Probing the dynamics of the photo-induced decarboxylation of neutral and ionic pyruvic acid.

The dynamics of the electronically excited pyruvic acid (PA) and of its unimolecular decomposition upon single photon ionisation are investigated by means of a table top fs laser and VUV synchrotron radiation. The latter is coupled with photo-ion/photo-electron coincidence acquisition devices that allow the identification of the ionic products coming from state-to-state fragmentation upon ionisation. The fs-based setup provides time-resolved mass spectra with 266 nm (= 4.661 eV) excitation and an 800 nm multiphoton probe. For interpretation, we carried out theoretical computations using a composite scheme combining density functional theory full molecular geometric optimisation and post-Hartree-Fock correction inclusion. We therefore determined the neutral and ionic species formed during these experiments and the corresponding dissociation channels. Although several PA isomers are found, we show that solely the most stable isomer of PA (i.e. Tc) is present in the molecular beam prior to ionisation. We determined its adiabatic ionisation energy (AIE = 10.031 ± 0.005 eV). The fragmentation of the Tc+ ion occurs at ∼0.4 eV above the threshold and it is dominated by the CC bond breaking channel, forming the HOCO fragment in conjunction with the CH3CO+ ion. The decarboxylation of Tc+ channels has a minor contribution, although they are more favourable thermodynamically. These findings are in contrast with the dominance of decarboxylation while fragmenting Tc populated in the S1-S3 states. For explanation, we invoke an indirect process populating first a short lived autoionising neutral state located in energy at the HOCO + CH3CO+ dissociation limit. Later on, fragmentation occurs, followed by autoionisation. On the other hand, the fs-based experiment does not reveal any appreciable dynamics for the Tc isomer of PA after a 266 nm excitation because of non-favourable Franck-Condon factors at this energy. In sum, our work highlights the importance of the couplings between the parent ion vibrational modes and the dissociative channels in the vicinity of the loss ionic fragmentation thresholds.

Prognostic Value of Preoperative MRI Metrics for Diffuse Lower-Grade Glioma Molecular Subtypes.

BACKGROUND AND PURPOSE: Despite the improved prognostic relevance of the 2016 WHO molecular-based classification of lower-grade gliomas, variability in clinical outcome persists within existing molecular subtypes. Our aim was to determine prognostically significant metrics on preoperative MR imaging for lower-grade gliomas within currently defined molecular categories. MATERIALS AND METHODS: We undertook a retrospective analysis of 306 patients with lower-grade gliomas accrued from an institutional data base and The Cancer Genome Atlas. Two neuroradiologists in consensus analyzed preoperative MRIs of each lower-grade glioma to determine the following: tumor size, tumor location, number of involved lobes, corpus callosum involvement, hydrocephalus, midline shift, eloquent cortex involvement, ependymal extension, margins, contrast enhancement, and necrosis. Adjusted hazard ratios determined the association between MR imaging metrics and overall survival per molecular subtype, after adjustment for patient age, patient sex, World Health Organization grade, and surgical resection status. RESULTS: For isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas, tumor size (hazard ratio, 3.82; 95% CI, 1.94-7.75; P < .001), number of involved lobes (hazard ratio, 1.70; 95% CI, 1.28-2.27; P < .001), hydrocephalus (hazard ratio, 4.43; 95% CI, 1.12-17.54; P = .034), midline shift (hazard ratio, 1.16; 95% CI, 1.03-1.30; P = .013), margins (P = .031), and contrast enhancement (hazard ratio, 0.34; 95% CI, 0.13-0.90; P = .030) were associated with overall survival. For IDH-mutant 1p/19q-codeleted lower-grade gliomas, tumor size (hazard ratio, 2.85; 95% CI, 1.06-7.70; P = .039) and ependymal extension (hazard ratio, 6.34; 95% CI, 1.07-37.59; P = .042) were associated with overall survival. CONCLUSIONS: MR imaging metrics offers prognostic information for patients with lower-grade gliomas within molecularly defined classes, with the greatest prognostic value for IDH wild-type lower-grade gliomas.

