Will it gel? Successful computational prediction of peptide gelators using physicochemical properties and molecular fingerprints

The self-assembly of low molecular weight gelators to form gels has enormous potential for cell culturing, optoelectronics, sensing, and for the preparation of structured materials. There is an enormous “chemical space” of gelators. Even within one class, functionalised dipeptides, there are many structures based on both natural and unnatural amino acids that can be proposed and there is a need for methods that can successfully predict the gelation propensity of such molecules. We have successfully developed computational models, based on experimental data, which are robust and are able to identify in silico dipeptide structures that can form gels. A virtual computational screen of 2025 dipeptide candidates identified 9 dipeptides that were synthesised and tested. Every one of the 9 dipeptides synthesised and tested were correctly predicted for their gelation properties. This approach and set of tools enables the “dipeptide space” to be searched effectively and efficiently in order to deliver novel gelator molecules

Ringing the eigenmodes from compact manifolds

We present a method for finding the eigenmodes of the Laplace operator acting on any compact manifold. The procedure can be used to simulate cosmic microwave background fluctuations in multi-connected cosmological models. Other applications include studies of chaotic mixing and quantum chaos.Comment: 11 pages, 8 figures, IOP format. To be published in the proceedings of the Cleveland Cosmology and Topology Workshop 17-19 Oct 1997. Submitted to Class. Quant. Gra

Sidechain control of porosity closure in multiple peptide-based porous materials by cooperative folding

Porous materials find application in separation, storage and catalysis. We report a crystalline porous solid formed by coordination of metal centres with a glycylserine dipeptide. We prove experimentally that the structure evolves from a solvated porous into a non-porous state as result of ordered displacive and conformational changes of the peptide that suppress the void space in response to environmental pressure. This cooperative closure, which recalls the folding of proteins, retains order in three-dimensions and is driven by the hydroxyl groups acting as H-bond donors in the peptide sequence through the serine residue. This ordered closure is also displayed by multipeptide solid solutions in which the combination of different sequences of amino acids controls their guest response in a non-linear way. This functional control can be compared to the effect of single point mutations in proteins, where the exchange of single amino acids can radically alter structure and functio

Second-generation nitazoxanide derivatives: thiazolides are effective inhibitors of the influenza A virus

Aim: The only small molecule drugs currently available for treatment of influenza A virus (IAV) are M2 ion channel blockers and sialidase inhibitors. The prototype thiazolide, nitazoxanide, has successfully completed Phase III clinical trials against acute uncomplicated influenza. Results: We report the activity of seventeen thiazolide analogs against A/PuertoRico/8/1934(H1N1), a laboratory-adapted strain of the H1N1 subtype of IAV, in a cell culture-based assay. A total of eight analogs showed IC50s in the range of 0.14–5.0 μM. Additionally a quantitative structure–property relationship study showed high correlation between experimental and predicted activity based on a molecular descriptor set. Conclusion: A range of thiazolides show useful activity against an H1N1 strain of IAV. Further evaluation of these molecules as potential new small molecule therapies is justified

Chaos, Fractals and Inflation

In order to draw out the essential behavior of the universe, investigations of early universe cosmology often reduce the complex system to a simple integrable system. Inflationary models are of this kind as they focus on simple scalar field scenarios with correspondingly simple dynamics. However, we can be assured that the universe is crowded with many interacting fields of which the inflaton is but one. As we describe, the nonlinear nature of these interactions can result in a complex, chaotic evolution of the universe. Here we illustrate how chaotic effects can arise even in basic models such as homogeneous, isotropic universes with two scalar fields. We find inflating universes which act as attractors in the space of initial conditions. These universes display chaotic transients in their early evolution. The chaotic character is reflected by the fractal border to the basin of attraction. The broader implications are likely to be felt in the process of reheating as well as in the nature of the cosmic background radiation.Comment: 16 pages, RevTeX. See published version for fig

Search for the <i>bb </i>decay of the Standard Model Higgs boson in associated (<i>W/Z)H</i> production with the ATLAS detector

A search for the bb¯ decay of the Standard Model Higgs boson is performed with the ATLAS experiment using the full dataset recorded at the LHC in Run 1. The integrated luminosities used are 4.7 and 20.3 fb−1 from pp collisions at √s=7 and 8 TeV, respectively. The processes considered are associated (W/Z)H production, where W → eν/μν, Z → ee/μμ and Z → νν. The observed (expected) deviation from the background-only hypothesis corresponds to a significance of 1.4 (2.6) standard deviations and the ratio of the measured signal yield to the Standard Model expectation is found to be μ = 0.52 ± 0.32 (stat.) ± 0.24 (syst.) for a Higgs boson mass of 125.36 GeV. The analysis procedure is validated by a measurement of the yield of (W/Z)Z production with Z→bb¯ in the same final states as for the Higgs boson search, from which the ratio of the observed signal yield to the Standard Model expectation is found to be 0.74 ± 0.09 (stat.) ± 0.14 (syst.)

