Bond dissociation energy of O2 measured by fully state-to-state resolved threshold fragment yield spectra.

We have determined the bond dissociation energy of O2 by measuring fully state-to-state resolved threshold fragment yield spectra in the XUV energy region, O2X3Σg-,N″,J″→O(PJ3)+O(S1o3)/O(S2o5). Our results have yielded a bond dissociation energy value of 41 269.19 ± 0.10 cm-1, which is consistent with previous measurements but exhibits a significantly lower uncertainty, approximately five times smaller. It is noteworthy that this study is the first to simultaneously achieve fine structure state resolution for the parent O2 molecule and spin-orbit state resolution for the O(3PJ) fragments in the measurement of O2 bond dissociation energy. As a result, our findings have established a solid foundation for the obtained data.

Predissociation dynamics of D2 revealed by variation in fragment anisotropy parameters along the Fano profile.

We conducted a study on the variations of the fragment anisotropy parameters (ß) along the Fano profiles for the predissociation of the D2 molecule. These variations, known as ß profiles, were measured for the D(2l) fragments from the predissociation of the 4pπD'Πu1υ'=1 and 4pσB″Σu+1υ'=2 states. The measured ß profiles show significant asymmetry and broader linewidths compared to the corresponding Fano profiles. By fitting the ß profiles, we were able to determine the fragment anisotropy parameters associated with the resonance state, continuum state, and the interference effect between them. Additionally, we determined the ratios of the absorption cross sections between the unperturbed and perturbed continuum states interacting with the resonance states although these ratios were found to be very small. Furthermore, we derived approximate formulas to calculate the parameters characterizing the ß profile. Despite the linewidths of the four Fano profiles being narrower than our instrumental resolution, we were still able to determine the product of the linewidth with the Fano q parameters. These findings demonstrate the utility of the ß profile as an effective tool for studying the predissociation dynamics in diatomic molecules.

AI-assisted mass spectrometry imaging with in situ image segmentation for subcellular metabolomics analysis.

Subcellular metabolomics analysis is crucial for understanding intracellular heterogeneity and accurate drug-cell interactions. Unfortunately, the ultra-small size and complex microenvironment inside the cell pose a great challenge to achieving this goal. To address this challenge, we propose an artificial intelligence-assisted subcellular mass spectrometry imaging (AI-SMSI) strategy with in situ image segmentation. Based on the nanometer-resolution MSI technique, the protonated guanine and threonine ions were respectively employed as the nucleus and cytoplasmic markers to complete image segmentation at the subcellular level, avoiding mutual interference of signals from various compartments in the cell. With advanced AI models, the metabolites within the different regions could be further integrated and profiled. Through this method, we decrypted the distinct action mechanism of isomeric drugs, doxorubicin (DOX) and epirubicin (EPI), only with a stereochemical inversion at C-4'. Within the cytoplasmic region, fifteen specific metabolites were discovered as biomarkers for distinguishing the drug action difference between DOX and EPI. Moreover, we identified that the downregulations of glutamate and aspartate in the malate-aspartate shuttle pathway may contribute to the higher paratoxicity of DOX. Our current AI-SMSI approach has promising applications for subcellular metabolomics analysis and thus opens new opportunities to further explore drug-cell specific interactions for the long-term pursuit of precision medicine.

Bond dissociation energy of N2 measured by state-to-state resolved threshold fragment yield spectra.

The precise determination of the bond dissociation energy of N2 is crucial for thermochemistry database and theoretical calculations. However, there has been ongoing debate regarding its exact value. In this study, we used the velocity map imaging method combined with an extreme ultraviolet laser to measure the threshold fragment yield (TFY) spectra of N2 in the N(2D) + N(2D) photodissociation channels. By integrating the signals within a small circular area on the fragment velocity map images, we were able to obtain TFY spectra at nine different dissociation thresholds. These spectra are rotational state-resolved for the N2(J″) molecules and spin-orbit state-resolved for the dissociation channels involving N(2D) fragments. By employing the Wigner threshold law to simulate the TFY spectra and conducting statistical analysis on the comprehensive dataset, we determined the N2 bond dissociation energy to be 78 691.09 ± 0.15 cm-1. This work now places N2 among the few diatomic molecules with bond dissociation energies measured at sub-wavenumber precision.

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: ß-Protofibril Formed by ß-Hairpin Lateral or Longitudinal Association.

