Time-resolved velocity map imaging of methyl elimination from photoexcited anisole

To date, H-atom elimination from heteroaromatic molecules following UV excitation has been extensively studied, with the focus on key biological molecules such as chromophores of DNA bases and amino acids. Extending these studies to look at elimination of other non-hydride photoproducts is essential in creating a more complete picture of the photochemistry of these biomolecules in the gas-phase. To this effect, CH3 elimination in anisole has been studied using time resolved velocity map imaging (TR-VMI) for the first time, providing both time and energy information on the dynamics following photoexcitation at 200 nm. The extra dimension of energy afforded by these measurements has enabled us to address the role of πσ* states in the excited state dynamics of anisole as compared to the hydride counterpart (phenol), providing strong evidence to suggest that only CH3 fragments eliminated with high kinetic energy are due to direct dissociation involving a 1πσ* state. These measurements also suggest that indirect mechanisms such as statistical unimolecular decay could be contributing to the dynamics at much longer times

Raman scattering mediated by neighboring molecules

Raman scattering is most commonly associated with a change in vibrational state within individual molecules, the corresponding frequency shift in the scattered light affording a key way of identifying material structures. In theories where both matter and light are treated quantum mechanically, the fundamental scattering process is represented as the concurrent annihilation of a photon from one radiation mode and creation of another in a different mode. Developing this quantum electrodynamical formulation, the focus of the present work is on the spectroscopic consequences of electrodynamic coupling between neighboring molecules or other kinds of optical center. To encompass these nanoscale interactions, through which the molecular states evolve under the dual influence of the input light and local fields, this work identifies and determines two major mechanisms for each of which different selection rules apply. The constituent optical centers are considered to be chemically different and held in a fixed orientation with respect to each other, either as two components of a larger molecule or a molecular assembly that can undergo free rotation in a fluid medium or as parts of a larger, solid material. The two centers are considered to be separated beyond wavefunction overlap but close enough together to fall within an optical near-field limit, which leads to high inverse power dependences on their local separation. In this investigation, individual centers undergo a Stokes transition, whilst each neighbor of a different species remains in its original electronic and vibrational state. Analogous principles are applicable for the anti-Stokes case. The analysis concludes by considering the experimental consequences of applying this spectroscopic interpretation to fluid media; explicitly, the selection rules and the impact of pressure on the radiant intensity of this process

Mapping Low-Density Intergalactic Gas: a Third Helium Lyman-alpha Forest

We present a new HST/STIS spectrum of the z=3.18 quasar PKS 1935-692 and summarize the spectral features shortwards of 304A in the rest frame likely to be caused by foreground HeII Lyman-alpha absorption. In accord with previous results on two other quasars at similar redshifts, we demonstrate a correlation with the HI Lyman-alpha forest absorption, and show that much of the helium absorption is caused by a comparable quantity of more diffuse gas with Omega~0.01, that is not detected in HI. The helium ionization zone around the quasar is detected as well as a void seen in both HI and HeII. The properties of the absorption are in broad agreement with those of the other quasars and with models of the protogalactic gas distribution and ionization at this redshift.Comment: 17 pages including 5 figures. As accepted for publication in The Astronomical Journal (minor revisions

Methodological Diversity in Citizen Science Mosquito Surveillance: A Scoping Review

Global concern regarding mosquito-borne disease emergence and re-emergence has driven the development of citizen science mosquito surveillance initiatives. Although these initiatives have shown great potential to assist local health authorities, ensuring outcomes are translatable to improved public health policy and practice remains challenging. Here we present a summary of citizen science mosquito surveillance programs worldwide, their focus, strategies, and outcomes, with a view to how best to apply this approach in their local areas. A scoping review of studies and reports was conducted through systematic search on electronic databases (Scopus, PubMed, Web of Science, and Google Scholar), grey literature, and other documents listed in the references of selected articles. A total of 33 citizen science studies included in this review described 29 citizen science mosquito surveillance projects operating in 16 countries, besides three programs with wide geographic coverage. The selected programs focused on different strategies and methods according to their local and national contextual needs. The majority of the programs reported being free or low in cost, and amenable to participants. Also, citizen scientists valued the opportunity to actively contribute to a scientific activity in which they saw value. Local and national programs have been successful in involving the broader public and yielding data on mosquito populations. However, to ensure the best public health outcomes, sustainability, and scalability, there is a need to continue engaging with stakeholders, including community members, researchers, public health agents, industry, and policymakers, and to bridge existing collaborations across different sectors

Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib.

BackgroundEarly detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics.MethodsA nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death.ResultsPlasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.ConclusionsHeretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264

What's the point of knowing how?

