence under conditions where the approach to equilibrium could be observed. Measurements were made over the temperature range 798-828 K and with [He] from 2.33 to 7.21 × 1018 molecule cm-3. These data were then combined with a wide range of existing experimental data with helium as the bath gas (112 measurements of k1 and k-1, covering the temperature range 285-1094 K, and [He] = 7.1 × 1015-1.9 × 1019 molecule cm-3) and fitted using the master equation solver MESMER. The required vibrational frequencies and rotational constants of the system were obtained from ab initio calculations, and the activation threshold for association (ΔEthresh), enthalpy of reaction (ΔrH0⊖), imaginary frequency (υimag), and helium energy-transfer parameters (⟨ΔE⟩d,298(T/298)n) were optimized. The resulting parameters (errors are 2σ) are ΔEthresh = 11.43 ± 0.34 kJ mol-1, ΔrH0⊖ = -145.34 ± 0.60 kJ mol-1, υimag = 730 ± 130 cm-1, ⟨ΔE⟩d,298 = 54.2 ± 7.6 cm-1, and n = 1.17 ± 0.12. A value of ΔfH298.15⊖(C2H5) = 120.49 ± 0.57 kJ mol-1 is obtained by combining ΔrH0⊖ with standard enthalpies of formation for H and C2H4 and making the appropriate temperature corrections. The dependence of these parameters on how the internal rotor and CH2 inversion modes are treated has been explored. The experimental data for other bath gases have been analyzed, and data sets compatible with the potential energy surface parameters determined above have been identified. The parameters are virtually identical but with slightly smaller error limits. Parameterization of k1, k-1 using the Troe formalization has been used to investigate competition between ethyl decomposition and reaction with oxygen under combustion conditions.

The basis of report-difference superiority in delayed perceptual comparison tasks.

A major role for visual short-term memory (VSTM) is to mediate perceptual comparisons of visual information across successive glances and brief temporal interruptions. Research that has focused on the comparison process has noted a marked tendency for performance to be better when participants are required to report a difference between the displays rather than report the absence of a difference (i.e. a sameness). We refer to this performance asymmetry as report-difference superiority (RDS). It has been suggested that RDS reflects the operation of a reflexive mechanism that generates a mismatch signal during the comparison of visual input with information maintained in VSTM. This bottom-up mechanism therefore gives evidence for the presence of a feature change but not for the absence of such a change; consequently, a sameness is harder to detect than a difference between two displays. We test this explanation, and determine whether by itself it is a sufficient explanation of the RDS. In a delayed comparison task we find the RDS effect is most prevalent when items retain the same display locations; however, the effect does persist even when compared item locations were scrambled across memory and test arrays. However, with a conjunction task this scrambling of locations was effective in wholly abolishing the RDS effect. We consider that the RDS effect is a consequence of local comparisons of features, as well as global statistical comparisons.

The "now moment" is believed privileged because "now" is when happening is experienced.

Hoerl & McCormack risk misleading people about the cognitive underpinnings of the belief in a privileged "now moment" because they do not explicitly acknowledge that the sense of existing in the now moment is an intrinsically temporally dynamic one. The sense of happening that is exclusive to the now moment is a better candidate for the source of belief in a privileged now.

Energy transfer in intermolecular collisions of polycyclic aromatic hydrocarbons with bath gases He and Ar.

Classical trajectory simulations of intermolecular collisions were performed for a series of polycyclic aromatic hydrocarbons interacting with the bath gases helium and argon for bath gas temperature from 300 to 2500 K. The phase-space average energy transferred per deactivating collision, ⟨∆Edown⟩, was obtained. The Buckingham pairwise intermolecular potentials were validated against high-level quantum chemistry calculations and used in the simulations. The reactive force-field was used to describe intramolecular potentials. The dependence of ⟨∆Edown⟩ on initial vibrational energy is discussed. A canonical sampling method was compared with a microcanonical sampling method for selecting initial vibrational energy at high bath gas temperatures. Uncertainties introduced by the initial angular momentum distribution were identified. The dependence of the collisional energy transfer parameters on the type of bath gas and the molecular structure of polycyclic aromatic hydrocarbons was examined.