Urinary and Plasma Metabolomics Identify the Distinct Metabolic Profile of Disease State in Chronic Mouse Model of Multiple Sclerosis.

Identification of non-invasive biomarkers of disease progression in multiple sclerosis (MS) is critically needed for monitoring the disease progression and for effective therapeutic interventions. Urine is an attractive source for non-invasive biomarkers because it is easily obtained in the clinic. In search of a urine metabolite signature of progression in chronic experimental autoimmune encephalomyelitis (EAE), we profiled urine at the chronic stage of the disease (day 45 post immunization) by global untargeted metabolomics. Using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry, we found 105 metabolites (P < 0.05) significantly altered at the chronic stage, indicating a robust alteration in the urine metabolite profile during disease. Assessment of altered metabolites against the Kyoto Encyclopedia of Genes and Genomes revealed distinct non-overlapping metabolic pathways and revealed phenylalanine-tyrosine and associated metabolism being the most impacted. Combined with previously performed plasma profiling, eight common metabolites were significantly altered in both of the biofluids. Metaboanalyst analysis of these common metabolites revealed that phenylalanine metabolism and Valine, leucine, and isoleucine biosynthetic pathways are central metabolic pathways in both bio-fluids and could be analyzed further, either for the discovery of therapeutics or biomarker development. Overall, our study suggests that urine and plasma metabolomics may contribute to the identification of a distinct metabolic fingerprint of EAE disease discriminating from the healthy control which may aid in the development of an objective non-invasive monitoring method for progressive autoimmune diseases like MS. Graphical Abstract Untargeted urinary metabolomics of a chronic mouse model of multiple sclerosis identified Phenylalanine, tyrosine & tryptophan metabolism as the significantly altered metabolic pathway. Eight common metabolites were identified when we combined urinary and plasma metabolic signature, which revealed a perturbation of Phenylalanine metabolism and valine, leucine & isoleucine metabolic pathways, involved in CNS dysfunction during diseases. The identified eight metabolic signature of urine and plasma may be of clinical relevance as potential biomarkers and guide towards the identification of specific metabolic pathways as novel drug targets.

A HElium NanoDroplet Isolation (HENDI) investigation of the weak hydrogen bonding in the propyne dimer (CH3CCH)2.

A HElium Nanodroplet Isolation (HENDI) experiment was performed to explore the absorption spectra of the propyne monomer (CH3CCH), dimer and (CH3CCH)≥3 multimers in the vicinity of the CH stretch region ν1 of the monomer. Ab initio calculations were performed at the MP2 level to document the potential energy surface of the dimer. This provided the necessary parameters to simulate the absorption spectrum of the dimer and thus facilitate the interpretation of the experiment. The central result was to observe three isomers of the dimer, hence reflecting the complexity of the weak CHπ H-bonding when several H-donors are at play.

Predicting Genotype and Survival in Glioma Using Standard Clinical MR Imaging Apparent Diffusion Coefficient Images: A Pilot Study from The Cancer Genome Atlas.

BACKGROUND AND PURPOSE: Few studies have shown MR imaging features and ADC correlating with molecular markers and survival in patients with glioma. Our purpose was to correlate MR imaging features and ADC with molecular subtyping and survival in adult diffuse gliomas. MATERIALS AND METHODS: Presurgical MRIs and ADC maps of 131 patients with diffuse gliomas and available molecular and survival data from The Cancer Genome Atlas were reviewed. MR imaging features, ADC (obtained by ROIs within the lowest ADC area), and mean relative ADC values were evaluated to predict isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion status, MGMT promoter methylation, and overall survival. RESULTS: IDH wild-type gliomas tended to exhibit enhancement, necrosis, and edema; >50% enhancing area (P < .001); absence of a cystic area (P = .013); and lower mean relative ADC (median, 1.1 versus 1.6; P < .001) than IDH-mutant gliomas. By means of a cutoff value of 1.08 for mean relative ADC, IDH-mutant and IDH wild-type gliomas with lower mean relative ADC (<1.08) had poorer survival than those with higher mean relative ADC (median survival time, 24.2 months; 95% CI, 0.0-54.9 months versus 62.0 months; P = .003; and median survival time, 10.4 months; 95% CI, 4.4-16.4 months versus 17.7 months; 95% CI, 11.6-23.7 months; P = .041, respectively), regardless of World Health Organization grade. Median survival of those with IDH-mutant glioma with low mean relative ADC was not significantly different from that in those with IDH wild-type glioma. Other MR imaging features were not statistically significant predictors of survival. CONCLUSIONS: IDH wild-type glioma showed lower ADC values, which also correlated with poor survival in both IDH-mutant and IDH wild-type gliomas, irrespective of histologic grade. A subgroup with IDH-mutant gliomas with lower ADC had dismal survival similar to that of those with IDH wild-type gliomas.