The fibrillar protein deposits of the human islet amyloid polypeptide (hIAPP) in the pancreatic islet of Langerhans are pathological hallmark of type II diabetes. Extensive experimental studies have revealed that the oligomeric formations of the hIAPP are more toxic than the mature fibrils. Exploring the oligomeric conformations in the early aggregation state is valuable for effective therapeutics. In this work, using the all-atom explicit-solvent replica exchange molecular dynamic (REMD) simulations, we investigated the structural features and the assembly mechanisms of the full-length hIAPP trimer in solution. The hIAPP trimer adopted more ß-sheets than a-helix conformations, and three types of ordered conformations including open ß-barrel, single-layer, and double-layer U-shaped ß-sheet structures with five ß-strands were captured in our simulations. A representative single-layer ß-sheet conformation with a CCS value of 1400 Å2 in our simulations matches exactly the experimentally ESI-IMS-MS-derived hIAPP trimer sample. These five ß-strand conformations formed via the ß-hairpin lateral and longitudinal association, respectively, showing two ß-protofibril formation models. To the best of our knowledge, it is the first time to reveal two routes to ß-sheet formation in the hIAPP trimers on the atomic level. The contact probabilities between pairs of the ß-stranded residue show that the hydrophobic interactions between the residues F15 ∼ V17 and A25 ∼ L27 are responsible for the inter- and intra-peptide ß-hairpin formations. All of these results indicate that the ß-sheet formation is the first step in the conformational changes toward pathological aggregation and provides evidence of the ß-sheet assembly mechanism into hIAPP aggregation.

Nanometer Resolution Mass Spectro-Microtomography for In-Depth Anatomical Profiling of Single Cells.

Visually identifying the molecular changes in single cells is of great importance for unraveling fundamental cellular functions as well as disease mechanisms. Herein, we demonstrated a mass spectro-microtomography with an optimal voxel resolution of ∼300 × 300 × 25 nm3, which enables three-dimensional tomography of chemical substances in single cells. This mass imaging method allows for the distinguishment of abundant endogenous and exogenous molecules in subcellular structures. Combined with statistical analysis, we demonstrated this method for spatial metabolomics analysis of drug distribution and subsequent molecular damages caused by intracellular drug action. More interestingly, thanks to the nanoprecision ablation depth (∼12 nm), we realized metabolomics profiling of cell membrane without the interference of cytoplasm and improved the distinction of cancer cells from normal cells. Our current method holds great potential to be a powerful tool for spatially resolved single-cell metabolomics analysis of chemical components during complex biological processes.

Spectra and Predissociation Dynamics of the 4pσB''1∑u+ and 4pπD' 1Πu States of D2.

The spectra and predissociation dynamics of the Rydberg states 4pσB″1∑u+(υ'=2) and 4pπD'1Πu±(υ'=1) of the D2 molecule have been studied by a combination of XUV laser pump, UV laser probe, and velocity map imaging methods. The D(2l) fragment yield spectrum and the D2 excitation spectrum have been measured. Although the predissociation rates were found to be small and comparable to the radiative decay rates, the D(2l) fragments were observed for all the Rydberg states. The measured D(2l) fragment angular distributions are in good agreement with a reported model that has an analytical formula for anisotropy parameters. The results demonstrated that the 4pσB″1∑u+ and 4pπD'1Π u+ states dissociate via direct and indirect coupling with an 1∑u+ state, respectively. For predissociation of the 4pσB″1∑u+ state, the experimental data showed that D(1s) + D(2s) is the main channel, supporting previous theoretical predictions that the predissociation occurs by coupling to the vibrational continuum of the 3pσB'1∑u+ state.

Photodissociation of HCl in the photon energy range 14.6-15.0 eV: Channel-resolved branching ratios and fragment angular distributions.

For the HCl molecule, four photodissociation channels are open in the excitation energy region 14.6-15.0 eV: H(2s) + Cl(2P3/2), H(2p) + Cl(2P3/2), H(2s) + Cl(2P1/2), and H(2p) + Cl(2P1/2). We measured the fragment angular distributions and the branching ratios of the four dissociation channels by using the extreme ultraviolet laser pump and UV laser probe, delay-time-curve, and velocity map imaging methods. The channel-resolved fragment angular distributions and fragment yield spectra show that various Rydberg states (superexcited states) contribute to the absorption cross sections, including the [A2Σ+]4pσ, [A2Σ+]4pπ, [A2Σ+]3dσ, [A2Σ+]3dπ, and [A2Σ+]5sσ states. Most of the H(2s) + Cl(2P1/2) channels correlate with the 1Σ+ states, while the other channels correlate with mixing excitations of the 1Σ+ and 1,3Π states. The channel branching ratios are dependent on the excitation energies. When the four channels are open, the channel branching ratios of H(2s) + Cl(2P3/2) and H(2p) + Cl(2P1/2) are small. Based on the recent ab initio potential energy curves, the Rydberg states converging to the ion-core A2Σ+ are proposed to be predissociated by the nuclear vibrational continua of the Rydberg states converging to the ion-core X2Π.