Perceptual Errors Support the Notion of Masking by Object Substitution.

Two experiments examined the effect of object substitution masking (OSM) on the perceptual errors in reporting the orientation of a target. In Experiment 1, a four-dot trailing mask was compared with a simultaneous-noise mask. In Experiment 2, the four-dot and noise masks were factorially varied. Responses were modelled using a mixture regression model and Bayesian inference to deduce whether the relative impacts of OSM on guessing and precision were the same as those of a noise mask, and thus whether the mechanism underpinning OSM is based on increasing noise rather than a substitution process. Across both experiments, OSM was associated with an increased guessing rate when the mask trailed target offset and a reduction in the precision of the target representation (although the latter was less reliable across the two experiments). Importantly, the noise mask also influenced both guessing and precision, but in a different manner, suggesting that OSM is not simply caused by increasing noise. In Experiment 2, the effects of OSM and simultaneous-noise interacted, suggesting the two manipulations involve common mechanisms. Overall results suggest that OSM is often a consequence of a substitution process, but there is evidence that the mask increases noise levels on trials where substitution does not occur.

Stereoretentive Etherification of an α-Aryl-ß-amino Alcohol Using a Selective Aziridinium Ring Opening for the Synthesis of AZD7594.

A selective aziridinium ring-opening was used to etherify an α-aryl-ß-amino alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a stability study of the activated α-aryl-ß-amino alcohol in this system. Process analytical techniques were used to establish reaction understanding, and mixing on large scale was modeled in silico. The process provided a selective and efficient method of preparing the nonsteroidal, inhaled selective glucocorticoid receptor modulator AZD7594.

Process Design and Optimization in the Pharmaceutical Industry: A Suzuki-Miyaura Procedure for the Synthesis of Savolitinib.

A multidisciplinary approach covering synthetic, physical, and analytical chemistry, high-throughput experimentation and experimental design, process engineering, and solid-state chemistry is used to develop a large-scale (kilomole) Suzuki-Miyaura process. Working against clear criteria and targets, a full process investigation and optimization package is described highlighting how and why key decisions are made in the development of large-scale pharmaceutical processes.

Change perception and change interference within and across feature dimensions.

The ability to perceive a change in a visual object is reduced when that change is presented in competition with other changes which are task-irrelevant. We performed two experiments which investigate the basis of this change interference effect. We tested whether change interference occurs as a consequence of some form of attentional capture, or whether the interference occurs at a stage prior to attentional selection of the task-relevant change. A modified probe-detection task was used to explore this issue. Observers were required to report the presence/absence of a specified change-type (colour, shape) in the probe, in a context in which - on certain trials - irrelevant changes occur in non-probe items. There were two key variables in these experiments: the attentional state of the observer, and the dimensional congruence of changes in the probe and non-probe items. Change interference was strongest when the irrelevant changes were the same as those on the report dimension. However the interference pattern persisted even when observers did not know the report dimension at the time the changes occurred. These results seem to rule out attention as a factor. Our results fit best with an interpretation in which change interference produces feature-specific sensory noise which degrades the signal quality of the target change.

Exploiting CELLULOSE SYNTHASE (CESA) Class Specificity to Probe Cellulose Microfibril Biosynthesis.

Cellulose microfibrils are the basic units of cellulose in plants. The structure of these microfibrils is at least partly determined by the structure of the cellulose synthase complex. In higher plants, this complex is composed of 18 to 24 catalytic subunits known as CELLULOSE SYNTHASE A (CESA) proteins. Three different classes of CESA proteins are required for cellulose synthesis and for secondary cell wall cellulose biosynthesis these classes are represented by CESA4, CESA7, and CESA8. To probe the relationship between CESA proteins and microfibril structure, we created mutant cesa proteins that lack catalytic activity but retain sufficient structural integrity to allow assembly of the cellulose synthase complex. Using a series of Arabidopsis (Arabidopsis thaliana) mutants and genetic backgrounds, we found consistent differences in the ability of these mutant cesa proteins to complement the cellulose-deficient phenotype of the cesa null mutants. The best complementation was observed with catalytically inactive cesa4, while the equivalent mutation in cesa8 exhibited significantly lower levels of complementation. Using a variety of biophysical techniques, including solid-state nuclear magnetic resonance and Fourier transform infrared microscopy, to study these mutant plants, we found evidence for changes in cellulose microfibril structure, but these changes largely correlated with cellulose content and reflected differences in the relative proportions of primary and secondary cell walls. Our results suggest that individual CESA classes have similar roles in determining cellulose microfibril structure, and it is likely that the different effects of mutating members of different CESA classes are the consequence of their different catalytic activity and their influence on the overall rate of cellulose synthesis.