Why is it useful to talk and think about knowledge-how? Using Edward Craig’s discussion of the function of the concepts of knowledge and knowledge-how as a jumping off point, this paper argues that considering this question can offer us new angles on the debate about knowledge-how. We consider two candidate functions for the concept of knowledge-how: pooling capacities, and mutual reliance. Craig makes the case for pooling capacities, which connects knowledge-how to our need to pool practical capacities. I argue that the evidence is much more equivocal. My suggested diagnosis is that the concept of knowledge-how plays both functions, meaning that the concept of knowledge-how is inconsistent, and that the debate about knowledge-how is at least partly a metalinguistic negotiation. In closing, I suggest a way to revise the philosophical concept of knowledge how

Theory of mechanical unfolding of homopolymer globule: all-or-none transition in force-clamp mode vs phase coexistence in position-clamp mode

Equilibrium mechanical unfolding of a globule formed by long flexible homopolymer chain collapsed in a poor solvent and subjected to an extensional force f (force-clamp mode) or extensional deformation D (position-clamp mode) is studied theoretically. Our analysis, like all previous analysis of this problem, shows that the globule behaves essentially differently in two modes of extension. In the force-clamp mode, mechanical unfolding of the globule with increasing applied force occurs without intramolecular microphase segregation, and at certain threshold value of the pulling force the globule unfolds as a whole ("all-or-none" transition). The value of the threshold force and the corresponding jump in the distance between the chain ends increase with a deterioration of the solvent quality and/or with an increase in the degree of polymerization. In the position-clamp mode, the globule unfolding occurs via intramolecular microphase coexistence of globular and extended microphases followed by an abrupt unraveling transition. Reaction force in the microphase segregation regime demonstrates an "anomalous" decrease with increasing extension. Comparison of deformation curves in force and position-clamp modes demonstrates that at weak and strong extensions the curves for two modes coincide, differences are observed in the intermediate extension range. Another unfolding scenario is typical for short globules: in both modes of extension they unfold continuously, without jumps or intramolecular microphase coexistence, by passing a sequence of uniformly elongated configurations.Comment: 19 pages, 13 figures, 1 tabl

Personalizing neoadjuvant chemotherapy for locally advanced colon cancer:protocols for the international phase III FOxTROT2 and FOxTROT3 randomized controlled trials

AIM: FOxTROT1 established a new standard of care for managing locally advanced colon cancer (CC) with neoadjuvant chemotherapy (NAC). Six weeks of neoadjuvant oxaliplatin and fluoropyrimidine (OxFp) chemotherapy was associated with greater 2-year disease-free survival (DFS) when compared with proceeding straight to surgery (STS). There is now a need to refine the use of NAC and identify those most likely to benefit. FOxTROT2 will aim to investigate NAC in older adults and those with frailty. FOxTROT3 will aim to assess whether intensified triplet NAC provides additional benefits over OxFp.METHOD: FOxTROT2 and FOxTROT3 are international, open-label, phase III randomized controlled trials. Eligible patients will be identified by the multidisciplinary team. Patient age, frailty and comorbidities will be considered to guide trial entry. Participants will be randomized 2:1 to the intervention or control arm: 6 weeks of dose-adapted neoadjuvant OxFp versus STS in FOxTROT2 and 6 weeks of neoadjuvant modified oxaliplatin, 5-fluorouracil and irinotecan versus OxFp in FOxTROT3. The primary endpoint in FOxTROT2 is 3-year DFS. In FOxTROT3, tumour regression grade and 3-year DFS are co-primary endpoints.DISCUSSION: FOxTROT2 and FOxTROT3 will establish the FOxTROT platform, a key part of our long-term strategy to develop neoadjuvant treatments for CC. FOxTROT2 will investigate NAC in a population under-represented in FOxTROT1 and wider research. FOxTROT3 will assess whether it is possible to induce greater early tumour responses and whether this translates to superior long-term outcomes. Looking ahead, the FOxTROT platform will facilitate further trial comparisons and extensive translational research to optimize the use of NAC in CC.</p

Lattice results for the decay constant of heavy-light vector mesons

We compute the leptonic decay constants of heavy-light vector mesons in the quenched approximation. The reliability of lattice computations for heavy quarks is checked by comparing the ratio of vector to pseudoscalar decay constant with the prediction of Heavy Quark Effective Theory in the limit of infinitely heavy quark mass. Good agreement is found. We then calculate the decay constant ratio for B mesons: $f_{B^*}/f_B= 1.01(0.01)(^{+0.04}_{-0.01})$. We also quote quenched $f_{B^*}=177(6)(17)$ MeV.Comment: 11 pages, 3 postscript figs., revtex; two references adde