Predissociation dynamics of D2 + hv→ D(1s1/2) + D(2p1/2,3/2, 2s1/2) revealed by the spin-orbit state resolved fragment branching ratios and angular distributions.

For molecular photodissociations, the spin-orbit state resolved fragment branching ratios and angular distributions provide deep insight into the dynamics. For the first excited state of the H(2p1/2,3/2) atom, a branching ratio measurement is a challenge because of small energy spacing between them. For the D(2p1/2,3/2) fragments from the predissociation of D2 + 14.76 eV → D(1s) + D(2s, 2p1/2,3/2) in the 2pπC1Πu (υ = 19) state, we made such measurements by pumping the D(2s, 2p1/2,3/2) fragments to high-lying Rydberg states that are subsequently ionized by a delayed-pulse electric field. In the 2pπC1Πu (υ = 19) state, the D2 molecule dissociates via both shape and Feshbach resonances correlating to the channels D(1s) + D(2p3/2) and D(1s) + D(2p1/2), respectively. The measured spin-orbit branching ratios, 2p3/2/(2p1/2 + 2p3/2), correspond to the diabatic limit, 2/3, which indicates strong spin-orbit state mixings near the dissociation limits. The spin-orbit state resolved fragment angular distributions also support the diabatic dissociation mechanism and illustrate simultaneous shape and Feshbach resonances for the R(0) transition.

Influence of fullerenol on hIAPP aggregation: amyloid inhibition and mechanistic aspects.

Fullerenols have garnered significant scientific interest in nano-technology and biomedicine. A detailed understanding of their interactions with proteins is fundamentally important for their biomedical applications. Human islet amyloid polypeptide (hIAPP) is an intrinsically disordered protein and its aggregation is associated with type 2 diabetes. Here, we investigated the nano-bio-interactions of fullerenol with hIAPP and focused on the effect of C60(OH)24 on hIAPP aggregation by replica-exchange molecular dynamic simulations. Our simulations show that isolated hIAPP dimers transiently populated amyloid-precursor (ß-hairpin) containing ß-sheet structure, whereas C60(OH)24 completely suppressed this fibril-prone structure, thus inhibiting hIAPP aggregation. The simulation-predicted inhibitory effect of fullerenols was validated by atom force microscopy and thioflavin T fluorescence experiments. We find C60(OH)24 binds to hIAPP via hydrogen bonding interactions with polar residues T9, Q10, N14, N21, N22, N31, N35 and T36 as well as the collective van der Waals and hydrogen-bonding interaction with Y37. Molecular dynamic simulations show that C60(OH)24 destabilized the hIAPP protofibril by mostly binding to the 20SNNFGAILSS29 amyloid core region. This study not only helps to understand the mechanisms involved in hIAPP aggregation and amyloid inhibition, but also provides new clues for the development of therapeutic candidates against type 2 diabetes.

Vacuum Ultraviolet Laser Desorption/Ionization Mass Spectrometry Imaging of Single Cells with Submicron Craters.

Mass spectrometry imaging (MSI) is a crucial label-free method to distinguish the localization patterns in single cells. MALDI-TOF MS and ToF-SIMS are now bearing the responsibility. However, MALDI-TOF MS is limited to micron spatial resolution and ToF-SIMS suffers from severe molecular fragmentation. Here, we proposed a new MSI methodology of vacuum ultraviolet laser desorption/ionization (VUVDI) with high spatial resolution, achieving higher ion yields and less fragmentation compared with ToF-SIMS at submicron level. The fluorescence image and mass spectrum of VUVDI were obtained simultaneously. In addition, the adjustable laser fluence acquired selective detection for different molecular and fragmental ions, thus realizing molecular identification. Furthermore, MSIs of single cells with submicron craters were presented. These results suggest VUVDI is a potential mass spectrometry method that provides a soft ionization source and submicron spatial resolution for molecular analysis in life science.

The Inhibitory Effect of Hydroxylated Carbon Nanotubes on the Aggregation of Human Islet Amyloid Polypeptide Revealed by a Combined Computational and Experimental Study.

