Time Resolved Photoelectron Spectroscopy of Thioflavin T Photoisomerization: A Simulation Study

The excited state isomerization of thioflavin T (ThT) is responsible for the quenching of its fluorescence in a non-restricted environment. The fluorescence quantum yield increases substantially upon binding to amyloid fibers. Simulations reveal that the variation of the twisting angle between benzothiazole and benzene groups (ϕ(1)) is responsible for the sub-picosecond fluorescence quenching. The evolution of the twisting process can be directly probed by photoelectron emission with energies ε ≥ 1.0 eV before the molecule reaches the ϕ(1)-twisted configuration (~300 fs)

Randomized phase 3 trial of ruxolitinib for COVID-19-associated acute respiratory distress syndrome

Objectives: Evaluate the safety and efficacy of the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib in COVID-19-associated acute respiratory distress syndrome requiring mechanical ventilation. Design: Phase 3 randomized, double-blind, placebo-controlled trial Ruxolitinib in Participants With COVID-19-Associated Acute Respiratory Distress Syndrome Who Require Mechanical Ventilation (RUXCOVID-DEVENT; NCT04377620). Setting: Hospitals and community-based private or group practices in the United States (29 sites) and Russia (4 sites). Patients: Eligible patients were greater than or equal to 12 years old, hospitalized with severe acute respiratory syndrome coronavirus 2 infection, and mechanically ventilated with a Pao2/Fio2 of less than or equal to 300 mm Hg within 6 hours of randomization. Interventions: Patients were randomized 2:2:1 to receive twice-daily ruxolitinib 15 mg, ruxolitinib 5 mg, or placebo, each plus standard therapy. Measurements and main results: The primary endpoint, 28-day mortality, was tested for each ruxolitinib group versus placebo using a mixed-effects logistic regression model and one-tailed significance test (significance threshold: p \u3c 0.025); no type 1 error was allocated to secondary endpoints. Between May 24, 2020 and December 15, 2020, 211 patients (age range, 24-87 yr) were randomized (ruxolitinib 15/5 mg, n = 77/87; placebo, n = 47). Acute respiratory distress syndrome was categorized as severe in 27% of patients (58/211) at randomization; 90% (190/211) received concomitant steroids. Day-28 mortality was 51% (39/77; 95% CI, 39-62%) for ruxolitinib 15 mg, 53% (45/85; 95% CI, 42-64%) for ruxolitinib 5 mg, and 70% (33/47; 95% CI, 55-83%) for placebo. Neither ruxolitinib 15 mg (odds ratio, 0.46 [95% CI, 0.201-1.028]; one-sided p = 0.029) nor 5 mg (odds ratio, 0.42 [95% CI, 0.171-1.023]; one-sided p = 0.028) significantly reduced 28-day mortality versus placebo. Numerical improvements with ruxolitinib 15 mg versus placebo were observed in secondary outcomes including ventilator-, ICU-, and vasopressor-free days. Rates of overall and serious treatment-emergent adverse events were similar across treatments. Conclusions: The observed reduction in 28-day mortality rate between ruxolitinib and placebo in mechanically ventilated patients with COVID-19-associated acute respiratory distress syndrome was not statistically significant; however, the trial was underpowered owing to early termination

Characterizing the dark state in thymine and uracil by double resonant spectroscopy and quantum computation

We report on gas phase double resonant spectroscopy of both the ground state and the dark excited state in isolated uracil and thymine. We also report lifetimes of the dark state for different excitation wavelengths. In combination with ab initio calculations the results suggest that the dark state is of triplet ((3)ππ*) character

Conical intersection dynamics of the primary photoisomerization event in vision.

Ever since the conversion of the 11-cis retinal chromophore to its all-trans form in rhodopsin was identified as the primary photochemical event in vision, experimentalists and theoreticians have tried to unravel the molecular details of this process. The high quantum yield of 0.65 (ref. 2), the production of the primary ground-state rhodopsin photoproduct within a mere 200 fs (refs 3-7), and the storage of considerable energy in the first stable bathorhodopsin intermediate all suggest an unusually fast and efficient photoactivated one-way reaction. Rhodopsin's unique reactivity is generally attributed to a conical intersection between the potential energy surfaces of the ground and excited electronic states enabling the efficient and ultrafast conversion of photon energy into chemical energy. But obtaining direct experimental evidence for the involvement of a conical intersection is challenging: the energy gap between the electronic states of the reacting molecule changes significantly over an ultrashort timescale, which calls for observational methods that combine high temporal resolution with a broad spectral observation window. Here we show that ultrafast optical spectroscopy with sub-20-fs time resolution and spectral coverage from the visible to the near-infrared allows us to follow the dynamics leading to the conical intersection in rhodopsin isomerization. We track coherent wave-packet motion from the photoexcited Franck-Condon region to the photoproduct by monitoring the loss of reactant emission and the subsequent appearance of photoproduct absorption, and find excellent agreement between the experimental observations and molecular dynamics calculations that involve a true electronic state crossing. Taken together, these findings constitute the most compelling evidence to date for the existence and importance of conical intersections in visual photochemistry