Up-front CID fragmentation is a phenomenon where molecular ions are activated and fragment as they enter the atmosphere-to-vacuum region of the mass spectrometer, and consequently can complicate the ...mass spectra and their analysis. This phenomenon can be minimized by controlling the voltages on lens/optic elements where ions are sampled from the atmospheric region, but this approach can also have a negative effect on overall ion sensitivity. In this study, we introduce gas-phase modifiers (acetonitrile, acetone, cyclohexane, water, and methanol) to the curtain gas to mitigate up-front CID fragmentation. These modifiers cluster with incoming ions, increasing the energy barrier to fragmentation and consequently reducing the complexity of mass spectra. The clustering is monitored by differential mobility spectrometry-mass spectrometry (DMS-MS) and precursor mass spectrum-scanning. Unlike typical singly charged species, peptide ion-modifier clusters were found to survive through the atmosphere-to-vacuum interface of the mass spectrometer, showing that highly charged peptides cluster most strongly with acetonitrile and acetone. In addition, when peptides cluster with acetonitrile, they produce a large increase in signal intensity for the most highly charged and fragile ions. This results in a significant reduction, up to 90% with some modifiers, in up-front CID fragmentation for these fragile highly charged peptides, increasing the overall analytical sensitivity and decreasing the limits of detection by up to 82% depending on the analyte. The proposed technique has no significant detrimental effect on the peptide mass fingerprinting of a BSA or mAb protein digest, but it does reduce the amount of redundant and data-deficient spectra needed to produce adequate sequence coverage using information-dependent acquisition methods by ~ 40%. We propose that this technique could have a benefit in the fields of proteomics and peptidomics where up-front CID fragmentation and chemical noise routinely mask targets of biological importance.
Graphical abstract
Molecular stream separation (MSS) is a promising complement for continuous-flow synthesis. MSS is driven by forces exerted on molecules by a field applied at an angle to the stream-carrying flow. MSS ...has only been performed with a 90° field-to-flow angle because of a rectangular geometry of canonic MSS; the second-order rotational symmetry of a rectangle prevents any other angle. Here, we propose a noncanonic circular geometry for MSS, which better aligns with the polar nature of MSS and allows changing the field-to-flow. We conducted in silico and experimental studies of circular geometry for continuous-flow electrophoresis (CFE, an MSS method). We proved two advantages of circular CFE over its rectangular counterpart. First, circular CFE can support better flow and electric-field uniformity than rectangular CFE. Second, the nonorthogonal field-to-flow orientation, achievable in circular CFE, can result in a higher stream resolution than the orthogonal one. Considering that circular CFE devices are not more complex in fabrication than rectangular ones, we foresee that circular CFE will serve as a new standard and a testbed for the investigation and creation of new CFE modalities.
•Most of the recent and probably fossil subduction zones on Earth are oblique.•Oblique subduction results in asymmetric mantle flow pattern leading to plate rotation.•Transition to continental ...subduction facilitates coeval trench advance and retreat.•Back-arc extension is led by toroidal mantle flow.•Sediments are transported in the trench and along the subduction interface.
Most subduction zones on Earth are oblique, i.e., the angle between the plate convergence vector and the trench notably differs from 90°. Therefore, modeling and understanding the strain partitioning in the forearc, the development of extensional basins in the back-arc region and the diachronous transition from subduction to collision require a 3D approach. Here, we assess how oblique oceanic subduction and subsequent collision and associated mantle flow around the subducted lithosphere control the thermo-mechanical evolution of active margins. We conducted a series of 3D thermo-mechanical subduction models and discuss the influence of different subduction obliquity angles, the role of mantle flow variations and their connection with sediment transport and back-arc deformation. Numerical models are complemented by scaled analogue models to visualize the mantle flow evolution. Oceanic subduction along an oblique trench results in asymmetric mantle return flow leading to the gradual decrease of the subduction obliquity angle driven by the gradual rotation of the lower plate and the along-trench variation of slab retreat. This creates laterally variable subduction velocities and slab geometries. Back-arc extension is governed by both the toroidal mantle flow along the slab edges and by the oblique subduction induced lateral mantle flow gradient. The diachronous transition from oceanic to continental subduction and collision facilitates the laterally variable trench advance and retreat and back-arc deformation. Tectonically induced lateral sediment transport in the trench and along the subduction interface decreases its strength and viscosity and can alter subduction velocities. Our model results provide critical insights into the evolution of oblique subduction and collisional systems, such as the Arabia-Eurasia convergence zone.