Quantum Cascade Laser Spectral Histopathology: Breast Cancer Diagnostics Using High Throughput Chemical Imaging.

Fourier transform infrared (FT-IR) microscopy coupled with machine learning approaches has been demonstrated to be a powerful technique for identifying abnormalities in human tissue. The ability to objectively identify the prediseased state and diagnose cancer with high levels of accuracy has the potential to revolutionize current histopathological practice. Despite recent technological advances in FT-IR microscopy, sample throughput and speed of acquisition are key barriers to clinical translation. Wide-field quantum cascade laser (QCL) infrared imaging systems with large focal plane array detectors utilizing discrete frequency imaging have demonstrated that large tissue microarrays (TMA) can be imaged in a matter of minutes. However, this ground breaking technology is still in its infancy, and its applicability for routine disease diagnosis is, as yet, unproven. In light of this, we report on a large study utilizing a breast cancer TMA comprised of 207 different patients. We show that by using QCL imaging with continuous spectra acquired between 912 and 1800 cm-1, we can accurately differentiate between 4 different histological classes. We demonstrate that we can discriminate between malignant and nonmalignant stroma spectra with high sensitivity (93.56%) and specificity (85.64%) for an independent test set. Finally, we classify each core in the TMA and achieve high diagnostic accuracy on a patient basis with 100% sensitivity and 86.67% specificity. The absence of false negatives reported here opens up the possibility of utilizing high throughput chemical imaging for cancer screening, thereby reducing pathologist workload and improving patient care.

Obtaining effective rate coefficients to describe the decomposition kinetics of the corannulene oxyradical at high temperatures.

Unimolecular reactions play an important role in combustion kinetics. An important task of reaction kinetic analysis is to obtain the phenomenological rate coefficients for unimolecular reactions based on the master equation approach. In most cases, the eigenvalues of the transition matrix describing collisional internal energy relaxation are of much larger magnitude than and well separated from the chemically significant eigenvalues, so that phenomenological rate coefficients may be unequivocally derived for incorporation in combustion mechanisms. However, when dealing with unimolecular reactions for a large molecule, especially at high temperatures, the large densities of states of the reactant cause the majority of the population distribution to lie at very high energy levels where the microcanonical reaction rate constants are large and the relaxation and chemical eigenvalues overlap, so that well-defined phenomenological rate coefficients cannot be determined. This work attempts to analyze the effect of overlapping eigenvalues on the high-temperature kinetics of a large oxyradical, based on microcanonical reaction rates and population distributions as well as the eigenvalue spectrum of the transition matrix from the master equation. The aim is to provide a pragmatic method for obtaining the most effective rate coefficients for competing elimination, dissociation, and bimolecular reactions for incorporation in combustion mechanisms. Our approach is demonstrated with a representative example, thermal decomposition and H addition reactions of the corannulene oxyradical.

Object substitution masking and its relationship with visual crowding.

