Capturing electron-driven chiral dynamics in UV-excited molecules.

Chiral molecules, used in applications such as enantioselective photocatalysis1, circularly polarized light detection2 and emission3 and molecular switches4,5, exist in two geometrical configurations that are non-superimposable mirror images of each other. These so-called (R) and (S) enantiomers exhibit different physical and chemical properties when interacting with other chiral entities. Attosecond technology might enable influence over such interactions, given that it can probe and even direct electron motion within molecules on the intrinsic electronic timescale6 and thereby control reactivity7-9. Electron currents in photoexcited chiral molecules have indeed been predicted to enable enantiosensitive molecular orientation10, but electron-driven chiral dynamics in neutral molecules have not yet been demonstrated owing to the lack of ultrashort, non-ionizing and perturbative light pulses. Here we use time-resolved photoelectron circular dichroism (TR-PECD)11-15 with an unprecedented temporal resolution of 2.9 fs to map the coherent electronic motion initiated by ultraviolet (UV) excitation of neutral chiral molecules. We find that electronic beatings between Rydberg states lead to periodic modulations of the chiroptical response on the few-femtosecond timescale, showing a sign inversion in less than 10 fs. Calculations validate this and also confirm that the combination of the photoinduced chiral current with a circularly polarized probe pulse realizes an enantioselective filter of molecular orientations following photoionization. We anticipate that our approach will enable further investigations of ultrafast electron dynamics in chiral systems and reveal a route towards enantiosensitive charge-directed reactivity.

Positive psychological effects of seated acupressure massage are associated with a rise in plasma oxytocin without affecting CGRP levels or circulating IL-6.

Work-related stress is a major public health issue. Given the relationship between acute stress responses and health, finding strategies to deal with the unpleasant symptoms brought on by stress is essential. Massage therapy is a popular stress-reduction technique, but its effectiveness has yet to be shown. In that matter, this study investigates the effects of a 17-minute session of seated Amma massage on young healthy people. Subjective stress perception, anxiety and self-confidence were assessed before and after the massage using the Spielberger State Anxiety Scale (STAI-Y, Spielberger et al., 1983) and the Competitive State Anxiety Inventory (EEAC, Cury et al., 1999), together with cardiovascular parameters. Cortisol, CGRP, IL-6, and oxytocin plasma levels were measured before and after the massage to investigate its possible mode of action. This study enrolled 59 people: 33 receiving the massage, and 26 controls only seated on the massage chair. Interaction Time x Group demonstrates significant differences for all psychological measurements (STAI, EEAC) before and after the Amma massage, showing a beneficial effect of this treatment, in particular on perceived anxiety and self-confidence. No evidence was found of any correlation between cortisol plasma levels and psychological outcomes. No relationship was shown between the decrease of perceived stress and measured CGRP or IL-6 release, but the data demonstrated that heart frequency could be slightly decreased. The oxytocin plasma levels were significantly increased by the massage and could be responsible for the recovery of psychological outcomes. We conclude that seated acupressure Amma massage could be a useful tool to ameliorate quality of life at work.

Dihydropyrene/Cyclophanediene Photoswitching Mechanism Revisited with Spin-Flip Time-Dependent Density Functional Theory: Nature of the Photoisomerization Funnel at Stake!

The complex photoisomerization mechanism of the dihydropyrene (DHP) photochromic system is revisited using spin-flip time-dependent density functional theory (SF-TD-DFT). The photoinduced ring-opening reaction of DHP into its cyclophanediene isomer involves multiple coupled electronic states of different character. A balanced treatment of both static and dynamic electron correlations is required to determine both the photophysical and photochemical paths in this system. The present results provide a refinement of the mechanistic picture provided in a previous complete active space self-consistent field plus second-order perturbation theory (CASPT2//CASSCF) study based on geometry optimizations at the CASSCF level. In particular, the nature of the conical intersection playing the central role of the photochemical funnel is different. While at the CASSCF level, the crossing with the ground state involves a covalent doubly excited state leading to a three-electron/three-center bond conical intersection, SF-TD-DFT predicts a crossing between the ground state and a zwitterionic state. These results are supported by multi-state CASPT2 calculations. This study illustrates the importance of optimizing conical intersections at a sufficiently correlated level of theory to describe a photochemical path involving crossings between covalent and ionic states.

Absorption band structure of the photochromic dimethyldihydropyrene/metacyclophanediene couple. Insight from vibronic coupling theory.