CSF Pressure Change in Relation to Opening Pressure and CSF Volume Removed.

BACKGROUND AND PURPOSE: Idiopathic intracranial hypertension is a complex neurologic disorder resulting from increased intracranial pressure. Our aim was to determine whether a correlation exists between the CSF pressure-volume relationship, specifically the craniospinal elastance and pressure-volume index, in patients with idiopathic intracranial hypertension and whether opening pressure affects this relationship. MATERIALS AND METHODS: Lumbar punctures performed for suspected idiopathic intracranial hypertension from 2006 to 2017 were identified. Opening and closing pressures, CSF volume removed, and clinical diagnosis of idiopathic intracranial hypertension were obtained from the medical records. The craniospinal elastance (pressure change per milliliter of CSF removed) and pressure-volume index were calculated, and the Pearson correlation coefficients between both the craniospinal elastance and pressure-volume index and opening pressure were determined. Linear regression models of craniospinal elastance and the pressure-volume index and interaction terms with opening pressure were assessed for covariate influence on this association. RESULTS: One hundred sixteen patients were included in the final analysis. The mean craniospinal elastance according to opening pressure group was 0.52 ± 0.18 for <20 cm H2O, 0.57 ± 0.20 for 20-29 cm H2O, 0.91 ± 0.28 for 30-39 cm H2O, and 1.20 ± 0.25 for ≥40 cm H2O. There was a positive linear association between opening pressure and craniospinal elastance with a 0.28 cm H2O/mL increase in craniospinal elastance (standard error = 0.03, P < .001) for every 10 cm H2O increase in opening pressure. Of the covariables analyzed, only age older than 50 years and total volume of CSF removed affected this association. CONCLUSIONS: As opening pressure increases, the craniospinal elastance increases in a linear fashion while the pressure-volume index decreases. Further studies are needed to determine whether these changes relate to the underlying pathophysiology of idiopathic intracranial hypertension or simply represent established CSF volume pressure dynamics.

Deep-Learning Convolutional Neural Networks Accurately Classify Genetic Mutations in Gliomas.

BACKGROUND AND PURPOSE: The World Health Organization has recently placed new emphasis on the integration of genetic information for gliomas. While tissue sampling remains the criterion standard, noninvasive imaging techniques may provide complimentary insight into clinically relevant genetic mutations. Our aim was to train a convolutional neural network to independently predict underlying molecular genetic mutation status in gliomas with high accuracy and identify the most predictive imaging features for each mutation. MATERIALS AND METHODS: MR imaging data and molecular information were retrospectively obtained from The Cancer Imaging Archives for 259 patients with either low- or high-grade gliomas. A convolutional neural network was trained to classify isocitrate dehydrogenase 1 (IDH1) mutation status, 1p/19q codeletion, and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status. Principal component analysis of the final convolutional neural network layer was used to extract the key imaging features critical for successful classification. RESULTS: Classification had high accuracy: IDH1 mutation status, 94%; 1p/19q codeletion, 92%; and MGMT promotor methylation status, 83%. Each genetic category was also associated with distinctive imaging features such as definition of tumor margins, T1 and FLAIR suppression, extent of edema, extent of necrosis, and textural features. CONCLUSIONS: Our results indicate that for The Cancer Imaging Archives dataset, machine-learning approaches allow classification of individual genetic mutations of both low- and high-grade gliomas. We show that relevant MR imaging features acquired from an added dimensionality-reduction technique demonstrate that neural networks are capable of learning key imaging components without prior feature selection or human-directed training.

