Time-resolved studies of the photodissociation of adenine

A novel time-resolved velocity map ion imaging (TR-VMI) experiment has been constructed and successfully applied to the study of non-statistical dissociation processes. The photodissociation of NH3 following the population of the ν2 ’ = 4 umbrella vibrational mode of the first electronically excited, Ã1A2”, singlet state, was initially studied. It was clearly observed that the N-H dissociation timescale was inversely proportional to kinetic energy released to the H fragment. Assignment of different kinetic energy regions of the TR-VMI transients to corresponding bending vibrational modes (ν2) of the X2B1 state NH2 photoproduct clearly suggests that dissociation into the vibrationless NH2 occurs in < 50 fs. Low kinetic energy channels, show extended dissociation timescales, strongly indicative of adiabatic dissociation to the first electronically excited state of NH2 (Ã2A1). With an aim of modelling the photodissociation dynamics of adenine, the photodissociation of pyrrole, imidazole, 2-methylimidazole, 4-methylimidazole and 2,4-dimethylimidazole following excitation at 200 nm were studied using time-resolved mass spectrometry (TR-MS) and VMI. In all cases ultrafast H elimination was observed in < 130 fs, consistent with direct dissociation via the repulsive 1πσ* potential energy surfaces. The photodissociation of 1- methyimidazole at this wavelength was also studied. Once again ultrafast H elimination was observed, but with greatly reduced yields, strongly suggesting H elimination from the non-heteroatom co-ordinates (C-H) also partaking in the photodissociation dynamics at this wavelength. TR-MS and VMI have also been applied to the study of the photodissociation of adenine, 9-methyladenine and 6-dimethylaminopurine. In all measured kinetic energy spectra a high kinetic energy channel has been observed, strongly suggesting the participation of 1πσ* potential energy surfaces of both the azole and amino co-ordinates in H elimination following excitation at 200 nm. Power dependence studies at 266 nm suggest H elimination, but subsequent TR-MS measurements seem to suggest that this is not due to the participation of the 1πσ* potential energy surfaces at this excitation wavelength

Time-resolved studies of the photodissociation of adenine

A novel time-resolved velocity map ion imaging (TR-VMI) experiment has been constructed and successfully applied to the study of non-statistical dissociation processes. The photodissociation of NH3 following the population of the ν2 ’ = 4 umbrella vibrational mode of the first electronically excited, Ã1A2”, singlet state, was initially studied. It was clearly observed that the N-H dissociation timescale was inversely proportional to kinetic energy released to the H fragment. Assignment of different kinetic energy regions of the TR-VMI transients to corresponding bending vibrational modes (ν2) of the X2B1 state NH2 photoproduct clearly suggests that dissociation into the vibrationless NH2 occurs in < 50 fs. Low kinetic energy channels, show extended dissociation timescales, strongly indicative of adiabatic dissociation to the first electronically excited state of NH2 (Ã2A1). With an aim of modelling the photodissociation dynamics of adenine, the photodissociation of pyrrole, imidazole, 2-methylimidazole, 4-methylimidazole and 2,4-dimethylimidazole following excitation at 200 nm were studied using time-resolved mass spectrometry (TR-MS) and VMI. In all cases ultrafast H elimination was observed in < 130 fs, consistent with direct dissociation via the repulsive 1πσ* potential energy surfaces. The photodissociation of 1- methyimidazole at this wavelength was also studied. Once again ultrafast H elimination was observed, but with greatly reduced yields, strongly suggesting H elimination from the non-heteroatom co-ordinates (C-H) also partaking in the photodissociation dynamics at this wavelength. TR-MS and VMI have also been applied to the study of the photodissociation of adenine, 9-methyladenine and 6-dimethylaminopurine. In all measured kinetic energy spectra a high kinetic energy channel has been observed, strongly suggesting the participation of 1πσ* potential energy surfaces of both the azole and amino co-ordinates in H elimination following excitation at 200 nm. Power dependence studies at 266 nm suggest H elimination, but subsequent TR-MS measurements seem to suggest that this is not due to the participation of the 1πσ* potential energy surfaces at this excitation wavelength.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Purely absorptive fifth-order three-dimensional electronic spectroscopy