Fibrillar deposits formed by the aggregation of the human islet amyloid polypeptide (hIAPP) are the major pathological hallmark of type 2 diabetes mellitus (T2DM). Inhibiting the aggregation of hIAPP is considered the primary therapeutic strategy for the treatment of T2DM. Hydroxylated carbon nanoparticles have received great attention in impeding amyloid protein fibrillation owing to their reduced cytotoxicity compared to the pristine ones. In this study, we investigated the influence of hydroxylated single-walled carbon nanotubes (SWCNT-OHs) on the first step of hIAPP aggregation: dimerization by performing explicit solvent replica exchange molecular dynamics (REMD) simulations. Extensive REMD simulations demonstrate that SWCNT-OHs can dramatically inhibit interpeptide ß-sheet formation and completely suppress the previously reported ß-hairpin amyloidogenic precursor of hIAPP. On the basis of our simulation results, we proposed that SWCNT-OH can hinder hIAPP fibrillation. This was further confirmed by our systematic turbidity measurements, thioflavin T fluorescence, circular dichroism (CD), transmission electron microscope (TEM), and atomic force microscopy (AFM) experiments. Detailed analyses of hIAPP-SWCNT-OH interactions reveal that hydrogen bonding, van der Waals, and π-stacking interactions between hIAPP and SWCNT-OH significantly weaken the inter- and intrapeptide interactions that are crucial for ß-sheet formation. Our collective computational and experimental data reveal not only the inhibitory effect but also the inhibitory mechanism of SWCNT-OH against hIAPP aggregation, thus providing new clues for the development of future drug candidates against T2DM.

A new instrument of VUV laser desorption/ionization mass spectrometry imaging with micrometer spatial resolution and low level of molecular fragmentation.

Mass spectrometry imaging (MSI) has important applications in material research, biology, and medicine. The MSI method based on UV laser desorption/ionization (UVLDI) can obtain images of intact samples, but has a high level of molecular fragmentation. In this work, we report a new MSI instrument that uses a VUV laser (125.3 nm) as a desorption/ionization source to exploit its advantages of high single photon energy and small focus size. The new instrument was tested by the mass spectra of Nile red and FGB (Fibrinogen beta chain) samples and mass spectrometric images of a fly brain section. For the tested samples, the VUVDI method offers lower levels of molecular fragmentations and higher sensitivities than those of the UVLDI method and second ion mass spectrometry imaging method using a Bi3+ beam. The ablation crater produced by the focused VUV laser on a quartz plate has an area of 10 µm2. The VUV laser is prepared based on the four-wave mixing method using three collimated laser beams and a heated Hg cell.

Oscillation of Branching Ratios Between the D(2s)+D(1s) and the D(2p)+D(1s) Channels in Direct Photodissociation of D_{2}.

The direct photodissociation of D_{2} at excitation energies above 14.76 eV occurs via two channels, D(2s)+D(1s) and D(2p)+D(1s). The branching ratios between the two have been measured from the dissociation threshold to 3200 cm^{-1} above it, and it is found that they show cosine oscillations as a function of the fragment wave vector magnitudes. The oscillation is due to an interference effect and can be simulated using the phase difference between the wave functions of the two channels, analogous to Young's double-slit experiment. By fitting the measured branching ratios, we have determined the depths and widths of the effective spherical potential wells related to the two channels, which are in agreement with the effective depths and widths of the ab initio interaction potentials. The results of this Letter illustrate the importance of the relative phase between the fragments in controlling the branching ratios of the photodissociation channels.

Performance of a nonempirical exchange functional from density matrix expansion: comparative study with different correlations.

Recently, Tao and Mo proposed a meta-generalized gradient approximation for the exchange-correlation energy with remarkable accuracy for molecules, solids, and surfaces. To better understand this functional, in this work, we make a comparative study of the TM and TMTPSS functionals, the latter of which is a combination of the TM exchange with the original TPSS correlation functional, on atoms, molecules, and hydrogen-bonded complexes by the use of eight well-known databases. Our calculations show that, while the TMTPSS functional achieves better accuracy for atomization energies or enthalpies of formation, harmonic vibrational frequencies, and atomic excitation energies than the TM functional, it is less accurate for proton affinities, molecular bond lengths, and in particular hydrogen-bonded complexes.

Electronic and Tunneling Predissociations in the 2pπC1Πu±(υ = 19) and 3pπD1Πu±(υ = 4, 5) States of D2 Studied by a Combination of XUV Laser and Velocity Map Imaging.

