Coherent control and quantum dynamics in complex chemical and biological environments

In ultrafast molecular sciences, short laser pulses are used to initiate and interrogate chemical and physical phenomena. This thesis presents simulations on different molecular examples within this framework, where the specific goal ranges from the design of ultrafast experiments, over their interpretation and to feasibility assessments for future applications. Additionally, simulation protocols are developed to consider the influence of complex environments on the studied processes, as this is essential for the aspired experimental connection and often very challenging. The first topic deals with the initiation of a synthetically relevant reaction with shaped laser pulses. The model system is a methyl transfer between cyclohexanone and trimethylaluminium, which includes a carbon-carbon bond formation as the key step in many pharmaceutical syntheses. The surrounding molecules of the chemical solution are found to considerably affect the one-dimensional model reaction coordinate describing the methyl transfer. Quantum control studies are performed by optimizing laser pulses, selectively steering a nuclear wavepacket toward the methyl transfer pathway. A simulation protocol based on multi-target Optimal Control Theory is employed to overcome the environmental complexities and excite the molecules in various different static solvent cages simultaneously. In combination with statistical estimates, it is found that theoretically the population yield in the target level can be considerable. Going beyond the static inclusion of solvent cages, the temporal evolution of the environmental influence is revealed along five different classical trajectories of 2.5~picoseconds each. The affected vibrational levels of the target molecule are found to fluctuate on the femtosecond time scale, i.e. the environmental influence can switch between extreme cases several times during the time where the controlling laser pulse is active. Optimized laser pulses can also be efficient in scenarios which they were not optimized for, which has several implications for practical applications. The second topic revolves around photoexcited phenomena in nucleic acids. The RNA-nucleobase uracil is investigated with respect to its photostability. One reason for the canonical nucleobases being extraordinarily stable towards UV absorption is their ultrafast relaxation back to the electronic ground state. Besides presenting the first full quantum dynamical simulations on this process for uracil, quantum control optimizations are used to trap the wave packet and prevent relaxation. This artificially prepares the elusive state which can be a precursor for photodamage, as delayed relaxation has been directly connected with the formation of harmful lesions before. The optimized laser pulse is surprisingly smooth and within the accessibility of modern experimental setups, which renders this study a tangible instruction for possible spectroscopic experiments. Besides the artificial trap on isolated uracil, wavepacket simulations within its natural RNA environment reveal that this influence can also lead to trapping in the photoexcited state. Sampling over 10 different neighboring base sequences and a total of 275 environmental snapshots, this mechanism is found to be base-independent. In this connection, the third study goes from the formation of photodamage to its repair. An experimentally observed repair mechanism of the frequently occurring cyclobutane pyrimidine dimer - formed by two thymines in DNA - is investigated with quantum chemistry. The excited states of the neighboring guanine adenine sequence are characterized to distinguish between local and charge transfer excitation, validating the initial step of the experimentally suggested mechanism

Visualizing Conical Intersection Passages via Vibronic Coherence Maps Generated by Stimulated Ultrafast X--Ray Raman Signals

The rates and outcomes of virtually all photophysical and photochemical processes are determined by Conical Intersections. These are regions of degeneracy between electronic states on the nuclear landscape of molecules where electrons and nuclei evolve on comparable timescales and become strongly coupled, enabling radiationless relaxation channels upon optical excitation. Due to their ultrafast nature and vast complexity, monitoring Conical Intersections experimentally is an open challenge. We present a simulation study on the ultrafast photorelaxation of uracil, which demonstrates a new window into Conical Intersections obtained by recording the transient wavepacket coherence during this passage with an x-ray free electron laser pulse. We report two major findings. First, we find that the vibronic coherence at the conical intersection lives for several hundred femtoseconds and can be measured during this entire time. Second, the time-dependent energy splitting landscape of the participating vibrational and electronic states is directly extracted from Wigner spectrograms of the signal. These offer a novel physical picture of the quantum Conical Intersection pathways through visualizing their transient vibronic coherence distributions. The path of a nuclear wavepacket around the Conical Intersection is directly mapped by the proposed experiment.Comment: 7 pages, 5 Figures, to be published in PNA

A Brighter Future: The Effect of Social Class On Responses To Future Debt

© 2020, PsychOpen. All rights reserved. The present study serves as an exploratory investigation of the role of social class in responses to the threat of future debt. Previous work has shown that individuals of high and low subjective social class differ in the ways that they respond to a broad range of threats and uncertainties about the future. Across three studies, we found that lower social class individuals expect more future debt and suffer greater attendant stress than higher class individuals (Study 1). We found that experimental manipulations of debt salience increased stress for lower class and not for higher class individuals (Studies 2-3). Likewise, we found that higher class individuals experienced higher affect balance and perceptions of personal control when the possibility of future debt was made salient, specifically as a function of decreased fatalism about future debt (Study 3). These three studies reveal yet another situation in which individuals of lower and higher social class respond differently to threat, and serve as an important step toward understanding the psychological ramifications of rising debt in the United States