Dynamics of acetylene dimers hosted in helium droplets.

The CH antisymmetric stretch of the C2H2 moieties in acetylene dimers was explored over the range 3270-3290 cm-1 using the helium nanodroplet isolation (HENDI) technique. This work is part of a general investigation which addresses the dynamical consequences of coupling the deformation motions of weakly bound complexes with a finite size quantum liquid (the helium droplet). The acetylene dimer is attractive from this point of view because one of its deformation coordinates promotes a tunneling isomerization process. A numerical simulation of the observed spectrum allows deriving a set of effective spectroscopic constants which help understanding the dynamical role played by the droplet on the rotation and deformation of the dimer.

Femtosecond time-resolved photoelectron spectroscopy of the benzyl radical.

We present a joint experimental and computational study of the nonradiative deactivation of the benzyl radical, C7H7, after UV excitation. Femtosecond time-resolved photoelectron imaging was applied to investigate the photodynamics of the radical. The experiments were accompanied by excited state dynamics simulations using surface hopping. Benzyl has been excited at 265 nm into the D-band (ππ*) and the dynamics was probed using probe wavelengths of 398 nm or 798 nm. At a probe wavelength of 398 nm a single time constant of around 70-80 fs was observed. When the dynamics was probed at 798 nm, a second time constant τ2 = 1.5 ps was visible, which can be attributed to further non-radiative deactivation to the lower-lying D1/D2 states.

Multipronged mapping to the dynamics of a barium atom deposited on argon clusters.

The dynamics of an electronically excited barium atom deposited at the surface of an Ar≈500 cluster was explored in a multipronged approach which associates information from frequency-resolved nanosecond experiments and information from femtosecond time-resolved experiments. In both types of experiments, the dynamics is monitored by photoelectron and photoion spectroscopy.

Large amplitude motion of the acetylene molecule within acetylene-neon complexes hosted in helium droplets.

Superfluid helium droplets provide an ideal environment for spectroscopic studies with rotational resolution. Nevertheless, the molecular rotation is hindered because the embedded molecules are surrounded by a non-superfluid component. The present work explores the dynamical role of this component in the hindered rotation of C2H2 within the C2H2-Ne complex. A HENDI experiment was built and near-infrared spectroscopy of C2H2-Ne and C2H2 was performed in the spectral region overlapping the ν3/ν2 + ν4 + ν5 Fermi-type resonance of C2H2. The comparison between measured and simulated spectra helped to address the above issue.

Spectroscopy and Dynamics of K Atoms on Argon Clusters.

We present a combined experimental and simulation study of the 4s → 4p photoexcitation of the K atom trapped at the surface of ArN clusters made of a few hundred Ar atoms. Our experimental method based on photoelectron spectroscopy allows us to firmly establish that one single K atom is trapped at the surface of the cluster. The absorption spectrum is characterized by the splitting of the atomic absorption line into two broad bands, a Π band associated with p orbitals parallel to the cluster surface and a Σ band associated with the perpendicular orientation. The spectrum is consistent with observations reported for K atoms trapped on lighter inert gas clusters, but the splitting between the Π and Σ bands is significantly larger. We show that a large amount of K atoms are transiently stuck and eventually lost by the Ar cluster, in contrast with previous observations reported for alkaline earth metal systems. The excitation in the Σ band leads systematically to the ejection of the K atom from the Ar cluster. On the contrary, excitation in the Π band leads to the formation of a bound state. In this case, the analysis of the experimental photoelectron spectrum by means of nonadiabatic molecular dynamics simulation shows that the relaxation drives the system toward a basin where the coordination of the K atom is 2.2 Ar atoms on the average, in a poorly structured surface.

Reactive and Inelastic Channels in the Ca*···FCH3 Transition State: A Simple Branching Mechanism.