Understanding the mechanisms and energetics of ion solvation is critical in many scientific areas. Here, we present a methodlogy for studying ion solvation using differential mobility spectrometry ...(DMS) coupled to mass spectrometry. While in the DMS cell, ions experience electric fields established by a high frequency asymmetric waveform in the presence of a desired pressure of water vapor. By observing how a specific ion's behavior changes between the high- and low-field parts of the waveform, we gain knowledge about the aqueous microsolvation of that ion. In this study, we applied DMS to investigate the aqueous microsolvation of protonated quinoline-based drug candidates. Owing to their low binding energies with water, the clustering propensity of 8-substituted quinolinium ions was less than that of the 6- or 7-substituted analogues. We attribute these differences to the steric hinderance presented by subtituents in the 8-position. In addition, these experimental DMS results were complemented by extensive computational studies that determined cluster structures and relative thermodynamic stabilities.
In hyperspectral image (HSI) analysis, classification requires spectral dimensionality reduction (DR). While common DR methods use linear algebra, we propose a multilinear algebra method to jointly ...achieve denoising reduction and DR. Multilinear tools consider HSI data as a whole by processing jointly spatial and spectral ways. The lower rank-(K 1 , K 2 , K 3 ) tensor approximation LRTA-(K 1 , K 2 , K 3 ) was successfully applied to denoise multiway data such as color images. First, we demonstrate that the LRTA-(K 1 , K 2 , K 3 ) performs well as a denoising preprocessing to improve classification results. Then, we propose a novel method, referred to as LRTA dr -(K 1 , K 2 , D 3 ), which performs both spatial lower rank approximation and spectral DR. The classification algorithm Spectral Angle Mapper is applied to the output of the following three DR and noise reduction methods to compare their efficiency: the proposed LRTA dr -(K 1 , K 2 , D 3 ), PCA dr , and PCA dr associated with Wiener filtering or soft shrinkage of wavelet transform coefficients.
Background
First-line treatment with FOLFIRINOX significantly increases overall survival (OS) in patients with metastatic pancreatic adenocarcinoma (PA) compared with gemcitabine. The aim of this ...observational cohort was to evaluate the tolerability and efficacy of this regimen in unresectable locally advanced PA (LAPA).
Patients and Methods
From February 2010 to February 2012, all consecutive patients from 11 French centers treated by FOLFIRINOX for a histologically proven LAPA were prospectively enrolled. Unresectability was defined independently by each center’s multidisciplinary staff at diagnosis. Absence of metastatic disease was confirmed by chest-abdomen-pelvis computed tomography scan. FOLFIRINOX was delivered every 2 weeks as previously reported until progressive disease, major toxicity, or consolidation treatment by radiotherapy and/or surgery.
Results
Seventy-seven patients were enrolled. They received a median number of five cycles (1–30). Grade 3–4 toxicities were neutropenia (11 %), nausea (9 %), diarrhea (6 %), fatigue (6 %), and anemia (1 %). Grade 2–3 sensory neuropathy occurred in 25 % of patients. No toxic death was reported and only 6 % of patients had to stop treatment because of toxicity. Disease control rate was 84 with 28 % of objective response (Response Evaluation Criteria in Solid Tumors). Seventy-five percent of patients received a consolidation therapy: 70 % had radiotherapy and 36 % underwent a surgical resection, with a curative intent. Within the whole cohort, 1-year OS rate was 77 % (95 % CI 65–86) and 1-year progression-free survival rate was 59 % (95 % CI 46–70).
Conclusion
First-line FOLFIRINOX for LAPA seems to be effective and have a manageable toxicity profile. These promising results will have to be confirmed in a phase III randomized trial.
Stigma associated with depression and antidepressants is strong among the general population but also among patients and health professionals.
This cross-sectional study is aimed at: 1) evaluating ...the knowledge and attitude towards antidepressant by nursing student; 2) exploring the association between instruction in psychiatry and representation of depression and antidepressants.
2037 undergraduate students from 10 French nursing schools were invited to participate in 2017, 1475 (73%) completed the questionnaire.
The self-report questionnaire included the Drug Attitude Inventory (DAI) and questions about representation on depression and antidepressant. Four groups of students were built: 1) pre-teaching group (PT) as a reference group, 2) clinical training in psychiatry (CT), 3) receiving mental health theoretical education (TE), 4) receiving both (CT + TE).
The mean (standard deviation) DAI score was negative: -1.9 (±4.4) with only 40% of the nursing students conveying a positive attitude towards antidepressant. A combination of CT and TE was associated with a more positive attitude towards antidepressant in comparison with the PT condition. The CT + TE group was more prone to view antidepressants as effective and safe.
There is strong stigma against depression/antidepressants among nursing student. Education combined with clinical experiences in psychiatry improved these representations.
•60% of the nursing students had a negative attitude to antidepressant.•Students showed a stronger mistrust in antidepressant than general population.•Theoretical education + clinical practicum improved antidepressants representations.
Two ion populations of protonated Rivaroxaban, C19H18ClN3O5S + H+, are separated under pure N2 conditions using differential mobility spectrometry prior to characterization in a hybrid triple ...quadrupole linear ion trap mass spectrometer. These populations are attributed to bare protonated Rivaroxaban and to a proton-bound Rivaroxaban–ammonia complex, which dissociates prior to mass-selecting the parent ion. Ultraviolet photodissociation (UVPD) and collision-induced dissociation (CID) studies indicate that both protonated Rivaroxaban ion populations are comprised of the computed global minimum prototropic isomer. Two ion populations are also observed when the collision environment is modified with 1.5% (v/v) acetonitrile. In this case, the protonated Rivaroxaban ion populations are produced by the dissociation of the ammonium complex and by the dissociation of a proton-bound Rivaroxaban–acetonitrile complex prior to mass selection. Again, both populations exhibit a similar CID behavior; however, UVPD spectra indicate that the two ion populations are associated with different prototropic isomers. The experimentally acquired spectra are compared with computed spectra and are assigned to two prototropic isomers that exhibit proton sharing between distal oxygen centers.
Differential mobility spectrometry (DMS) is an ion mobility technique that has been adopted chiefly as a pre-filter for small- to medium-sized analytes (<1 000 Da). With the exception of a handful of ...studies that employ an analogue of DMS—field asymmetric waveform ion mobility spectroscopy (FAIMS)—the application of DMS to intact biomacromolecules remains largely unexplored. In this work, we employ DMS combined with gas-phase hydrogen deuterium exchange (DMS-HDX) to probe the gas-phase conformations generated from proteins that were initially folded, partially-folded, and unfolded in solution. Our findings indicate that proteins with distinct structural features in solution exhibit unique deuterium uptake profiles as function of their optimal transmission through the DMS. Ultimately we propose that DMS-HDX can, if properly implemented, provide rapid measurements of liquid-phase protein structural stability that could be of use in biopharmaceuticals development.
Graphical Abstract
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Abstract Tinnitus, also called phantom auditory perception, is a major health problem in western countries. As such, a significant amount of effort has been devoted to understanding its mechanisms, ...including studies in animals wherein a supposed “tinnitus state” can be induced. Here, we studied on the same awake animals the effects of a high-dose of salicylate and of an acoustic trauma both at levels known to induce tinnitus. Recordings of cortical activity (local field potentials) from chronically implanted electrodes in the same animals under each condition allowed direct comparison of the effects of salicylate and trauma (noise trauma was carried out several days after full recovery from salicylate administration). Salicylate induced a systematic and reversible increase in amplitude of cortical responses evoked by tone bursts over a wide range of frequencies and intensities. The effects of noise trauma, though much more variable than those of salicylate, resulted in both increases and decreases in the amplitude of cortical responses. These alterations of cortical response amplitudes likely reflect associated hypoacusis and hyperacusis. The effects of salicylate administration and noise trauma on spontaneous activity were also studied. Fourier analysis did not reveal any increase in power within any given frequency band; rather, both treatments induced a decrease of power spectrum over a relatively broad frequency band (∼10–30 Hz). Entropy rate of spontaneous activity, a measure of complexity (temporal correlations), was found to decrease after salicylate but not after acoustic trauma. The present data on evoked potentials confirm salicylate effects at the cortical level and partially extend such effects to acoustic trauma. While the present study showed that both salicylate and noise trauma induced some changes of spontaneous activity in auditory cortex, none of these changes are interpretable in terms of potential neural correlate of tinnitus.
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