We demonstrate a method to measure a purely absorptive fifth-order three-dimensional (3D) electronic spectrum based on a pulse-shaper assisted pump-probe beam geometry setup. The 3D spectra are measured as a function of two independently controlled population times. With phase-cycling and data processing, purely absorptive 3D spectra of chlorophyll a are obtained.Published versio

Dynamics of H-loss in adenine via the (1)pi sigma* state using a combination of ns and fs laser spectroscopy

One of the key questions underlying adenine's photochemistry following 266 nm excitation is whether or not the dissociative (1)pi sigma* state plays an active role in the ensuing dynamics. This work describes how laser fluence studies on the Ad(+) and H+ following photo-excitation using a combination of ns and fs UY pulses with time-of-flight mass-spectrometry, provides new evidence that implicates the contentious participation of the (1)pi sigma* state in the photochemistry of adenine. (C) 2007 Elsevier B.V. All rights reserved

Phase-cycling schemes for pump–probe beam geometry two-dimensional electronic spectroscopy

Experimental demonstrations and detailed theoretical explanations are provided for a thorough understanding of the various phase-cycling schemes in an optical pulse shaper assisted two-dimensional electronic spectroscopy (2DES) in a pump–probe beam geometry. We show that two and three-step phase-cycling schemes can be employed to retrieve both rephasing and nonrephasing 2D spectra. The studies were performed on the Qy transition of chlorophyll a

Direct observation of multistep energy transfer in LHCII with fifth-order 3D electronic spectroscopy

During photosynthesis, sunlight is efficiently captured by light-harvesting complexes, and the excitation energy is then funneled towards the reaction centre. These photosynthetic excitation energy transfer (EET) pathways are complex and proceed in a multistep fashion. Ultrafast two-dimensional electronic spectroscopy (2DES) is an important tool to study EET processes in photosynthetic complexes. However, the multistep EET processes can only be indirectly inferred by correlating different cross peaks from a series of 2DES spectra. Here we directly observe multistep EET processes in LHCII using ultrafast fifth-order three-dimensional electronic spectroscopy (3DES). We measure cross peaks in 3DES spectra of LHCII that directly indicate energy transfer from excitons in the chlorophyll b (Chl b) manifold to the low-energy level chlorophyll a (Chl a) via mid-level Chl a energy states. This new spectroscopic technique allows scientists to move a step towards mapping the complete complex EET processes in photosynthetic systems.NRF (Natl Research Foundation, S’pore)ASTAR (Agency for Sci., Tech. and Research, S’pore)Published versio

Time resolved velocity map imaging of H-atom elimination from photoexcited imidazole and its methyl substituted derivatives

The photoresistive properties of DNA bases, amino acids and corresponding subunits have received considerable attention through spectroscopic studies in recent years. One photoresistive property implicates the participation of 1πσ* states, allowing electronically excited states to evolve either back to the electronic ground state or undergo direct dissociation along a heteroatom–hydride (X–H) coordinate. To this effect, time-resolved velocity map imaging (TR-VMI) studies of imidazole (a subunit of both adenine and histidine) and methylated derivatives thereof have been undertaken, with the goal of understanding the effects of increasing molecular complexity, through methylation, on the dynamics following photoexcitation at 200 nm. The results of these measurements clearly show that H-atom elimination along the N–H coordinate results in a bimodal distribution in the total kinetic energy release (TKER) spectra in both imidazole and it's methylated derivatives: 2-methyl, 4-methyl and 2,4-dimethylimidazole. The associated time constants for H-atoms eliminated with both high and low kinetic energies are all less than 500 fs. A noticeable increase in the time constants for the methylated derivatives is also observed. This could be attributed to either: ring methylation hindering in-plane and out-of-plane ring distortions which have been implicated as mediating excited state dynamics of these molecules or; an increase in the density of vibrational states at 200 nm causing an increased sampling of orthogonal modes, as opposed to modes which drive any dynamics that cause subsequent H-atom elimination. The results of these findings once again serve to illustrate the seemingly ubiquitous nature of 1πσ* states in the photoexcited state dynamics of biomolecules and their subunits

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease