Vibronic interactions in the visible and near-infrared spectra of C60− anions

Electron-phonon coupling is an important factor in understanding many properties of the C60 fullerides. However, there has been little success in quantifying the strength of the vibronic coupling in C60 ions, with considerable disagreement between experimental and theoretical results. We will show that neglect of quadratic coupling in previous models for C60- ions results in a significant overestimate of the linear coupling constants. Including quadratic coupling allows a coherent interpretation to be made of earlier experimental and theoretical results which at first sight are incompatible

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Chemically Optimising Operational Efficiency of Molecular Rotary Motors

Unidirectional molecular rotary motors that harness photoinduced cis-trans (E-Z) isomerization are promising tools for the conversion of light energy to mechanical motion in nanoscale molecular machines. Considerable progress has been made in optimizing the frequency of ground-state rotation, but less attention has been focused on excited state processes. Here the excited state dynamics of a molecular motor with electron donor and acceptor substituents located to modify the excited-state reaction coordinate, without altering its stereochemistry, are studied. The substituents are shown to modify the photochemical yield of the isomerization without altering the motor frequency. By combining 50 fs resolution time-resolved fluorescence with ultrafast transient absorption spectroscopy the underlying excited-state dynamics are characterized. The Franck-Condon excited state relaxes in a few hundred femtoseconds to populate a lower energy dark state by a pathway that utilizes a volume conserving structural change. This is assigned to pyramidalization at a carbon atom of the isomerizing bridging double bond. The structure and energy of the dark state thus reached are a function of the substituent, with electron-withdrawing groups yielding a lower energy longer lived dark state. The dark state is coupled to the Franck Condon state and decays on a picosecond time scale via a coordinate that is sensitive to solvent friction, such as rotation about the bridging bond. Neither subpicosecond nor picosecond dynamics are sensitive to solvent polarity, suggesting that intramolecular charge transfer and solvation are not key driving forces for the rate of the reaction. Instead steric factors and medium friction determine the reaction pathway, with the sterically remote substitution primarily influencing the energetics. Thus, these data indicate a chemical method of optimizing the efficiency of operation of these molecular motors without modifying their overall rotational frequency

Photophysics of first-generation photomolecular motors: Resolving roles of temperature, friction, and medium polarity

Light-driven unidirectional molecular rotary motors have the potential to power molecular machines. Consequently, optimizing their speed and efficiency is an important objective. Here, we investigate factors controlling the photochemical yield of the prototypical unidirectional rotary motor, a sterically overcrowded alkene, through detailed investigation of its excited-state dynamics. An isoviscosity analysis of the ultrafast fluorescence decay data resolves friction from barrier effects and reveals a 3.4 ± 0.5 kJ mol−1 barrier to excited-state decay in nonpolar media. Extension of this analysis to polar solvents shows that this barrier height is a strong function of medium polarity and that the decay pathway becomes near barrierless in more polar media. Thus, the properties of the medium can be used as a route for controlling the motor’s excited-state dynamics. The connection between these dynamics and the quantum yield of photochemical isomerization is probed. The photochemical quantum yield is shown to be a much weaker function of solvent polarity, and the most efficient excited-state decay pathway does not lead to a strongly enhanced quantum yield for isomerization. These results are discussed in terms of the solvent dependence of the complex multidimensional excited-state reaction coordinate

Alkylated green fluorescent protein chromophores: Dynamics in the gas phase and in aqueous solution

Fluorescent labelling of macromolecular samples, including using the green fluorescent protein (GFP), has revolutionised the field of bioimaging. The ongoing development of fluorescent proteins require a detailed understanding of the photophysics of the biochromophore, and how chemical derivatisation influences the excited state dynamics. Here, we investigate the photophysical properties associated with the S1 state of three alkylated derivatives of the chromophore in GFP, in the gas phase using time-resolved photoelectron imaging, and in water using femtosecond fluorescence upconversion. The gas-phase lifetimes (1.6–10 ps), which are associated with the intrinsic (environment independent) dynamics, are substantially longer than the lifetimes in water (0.06–3 ps), attributed to stabilisation of both twisted intermediate structures and conical intersection seams in the condensed phase. In the gas phase, alkylation on the 3 and 5 positions of the phenyl ring slows the dynamics due to inertial effects, while a 'pre-twist' of the methine bridge through alkylation on the 2 and 6 positions significantly shortens the excited state lifetimes. Formation of a minor, long-lived (>>40 ps) excited state population in the gas phase is attributed to intersystem crossing to a triplet state, accessed because of a T1/S1 degeneracy in the so-called P-trap potential energy minimum associated with torsion of the single-bond in the bridging unit connecting to the phenoxide ring. A small amount of intersystem crossing is supported through TD-DFT molecular dynamics trajectories and MS-CASPT2 calculations. No such intersystem crossing occurs in water at T = 300 K or in ethanol at T ≈ 77 K, due to a significantly altered potential energy surface and P-trap geometry

Ultrafast ignition of a uni-directional molecular motor

Light-driven molecular motors convert light into mechanical energy via excited state reactions. In this work we follow sub-picosecond primary events in the cycle of a two-stroke unidirectional motor by fluorescence up-conversion and transient absorption

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research