A detailed insight behind the structure of absorption bands of the photochromic couple dimethyldihydropyrene (DHP)/metacyclophanediene (CPD) is studied employing vibronic coupling theory. Two separate model molecular Hamiltonians, including a maximum of four electronic states and 18 vibrational modes for DHP and five electronic states and 20 vibrational modes for CPD, are constructed in a diabatic electronic representation. The parameters of the Hamiltonians are estimated from the electronic energies obtained from extensive density functional theory (DFT) and time-dependent DFT calculations. Based on these Hamiltonians' parameters, a detailed analysis of potential energy curves is performed in conjunction with positional and energetic locations of several stationary points in multi-dimensional potential energy surfaces. Based on the results of electronic structure calculations, quantum nuclear dynamics studies on the electronic excited states of DHP and CPD are performed to understand the impact of non-adiabatic effects on the formation of vibronic structures of absorption bands of these photo-isomers.

Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors.

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates respiratory epithelium through angiotensin-converting enzyme-2 binding, raising concerns about the potentially harmful effects of renin-angiotensin system inhibitors (RASi) on Human Coronavirus Disease 2019 (COVID-19) evolution. This study aimed to provide insight into the impact of RASi on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 943 COVID-19 patients were admitted to our institution, of whom 772 were included in this analysis. Among them, 431 (55.8%) had previously known hypertension. The median age was 68 (56-79) years. Overall, 220 (28.5%) patients were placed under mechanical ventilation and 173 (22.4%) died. According to previous exposure to RASi, we defined two groups, namely, "RASi" (n = 282) and "RASi-free" (n = 490). Severe pneumonia (defined as leading to death and/or requiring intubation, high-flow nasal oxygen, noninvasive ventilation, and/or oxygen flow at a rate of ≥5 L/min) and death occurred more frequently in RASi-treated patients (64% versus 53% and 29% versus 19%, respectively). However, in a propensity score-matched cohort derived from the overall population, neither death (hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.57-1.50), p = 0.76) nor severe pneumonia (HR 1.03 (95%CI 0.73-1.44), p = 0.85) were associated with RASi therapy. (4) Conclusion: Our study showed no correlation between previous RASi treatment and death or severe COVID-19 pneumonia after adjustment for confounders.

Dependency of the Dimethyldihydropyrene Photochromic Properties on the Number of Pyridinium Electron-Withdrawing Groups.

Photochromic dimethyldihydropyrenes substituted with electron-withdrawing pyridinium groups have shown an increase of photo-induced ring-opening efficiency and a light sensitivity that is red shifted relative to the unsubstituted compound. However, a recently synthesized tetrapyridinium derivative showed a considerable decrease of the photo-isomerization quantum yield relative to the monopyridinium and bispyridinium derivatives. We provide a rationale for this unexpected photochemical behavior based on the comparative theoretical investigations of the relevant excited states of these systems. In particular, we found that the nature and order of the lowest two excited states depend on the number of pyridinium groups and on the symmetry of the system. While the lowest S1 excited state is photo-active in the monopyridinium and bispyridinium derivatives, the photo-isomerizing state is S2 in the reference unsubstituted compound and both S1 and S2 lead to isomerization in the tetrapyridinium derivative, albeit with a low efficiency. In the latter derivative, the photo-isomerization is hindered by the particular S1 /S2 conical intersection topology.

Electronic Excited States and UV-Vis Absorption Spectra of the Dihydropyrene/Cyclophanediene Photochromic Couple: a Theoretical Investigation.

Dihydropyrene (DHP)/cyclophanediene (CPD) is a fascinating photoswitchable organic system displaying negative photochromism. Upon irradiation in the visible region, the colored DHP can be converted to its open-ring CPD colorless isomer, which can be converted back to DHP by UV light. DHP and CPD thus possess very different absorption spectra whose absorption bands have never been assigned in detail so far. In this work, we characterize the vertical electronic transitions of the first six and seven excited states of DHP and CPD, respectively, aiming for a realistic comparison with experiment. We used state-of-the-art electronic structure methods [e.g., complete active space second-order perturbation theory (CASPT2), n-electron valence-state perturbation theory (NEVPT2), extended multiconfigurational quasi-degenerate perturbation theory (XMCQDPT2), and third-order algebraic diagrammatic construction ADC(3)] capable of describing differential electron correlation. Vertical transition energies were also computed with time-dependent density functional theory (TD-DFT) and compared to these accurate methods. After the reliability of TD-DFT was validated for the main optical transitions, this efficient method was used to simulate the absorption spectra of DHP and CPD in the framework of the Franck-Condon Herzberg-Teller approximation and also using the nuclear ensemble approach. Overall, for both methods, the simulated absorption spectra reproduce nicely the main spectral features of the DHP and CPD isomers, that is, the main four absorption bands of increasing intensity of DHP and the absorption rise below 300 nm for CPD.

Pulmonary Embolism and Coexisting Deep Vein Thrombosis: A Detrimental Association?

BACKGROUND: The prognostic significance of coexisting deep vein thrombosis (DVT) in acute pulmonary embolism (PE) is controversial. This study aimed to provide routine patient care data on the impact of this association on PE severity and 3-month outcomes in a population presenting with symptomatic venous thromboembolism (VTE) from the REMOTEV registry. METHODS AND RESULTS: REMOTEV is a prospective, non-interventional study of patients with acute symptomatic VTE, treated with direct oral anticoagulants (DOACs) or standard anticoagulation (vitamin K antagonists (VKA) or parenteral heparin/fondaparinux alone) for at least 3 months. From 1 November 2013 to 28 February 2018, among 1241 consecutive patients included, 1192 had a follow-up of at least 3 months and, among them, 1037 had PE with (727) or without DVT (310). The median age was 69 (55-80, 25th-75th percentiles). Patients with PE-associated DVT had more severe forms of PE (p < 0.0001) and, when DVT was present, proximal location was significantly correlated to PE severity (p < 0.01). However, no difference in all-cause mortality rate (hazard ratio (HR) 1.36 (CI 95% 0.69-2.92)), nor in the composite criterion of all-cause mortality and recurrence rate (HR 1.56 (CI 95% 0.83-3.10)) was noted at 3 months of follow-up. CONCLUSION: In REMOTEV, coexisting DVT was associated with a higher severity of PE, with no impact on short-term prognosis.

RASPT2 study of the valence excited states of an iron-porphyrin-carbonyl model complex.

Multireference wavefunction calculations of the singlet valence excited states of an iron-porphyrin-pyrazine-carbonyl complex up to the Soret band (about 3 eV) are presented. This complex is chosen to be a model for the active site of carboxyhemoglobin/carboxymyoglobin. The investigations are performed at the restricted active space second-order perturbation (RASPT2) level involving an extended active space on the porphyrin ligand in addition to the active orbitals needed for the description of the metal-ligand interactions. Metal-to-ligand-charge-transfer states d → π* and some metal-centered d → d transitions are found in the lowest part of the spectrum, below the first π → π* intraporphyrin transitions (Q band). Doubly excited states involving simultaneous intraporphyrin and metal-centered excitations are found in the vicinity of the second set of intraporphyrin transitions (the so-called Soret band). The effect of the extension of the active space on the porphyrin ligand beyond the Gouterman's orbitals set is investigated together with the effect of inclusion of the ionization potential electron affinity shift in the RASPT2 treatment. © 2019 Wiley Periodicals, Inc.

Methodological CASPT2 study of the valence excited states of an iron-porphyrin complex.

The singlet valence excited states of an iron-porphyrin-pyrazine-carbonyl complex are investigated up to the Soret band (about 3 eV) using multi-state complete active space with perturbation at the second order (MS-CASPT2). This complex is a model for the active site of carboxy-hemoglobin/myoglobin. The spectrum of the excited states is rather dense, comprising states of different nature: d→π* transitions, d→d states, π→π* excitations of the porphyrin, and doubly excited states involving simultaneous intra-porphyrin π→π* and d→d transitions. Specific features of the MS-CASPT2 method are investigated. The effect of varying the number of roots in the state average calculation is quantified as well as the consequence of targeted modifications of the active space. The effect of inclusion of standard ionization potential-electron affinity (IPEA) shift in the perturbation treatment is also investigated.

A comprehensive theoretical investigation of the electronic states of Ca2 up to the Ca(4s(2) 1S) + Ca(4s5p 1P) dissociation limit.

A theoretical survey of the electronic structure of Ca(2) is presented using two-electron pseudopotentials complemented by core-polarization operators on Ca atoms and multireference configuration interaction/quasidegenerate perturbation theory (MRCI/QDPT) treatment of molecular excited states. The spectroscopic constants of 70 electronic states up to 30,000 cm(-1) above the ground state are determined. This implies all Ca(2) states dissociating up to the Ca(4s(2) (1)S) + Ca(4s5p (3,1)P) dissociation limits. All spin states (singlet, triplet, and quintet) are investigated. The work emphasizes the variety of interactions implying singly valence and lowest Rydberg excited states, doubly excited states generated by atom pairs (3)P(4s4p) + (3)P(4s4p), or (3)P(4s4p) + (3)D(4s3d), 4p3d double excitations asymptotically localized on a single-atom. Zwitterionic Ca(+) + Ca(-) configurations are evidenced and shown to induce specific electronic patterns in (1)Σ(g)(+), (3)Σ(g)(+), (1)Σ(u)(+), (3)Σ(u)(+), (1)Π(g), (3)Π(g), (1)Π(u), and (3)Π(u) symmetry manifolds. They also provide insight for qualitative features (barriers) found for the lower electronic states already investigated in previous publications by other authors.