Object substitution masking (OSM) occurs when the perceptibility of a brief target is reduced by a trailing surround mask typically composed of four dots. Camp et al. (Journal of Experimental Psychology: Human Perception and Performance, 41, 940-957, 2015) found that crowding a target by adding adjacent flankers, in addition to OSM, had a more deleterious effect on performance than expected based on the combined individual effects of crowding and masking alone. The current experiments test why OSM and crowding interact in this way. In three experiments, target-flanker distance is manipulated whilst also varying mask duration in a digit identification task. The OSM effect-as indexed by the performance difference between unmasked and masked conditions-had a quadratic function with respect to target-flanker distance. Results suggest it is OSM affecting crowding rather than the converse: Masking seems to amplify crowding at intermediate target-distractor distances at the edge of the crowding interference zone. These results indicate that OSM and crowding share common mechanisms. The effect of OSM is possibly a consequence of changes to the types of feature detectors which are pooled together for target identification when that target must compete for processing with a trailing mask in addition to competition from adjacent flankers.

Evaluating the Precision of Auditory Sensory Memory as an Index of Intrusion in Tinnitus.

OBJECTIVES: The purpose of this study was to investigate the potential of measures of auditory short-term memory (ASTM) to provide a clinical measure of intrusion in tinnitus. DESIGN: Response functions for six normal listeners on a delayed pitch discrimination task were contrasted in three conditions designed to manipulate attention in the presence and absence of simulated tinnitus: (1) no-tinnitus, (2) ignore-tinnitus, and (3) attend-tinnitus. RESULTS: Delayed pitch discrimination functions were more variable in the presence of simulated tinnitus when listeners were asked to divide attention between the primary task and the amplitude of the tinnitus tone. CONCLUSIONS: Changes in the variability of auditory short-term memory may provide a novel means of quantifying the level of intrusion associated with the tinnitus percept during listening.

Infrared spectral histopathology using haematoxylin and eosin (H&E) stained glass slides: a major step forward towards clinical translation.

Infrared spectral histopathology has shown great promise as an important diagnostic tool, with the potential to complement current pathological methods. While promising, clinical translation has been hindered by the impracticalities of using infrared transmissive substrates which are both fragile and prohibitively very expensive. Recently, glass has been proposed as a potential replacement which, although largely opaque in the infrared, allows unrestricted access to the high wavenumber region (2500-3800 cm-1). Recent studies using unstained tissue on glass have shown that despite utilising only the amide A band, good discrimination between histological classes could be achieved, and suggest the potential of discriminating between normal and malignant tissue. However unstained tissue on glass has the potential to disrupt the pathologist workflow, since it needs to be stained following infrared chemical imaging. In light of this, we report on the very first infrared Spectral Histopathology SHP study utilising coverslipped H&E stained tissue on glass using samples as received from the pathologist. In this paper we present a rigorous study using results obtained from an extended patient sample set consisting of 182 prostate tissue cores obtained from 100 different patients, on 18 separate H&E slides. Utilising a Random Forest classification model we demonstrate that we can rapidly classify four classes of histology of an independent test set with a high degree of accuracy (>90%). We investigate different degrees of staining using nine separate prostate serial sections, and demonstrate that we discriminate on biomarkers rather than the presence of the stain. Finally, using a four-class model we show that we can discriminate normal epithelium, malignant epithelium, normal stroma and cancer associated stroma with classification accuracies over 95%.

FTIR imaging of the molecular burden around Aß deposits in an early-stage 3-Tg-APP-PSP1-TAU mouse model of Alzheimer's disease.

Alzheimer's disease is one of the major causes of dementia in the elderly. The disease is caused by the misfolding of water soluble alpha-helical proteins, which leads to the accumulation of ß-sheets in the form of amyloid plaques, which can subsequently affect surrounding tissue areas by oxidative stress neurotoxicity. The aim of the present study was to design a novel methodology to analyze the extent to the neuronal burden around protein-rich Aß plaques suspected to affect molecular components by oxidative stress induced by inflammatory states. To do so, sagittal brain tissue sections from triple transgenic APPxPSP1xTAU mice were used to carry high magnification FTIR-FPA bench-top chemical imaging. The study used the combination of chemometric procedures involving spectral curve fitting and image processing to study the molecular changes occurring around the plaques. The study shows the performance of the approach by demonstrating its usefulness to co-localize molecular changes to different areas around the plaques. The results, although very preliminary, point to the strong interplay between the distance from the plaque and co-accumulation of molecular components indicative of inflammatory states.