The predissociation mechanism of D2 near the threshold for the production of the D(2s, 2p) fragments has been studied by measuring the fragment yield spectra, fragment velocity map images, and fragment branching ratios D(2s)/(D(2s) + D(2p)) using a combination of XUV laser and velocity map imaging. The predissociation dynamics of the 2pπC1Πu±(υ = 19) and 3pπD1Πu±(υ = 4,5) states were studied. The 2pπC1Πu±(υ = 19) state is a bound state due to a shallow barrier. For the R(0) transition to the 2pπC1Πu+(υ = 19) state, the experimental results suggest that the predissociation occurs via three channels with decreasing importance: l-uncoupling with the 2pσB1Σu+ state, tunneling, and l-uncoupling with the 3pσB'1Σu+ state. For the R(1) transition to the 2pπC1Πu+(υ = 19) state, the first channel plays the dominant role. For the Q(1) transition to the 2pπC1Πu-(υ = 19) state, the predissociation occurs via tunneling as required by symmetry. For the predissociation of the 3pπD1Πu+(υ = 4,5) states, the experimental data confirm the earlier results indicating that the main perturbing state is 3pσB'1Σu+. The Beutler-Fano profiles and the associated spectroscopic parameters for the various predissociations have also been obtained. The measured Fano-parameters q for the P- and R-branches of the 3pπD1Πu+ state are found to have opposite signs, and their relationships are in agreement with a formula derived from the Fano equation. Rotationally resolved Beutler-Fano profiles were measured for the P(2) and P(3) lines.

Accurate excitation energies of molecules and oligomers from a semilocal density functional.

Excitation energy plays an important role in energy conversion, biological processes, and optical devices. In this work, we apply the Tao-Mo (TM) nonempirical meta-generalized gradient approximation and the combination TMTPSS (TMx + TPSSc), with TPSSc being the correlation part of the original TPSS (Tao-Perdew-Staroverov-Scuseria) to study excitation energies of small molecules and oligomers. Our test set consists of 17 molecules with 134 total excited states, including singlet, triplet, valence, and Rydberg excited states. Our calculation shows that both the TMTPSS and TM functionals yield good overall performance, with mean absolute errors (MAEs) of 0.37 eV and 0.42 eV, respectively, outperforming commonly used semilocal functionals LSDA (MAE = 0.55 eV), PBE (MAE = 0.58 eV), and TPSS (MAE = 0.47 eV). In particular, TMTPSS can yield nearly the same accuracy of B3LYP (MAE = 0.36 eV), with lower computational cost. The accuracy for semilocal density functional theory continues to hold for conjugated oligomers, but they become less accurate than hybrid functionals, due to the insufficient nonlocality.

A rapid screening platform for catalyst discovery in azide-alkyne cycloaddition by ICP-MS/MS.

We developed a rapid high-throughput screening platform using a modified ICP-MS/MS system for monovalence metal ions catalysts discovery in azide-alkyne cycloaddition. Among the ten monovalence metal ions in the first row of periodic table containing Sc+, Ti+, V+, Cr+, Mn+, Fe+, Co+, Ni+, Cu+, and Zn+, five monovalence metal ions of Sc+, Co+, Ni+, Cu+ and Zn+ ions show relatively stronger catalytic activities than others. The catalytic mechanism of Sc+, Co+ and Ni+ ions is similar to the Cu+ ions, but Zn+ ions take a different catalytic route. A yields range of 77-98% for azide-alkyne cycloaddition was achieved with Sc+, Co+, Ni+, Cu+ and Zn+ ions as catalyst, respectively by using a UV laser ablation reactor in 20min, notable that the yields of Co+ and Sc+ ions were even higher than the common catalyst of Cu+ ions. The proposed platform would be used not only for catalyst discovery in azide-alkyne cycloaddition, but also for the discovery of single atom/ion catalysts in other organic reactions.

Performance of a nonempirical density functional on molecules and hydrogen-bonded complexes.

Recently, Tao and Mo derived a meta-generalized gradient approximation functional based on a model exchange-correlation hole. In this work, the performance of this functional is assessed on standard test sets, using the 6-311++G(3df,3pd) basis set. These test sets include 223 G3/99 enthalpies of formation, 99 atomization energies, 76 barrier heights, 58 electron affinities, 8 proton affinities, 96 bond lengths, 82 harmonic vibrational frequencies, 10 hydrogen-bonded molecular complexes, and 22 atomic excitation energies. Our calculations show that the Tao-Mo functional can achieve high accuracy for most properties considered, relative to the local spin-density approximation, Perdew-Burke-Ernzerhof, and Tao-Perdew-Staroverov-Scuseria functionals. In particular, it yields the best accuracy for proton affinities, harmonic vibrational frequencies, hydrogen-bond dissociation energies and bond lengths, and atomic excitation energies.