Relaxation dynamics of photoexcited calcium deposited on argon clusters: theoretical simulation of time-resolved photoelectron spectra.

Relaxation dynamics following photoexcitation of a calcium atom deposited on an icosahedral-like argon cluster Ar(n) (n approximately = 55) is investigated through theoretical simulations. Based on ab initio calculations of the CaAr molecule, a diatomics-in-molecules model is set up to efficiently describe the electronic excited states of the system. The excited state dynamics is studied using molecular dynamics with electronic transitions (Tully, J. C. J. Chem. Phys. 1990, 93, 1061). The signature of this dynamics in the time-resolved photoelectron spectra is investigated, to assess the possibility of detecting competing vibrational and electronic relaxations through pump-probe experiments. The vibrational relaxation, influenced by nonadiabatic transitions, can clearly be seen in the time-resolved photoelectron spectra. The details of the electronic relaxation, as well as the possible ejection of the chromophore, are found to be sensitive to the local environment of the calcium atom deposited on the argon cluster.

Laser control of vibrational excitation in carboxyhemoglobin: a quantum wave packet study.

A coherent control algorithm is applied to obtain complex-shaped infrared laser pulses for the selective vibrational excitation of carbon monoxide at the active site of carbonmonoxyhemoglobin, modeled by the six-coordinated iron-porphyrin-imidazole-CO complex. The influence of the distal histidine is taken into account by an additional imidazole molecule. Density-functional theory is employed to calculate a multidimensional ground-state potential energy surface, and the vibrational dynamics as well as the laser interaction is described by quantum wave-packet calculations. At each instant in time, the optimal electric field is calculated and used for the subsequent quantum dynamics. The results presented show that the control scheme is applicable to complex systems and that it yields laser pulses with complex time-frequency structures, which, nevertheless, have a clear physical interpretation.

Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitor.

BACKGROUND: Neonatal ventral hippocampal (NVH) lesions in rats induce behavioral abnormalities at adulthood thought to simulate some aspects of the positive, negative, and cognitive deficits classically observed in schizophrenic patients. Such lesions induce a postpubertal emergence of prepulse inhibition (PPI) deficits of the startle reflex reminiscent of the sensorimotor gating deficits observed in a majority of schizophrenic patients. To study the potential involvement of the glycinergic neurotransmission in such deficits, we investigated the capacity of glycine (an obligatory N-methyl-D-aspartate [NMDA] receptor co-agonist) and ORG 24598 (a selective glycine transporter 1 inhibitor) to reverse NVH lesion-induced PPI deficits in rats. METHODS: Ibotenic acid was injected bilaterally into the ventral hippocampus of 7-day-old pups. Prepulse inhibition of the startle reflex was measured at adulthood. RESULTS: Glycine (.8 and 1.6 g/kg IP) and ORG 24598 (10 mg/kg IP) fully and partially reversed lesion-induced PPI deficits, respectively. CONCLUSIONS: These findings confirm that an impaired glutamatergic neurotransmission may be responsible for PPI deficits exhibited by NVH-lesioned rats and support the hypoglutamatergic hypothesis of schizophrenia. They also suggest that drugs acting either directly at the NMDA receptor glycine site or indirectly on the glycine transporter 1 could offer promising targets for the development of novel therapies for schizophrenia.

1-Benzyloxy-4,5-dihydro-1H-imidazol-2-yl-amines, a novel class of NR1/2B subtype selective NMDA receptor antagonists.

Screening of the Roche compound depository led to the identification of (1-benzyloxy-4,5-dihydro-1H-imidazol-2-yl)-butyl amine 4, a structurally novel NR1/2B subtype selective NMDA receptor antagonist. The structure-activity relationships developed in this series resulted in the discovery of a novel class of potent and selective NMDA receptor blockers displaying activity in vivo.

4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and 4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolines as potent NR1/2B subtype selective NMDA receptor antagonists.

A series of 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs alpha1 and M1 receptors) and activity in vivo.

2-(3,4-Dihydro-1H-isoquinolin-2yl)-pyridines as a novel class of NR1/2B subtype selective NMDA receptor antagonists.

Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype selective NMDA receptor antagonists. We would now like to report our findings on structurally related pyridine analogues. The SAR developed in this series resulted in the discovery of high affinity antagonists which are selective (vs alpha1 and M1 receptors) and active in vivo.

4-Aminoquinolines as a novel class of NR1/2B subtype selective NMDA receptor antagonists.

Screening of the Roche compound library led to the identification of 4-aminoquinoline 4 as structurally novel NR1/2B subtype selective NMDA receptor antagonist. The SAR which was developed in this series resulted in the discovery of highly potent and in vivo active blockers.