Stereoselective Csp3−Csp2 Cross‐Couplings of Chiral Secondary Alkylzinc Reagents with Alkenyl and Aryl Halides

We report palladium‐catalyzed cross‐coupling reactions of chiral secondary non‐stabilized dialkylzinc reagents, prepared from readily available chiral secondary alkyl iodides, with alkenyl and aryl halides. This method provides α‐chiral alkenes and arenes with very high retention of configuration (dr up to 98:2) and satisfactory overall yields (up to 76 % for 3 reaction steps). The configurational stability of these chiral non‐stabilized dialkylzinc reagents was determined and exceeded several hours at 25 °C. DFT calculations were performed to rationalize the stereoretention during the catalytic cycle. Furthermore, the cross‐coupling reaction was applied in an efficient total synthesis of the sesquiterpenes (S)‐ and (R)‐curcumene with control of the absolute stereochemistry

Blood Flow Restriction Training for the Rotator Cuff: A Randomized Controlled Trial

Context: Blood flow restriction (BFR) training utilizes a tourniquet, applied to the proximal portion of one or more extremities, to occlude blood flow during exercise. Significant gains in strength and cross-sectional area can be achieved in muscles, both distal and proximal to BFR cuff application. Purpose: To compare strength gains of the rotator cuff and changes in tendon size in subjects who performed side-lying external-rotation exercise with or without BFR. Methods: Forty-six subjects (mean age 25.0 [2.2] y) were randomized to either a BFR + exercise group or to the exercise-only group. Subjects performed 4 sets of the exercise (30/15/15/15 repetitions) at 30% 1-repetition maximum 2 days per week for 8 weeks. Results: Subjects in both groups experienced strength gains in the supraspinatus and the external rotators (P = .000, P = .000). However, there was no difference in strength gains between groups for the supraspinatus (P = .750) or the external rotators (P = .708). Subjects in both groups experienced increases in supraspinatus tendon thickness (BFR P = .041, exercise only P = .011). However, there was no difference between groups (P = .610). Conclusions: Exercise with BFR applied to the proximal upper extremity did not augment rotator cuff strength gains or tendon thickness when compared with subjects who only exercised. This study did demonstrate that performing multiple sets of high repetitions at a low load led to significant increases in rotator cuff strength and tendon size in the dominant upper extremity

Phase 1 Safety and Immunogenicity Evaluation of ADMVA, a Multigenic, Modified Vaccinia Ankara-HIV-1 B'/C Candidate Vaccine

in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers.. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses.ADMVA was well-tolerated and elicited durable humoral and cellular immune responses

Phase 1 Safety and Immunogenicity Evaluation of ADVAX, a Multigenic, DNA-Based Clade C/B' HIV-1 Candidate Vaccine

BACKGROUND: We conducted a Phase I dose escalation trial of ADVAX, a DNA-based candidate HIV-1 vaccine expressing Clade C/B' env, gag, pol, nef, and tat genes. Sequences were derived from a prevalent circulating recombinant form in Yunnan, China, an area of high HIV-1 incidence. The objective was to evaluate the safety and immunogenicity of ADVAX in human volunteers. METHODOLOGY/PRINCIPAL FINDINGS: ADVAX or placebo was administered intramuscularly at months 0, 1 and 3 to 45 healthy volunteers not at high risk for HIV-1. Three dosage levels [0.2 mg (low), 1.0 mg (mid), and 4.0 mg (high)] were tested. Twelve volunteers in each dosage group were assigned to receive ADVAX and three to receive placebo in a double-blind design. Subjects were followed for local and systemic reactogenicity, adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA. Cellular immunogenicity was assessed by a validated IFNgamma ELISpot assay and intracellular cytokine staining. ADVAX was safe and well-tolerated, with no vaccine-related serious adverse events. Local and systemic reactogenicity events were reported by 64% and 42% of vaccine recipients, respectively. The majority of events were mild. The IFNgamma ELISpot response rates to any HIV antigen were 0/9 (0%) in the placebo group, 3/12 (25%) in the low-dosage group, 4/12 (33%) in the mid-dosage group, and 2/12 (17%) in the high-dosage group. Overall, responses were generally transient and occurred to each gene product, although volunteers responded to single antigens only. Binding antibodies to gp120 were not detected in any volunteers, and HIV seroconversion did not occur. CONCLUSIONS/SIGNIFICANCE: ADVAX delivered intramuscularly is safe, well-tolerated, and elicits modest but transient cellular immune responses. TRIAL REGISTRATION: Clinicaltrials.gov NCT00249106.published_or_final_versio

Resistance to First-Line Anti-TB Drugs Is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis

Background and objective: The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug resistance and clinical outcome is not known. Methods: In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO. Results: Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (>10% survival after exposure to 1mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters, but a tendency towards lower rate of weight gain after two months of treatment. Conclusion: There is a correlation between resistance to first-line anti-TB drugs and reduced NO susceptibility in clinical strains of M. tuberculosis. Further studies including the mechanisms of reduced NO susceptibility are warranted and could identify targets for new therapeutic interventions