To study the excited state dynamics between a calcium atom and the CH3F molecule, a Ca···CH3F 1:1 complex has been prepared by a supersonic expansion with laser ablation of calcium metal in the gas phase. Tunable laser excitation of these complexes in molecular states correlating to Ca (1)P1(4s4p) + CH3F allows observing two competitive channels: the direct dissociation and the reactive channel into CaF* + CH3. The translational recoil, as well as the alignment of the fragments Ca* and CaF* have been analyzed by velocity map imaging and time-of-flight mass spectrometry. This revealed that both the dissociation and reaction processes are quasi direct and are of comparable intensity. We provide a simple interpretation for this process: the electronically excited potential surface of the Ca*···FCH3 complex initiates a fast predissociation from a suspended well to two repulsive surfaces that lead either to Ca (1)P1(4s4p) (Ω = 1) + CH3F or to CaF((2)Δ) + CH3.

A Multipronged Comparative Study of the Ultraviolet Photochemistry of 2-, 3-, and 4-Chlorophenol in the Gas Phase.

The S1((1)ππ*) state of the (dominant) syn-conformer of 2-chlorophenol (2-ClPhOH) in the gas phase has a subpicosecond lifetime, whereas the corresponding S1 states of 3- and 4-ClPhOH have lifetimes that are, respectively, ∼2 and ∼3-orders of magnitude longer. A range of experimental techniques-electronic spectroscopy, ultrafast time-resolved photoion and photoelectron spectroscopies, H Rydberg atom photofragment translational spectroscopy, velocity map imaging, and time-resolved Fourier transform infrared emission spectroscopy-as well as electronic structure calculations (of key regions of the multidimensional ground (S0) state potential energy surface (PES) and selected cuts through the first few excited singlet PESs) have been used in the quest to explain these striking differences in excited state lifetime. The intramolecular O-H···Cl hydrogen bond specific to syn-2-ClPhOH is key. It encourages partial charge transfer and preferential stabilization of the diabatic (1)πσ* potential (relative to that of the (1)ππ* state) upon stretching the C-Cl bond, with the result that initial C-Cl bond extension on the adiabatic S1 PES offers an essentially barrierless internal conversion pathway via regions of conical intersection with the S0 PES. Intramolecular hydrogen bonding is thus seen to facilitate the type of heterolytic dissociation more typically encountered in solution studies.

VUV photoionization and dissociative photoionization of the prebiotic molecule acetyl cyanide: theory and experiment.

The present combined theoretical and experimental investigation concerns the single photoionization of gas-phase acetyl cyanide and the fragmentation pathways of the resulting cation. Acetyl cyanide (AC) is inspired from both the chemistry of cyanoacetylene and the Strecker reaction which are thought to be at the origin of medium sized prebiotic molecules in the interstellar medium. AC can be formed by reaction from cyanoacetylene and water but also from acetaldehyde and HCN or the corresponding radicals. In view of the interpretation of vacuum ultraviolet (VUV) experimental data obtained using synchrotron radiation, we explored the ground potential energy surface (PES) of acetyl cyanide and of its cation using standard and recently implemented explicitly correlated methodologies. Our PES covers the regions of tautomerism (between keto and enol forms) and of the lowest fragmentation channels. This allowed us to deduce accurate thermochemical data for this astrobiologically relevant molecule. Unimolecular decomposition of the AC cation turns out to be very complex. The implications for the evolution of prebiotic molecules under VUV irradiation are discussed.

Coupled electronic and structural relaxation pathways in the postexcitation dynamics of Rydberg states of BaArN clusters.

We investigate, theoretically, the joint relaxation of orbital and structure in postexcitation dynamics of Rydberg states of cluster BaArN (N=250). Mixed quantum-classical dynamics is used to account for the nonadiabatic transitions among more than 160 electronic states, represented via a diatomics-in-molecules Hamiltonian. The simulation illustrates the complex multistep relaxation processes and provides detailed insight in the mechanisms contributing to the final-time experimental photoelectron spectrum.

VUV photoionization of gas phase adenine and cytosine: a comparison between oven and aerosol vaporization.

We studied the single photon ionization of gas phase adenine and cytosine by means of vacuum ultraviolet synchrotron radiation coupled to a velocity map imaging electron∕ion coincidence spectrometer. Both in-vacuum temperature-controlled oven and aerosol thermodesorption were successfully applied to promote the intact neutral biological species into the gas phase. The photoion yields are consistent with previous measurements. In addition, we deduced the threshold photoelectron spectra and the slow photoelectron spectra for both species, where the close to zero kinetic energy photoelectrons and the corresponding photoions are measured in coincidence. The photoionization close and above the ionization energies are found to occur mainly via direct processes. Both vaporization techniques lead to similar electronic spectra for the two molecules, which consist of broadbands due to the complex electronic structure of the cationic species and to the possible contribution of several neutral tautomers for cytosine prior to ionization. Accurate ionization energies are measured for adenine and cytosine at, respectively, 8.267 ± 0.005 eV and 8.66 ± 0.01 eV, and we deduce precise thermochemical data for the adenine radical cation. Finally, we performed an evaluation and a comparison of the two vaporization techniques addressing the following criteria: measurement precision, thermal fragmentation, sensitivity, and sample consumption. The aerosol thermodesorption technique appears as a promising alternative to vaporize large thermolabile biological compounds, where extended thermal decomposition or low sensitivity could be encountered when using a simple oven vaporization technique.

State-selected unimolecular decomposition of δ-valerolactam+ and δ-valerolactam2+ cations: theory and experiment.

The near threshold photofragmentation pattern of δ-valerolactam(+) and δ-valerolactam(2)(+) has been recorded combining electron/ion coincidence techniques and vacuum ultraviolet synchrotron radiation. The experimental method yields the fragment intensity as a function of the internal energy deposited into the parent cation, up to 3.1 eV above the first ionization threshold. In parallel, ab initio studies on the δ-valerolactam(+) and δ-valerolactam(2)(+) cations and their ionic and neutral fragmentation products have been performed with the aim of determining the isomers of the ionic products observed experimentally as well as of their neutral counterparts. These computations were performed using the PBE0 exchange-correlation functional and the aug-cc-pVDZ basis set. We found good agreement between the calculated reaction enthalpies and experimental appearance energies of the ions. More generally, our experimental and theoretical results reveal that the fragmentation of the ionic species of interest leads to a multitude of neutral and ionic fragments, which may be formed after intramolecular isomerization and complex decomposition processes. Multistep reaction pathways are expected.

Correlation of perfusion parameters with genes related to angiogenesis regulation in glioblastoma: a feasibility study.

BACKGROUND AND PURPOSE: Integration of imaging and genomic data is critical for a better understanding of gliomas, particularly considering the increasing focus on the use of imaging biomarkers for patient survival and treatment response. The purpose of this study was to correlate CBV and PS measured by using PCT with the genes regulating angiogenesis in GBM. MATERIALS AND METHODS: Eighteen patients with WHO grade IV gliomas underwent pretreatment PCT and measurement of CBV and PS values from enhancing tumor. Tumor specimens were analyzed by TCGA by using Human Gene Expression Microarrays and were interrogated for correlation between CBV and PS estimates across the genome. We used the GO biologic process pathways for angiogenesis regulation to select genes of interest. RESULTS: We observed expression levels for 92 angiogenesis-associated genes (332 probes), 19 of which had significant correlation with PS and 9 of which had significant correlation with CBV (P < .05). Proangiogenic genes such as TNFRSF1A (PS = 0.53, P = .024), HIF1A (PS = 0.62, P = .0065), KDR (CBV = 0.60, P = .0084; PS = 0.59, P = .0097), TIE1 (CBV = 0.54, P = .022; PS = 0.49, P = .039), and TIE2/TEK (CBV = 0.58, P = .012) showed a significant positive correlation; whereas antiangiogenic genes such as VASH2 (PS = -0.72, P = .00011) showed a significant inverse correlation. CONCLUSIONS: Our findings are provocative, with some of the proangiogenic genes showing a positive correlation and some of the antiangiogenic genes showing an inverse correlation with tumor perfusion parameters, suggesting a molecular basis for these imaging biomarkers; however, this should be confirmed in a larger patient population.