Keeping calm in the face of change: towards optimisation of FRP by reasoning about change

Functional Reactive Programming (FRP) is an approach to reactive programming where systems are structured as networks of functions operating on signals (time-varying values). FRP is based on the synchronous data-flow paradigm and supports both (an approximation to) continuous-time and discrete-time signals (hybrid systems).What sets FRP apart from most other languages for similar applications is its support for systems with dynamic structure and for higher-order reactive constructs. This paper contributes towards advancing the state of the art of FRP implementation by studying the notion of signal change and change propagation in a setting of structurally dynamic networks of n-ary signal functions operating on mixed continuous-time and discrete-time signals. We first define an ideal denotational semantics (time is truly continuous) for this kind of FRP, along with temporal properties, expressed in temporal logic, of signals and signal functions pertaining to change and change propagation. Using this framework, we then show how to reason about change; specifically, we identify and justify a number of possible optimisations, such as avoiding recomputation of unchanging values. Note that due to structural dynamism, and the fact that the output of a signal function may change because time is passing even if the input is unchanging, the problem is significantly more complex than standard change propagation in networks with static structure

Texas Field Experiment Results: Performance of the Weatherization Assistance Program in Hot-Climate, Low-Income Homes

A field test involving 35 houses was performed in Texas between 2000 and 2003 to study the response of low-income homes in hot climates to weatherization performed as part of the U.S Department of Energy Weatherization Assistance Program and to investigate certain methods to improve weatherization performance. The study found that improved Program designs and the use of advanced energy audits resulted in better weatherization measures being installed (use of blower doors to guide the infiltration work, more frequent installation of attic insulation, and installation of wall insulation) in the study homes, improved space-heating savings performance compared to the Program as implemented in the hot climates in 1989, and more comfortable indoor temperatures. Two key policy dilemmas for Texas and other hot-climate states were highlighted by the study; namely, how to balance expenditures between installing cost-effective weatherization measures and performing health, safety, and repair items, and that health, safety, and repair items can have an adverse impact on energy savings, which further complicates the weatherization decision process. Several occupant and equipment-related behaviors were observed in the field test homes that help explain why audits may over predict energy consumptions and savings and why air-conditioning electricity savings are difficult to measure. Based on this study, it is recommended that states in hot climates be encouraged to select from an expanded list of measures using advanced audits or other techniques, and further studies examining the benefits obtained from air conditioner measures should be performed. In addition, guidelines should be developed for the hot-climate states on how to (a) balance the objectives of saving energy, improving health and safety, and addressing repair issues, and (b) select repair items

Structure-based design of nucleoside-derived analogues as sulfotransferase inhibitors

Sulfotransferases (STs) catalyse the transfer of a sulfonyl group (‘sulfation’) from the enzyme co-factor 3ʹ-phosphoadenosine 5ʹ-phosphosulfate (PAPS) to a variety of biomolecules. Tyrosine sulfation of proteins and carbohydrate sulfation play a crucial role in many protein-protein interactions and cell signalling pathways in the extracellular matrix. This is catalysed by several membrane-bound STs, including tyrosylprotein sulfotransferase 1 (TPST1) and heparan sulfate 2-O-sulfotransferase (HS2ST1). Recently, involvement of these enzymes and their post-translational modifications in a growing number of disease areas has been reported, including inflammation, cancer and Alzheimer’s disease. Despite their growing importance, the development of small molecules to probe the biological effect of TPST and carbohydrate ST inhibition remains in its infancy. We have used a structure-based approach and molecular docking to design a library of adenosine 3',5'-diphosphate (PAP) and PAPS mimetics based upon 2'-deoxyadenosine and using 2'-deoxy-PAP as a benchmark. The use of allyl groups as masked methyl esters was exploited in the synthesis of PAP-mimetics, and click chemistry was employed for the divergent synthesis of a series of PAPS-mimetics. A suite of in vitro assays employing TPST1 and HS2ST, and a kinase counter screen, were used to evaluate inhibitory parameters and relative specificity for the STs