Design, synthesis and evaluation of novel small molecule inhibitors of the histone methyltransferase DOT1L and ubiquitination facilitator Keap1

This thesis details the design, synthesis and evaluation of novel small molecule inhibitors of the histone methyltransferase DOT1L and the ubiquitination facilitator Keap1. The thesis is in two parts as outlined below. Part 1: The first part of this thesis details efforts towards identification of novel small molecule inhibitors of DOT1L, a histone methyltransferase which has been implicated in the development and proliferation of mixed lineage leukaemias (MLL). This work aims to optimise the drug-like properties of published DOT1L inhibitors while retaining potency, through further exploration of the nucleobase template. Structure-activity relationships (SARs) identified polar substituents and small heterocycles as favourable replacements for the halogen in 5-ITC, a small molecule inhibitor of DOT1L. Alternative nucleobase templates also demonstrated comparable DOT1L inhibition. To demonstrate proof of concept, a polar nitrile substituent was translated into the inhibitor Br-SAH as a direct replacement of the bromide. Activity was retained and a crystal structure obtained which demonstrated the nitrile occupied the same hydrophobic pocket. This work also demonstrated the use of a nitrile as a non-traditional replacement for heavy halogen atoms. Part 2: The second part of this thesis details identification of novel inhibitors of the Keap1-Nrf2 protein-protein interactions (PPI) using an approach based on kinetic target-guided synthesis (kTGS). Keap1 is a dimeric cytoplasmic protein that mediates the ubiquitination of Nrf2, a transcription factor that acts as a regulator of cellular antioxidant responses. Disruption of the PPI between Keap1 and Nrf2 has been shown to have a therapeutic benefit in diseases associated with oxidative stress and inflammation as well as providing a potential route to chemopreventative agents for cancer. Biased kTGS was applied as proof of concept. A biased ligand was designed and screened against a focused library of azides. The 1,3-dipolar cycloaddition products formed in the presence of the Keap1 Kelch domain were evaluated and validated through chemical synthesis and screening. A novel triazole structure was identified with improved activity over the initial biased fragment thus demonstrating kTGS as a valid approach for identifying novel inhibitors of the Keap1-Nrf2 PPI interaction

CHANCE ENCOUNTERS BETWEEN BODY AND BUILDINGS: NEW TECHNOLOGIES IN ARCHITECTURE AND DANCE

The fields of dance and architecture initially seem in direct opposition – one dedicated to movement and the other to stasis. In many ways dance appears to hold the many qualities ever beyond architecture; the opportunity of flight, of ‘liveness’, of the ephemeral. Importing ways of thinking as well as doing from dance into architectural practice is conditioned through the shared focus on the encounters between bodies and spaces. In grappling with the impact of new technologies on the design process, new kinds of movement and spaces are being produced. A key tactic that has emerged within both fields is that of chance. This is arguably the most radical shift that has occurred in the architectural design process. As well as the growing explorations of interactive, multi-media and virtual technologies in dance performances, has been the expansion of notational and choreographic programs that utilize unpredictability. The move toward abstracted systems in these programs endeavours to incorporate energy, force, direction and intent, opening up choreographies to undetermined movements. In this context what dance may provide for architecture, are methods that respond to the difficulty in retaining the animate body in the virtual acrobatics generated by new, generative, architectural programs. In this paper I will be examining the transformation of the architecture drawing through generative modelling programs based in indeterminacy. The implications of these new methodologies in terms of the design process and the animate body, are viewed in relation to dance experimentation in this area. By specifically looking at the digitised body geometries of choreographer William Forsythe, I hope to open both fields to new encounters between bodies and buildings

Materials have driven the historical development of the Tennis Racket

© 2019 by the authors. The tennis racket has developed since the origins of Lawn Tennis in the 1870s. This study investigated how the tennis racket developed from 1874 to 2017, using measurements and material classifications for 525 samples. Racket measurements covered geometric, inertial and dynamic properties, and the number of strings. Rackets predating 1970 were mainly wooden, and typically characterised by head areas below 0.05 m2, masses over 350 g and natural frequencies below 120 Hz. Rackets from the 1970s were made from wood, metal and fibre-polymer composites, with most postdating 1980 made from fibre-polymer composites with a larger head, lower mass and higher natural frequency than their predecessors. Principal component analysis was used to reduce the dimensionality of the number of variables. Principal component one (PCA1) accounted for 35% of the variance in the measured racket properties, and was found to be significantly affected by material. Head width was best correlated with principal component one (r = 0.897, p < 0.001), followed by head length (r = 0.841, p < 0.001) and natural frequency (r = 0.813, p < 0.001). Early rackets were constrained by the limitations of wood, and the move to composites, which began in the 1970s, allowed this observed increase in head size and natural frequency. As material development has been a major driver of racket design in the past, we propose that new materials and manufacturing techniques, like additively manufactured composites, could further improve the tennis racket. The measurement techniques described here can be used to monitor developments in racket design

Seasonal and interannual variability of North American isoprene emissions as determined by formaldehyde column measurements from space

Formaldehyde (HCHO) columns measured from space by solar UV backscatter allow mapping of reactive hydrocarbon emissions. The principal contributor to these emissions during the growing season is the biogenic hydrocarbon isoprene, which is of great importance for driving regional and global tropospheric chemistry. We present seven years (1995-2001) of HCHO column data for North America from the Global Ozone Monitoring Experiment (GOME), and show that the general seasonal and interannual variability of these data is consistent with knowledge of isoprene emission. There are some significant regional discrepancies with the seasonal patterns predicted from current isoprene emission models, and we suggest that these may reflect flaws in the models. The interannual variability of HCHO columns observed by GOME appears to follow the interannual variability of surface temperature, as expected from current isoprene emission models

Effects of the physical state of tropospheric ammonium-sulfate-nitrate particles on global aerosol direct radiative forcing

International audienceThe effect of aqueous versus crystalline sulfate-nitrate-ammonium tropospheric particles on global aerosol direct radiative forcing is assessed. A global three-dimensional chemical transport model predicts sulfate, nitrate, and ammonium aerosol mass. An aerosol thermodynamics model is called twice, once for the upper side (US) and once for lower side (LS) of the hysteresis loop of particle phase. On the LS, the sulfate mass budget is 40% solid ammonium sulfate, 12% letovicite, 11% ammonium bisulfate, and 37% aqueous. The LS nitrate mass budget is 26% solid ammonium nitrate, 7% aqueous, and 67% gas-phase nitric acid release due to increased volatility upon crystallization. The LS ammonium budget is 45% solid ammonium sulfate, 10% letovicite, 6% ammonium bisulfate, 4% ammonium nitrate, 7% ammonia release due to increased volatility, and 28% aqueous. LS aerosol water mass partitions as 22% effloresced to the gas-phase and 78% remaining as aerosol mass. The predicted US/LS global fields of aerosol mass are employed in a Mie scattering model to generate global US/LS aerosol optical properties, including scattering efficiency, single scattering albedo, and asymmetry parameter. Global annual average LS optical depth and mass scattering efficiency are, respectively, 0.023 and 10.7 m2 (g SO42?)?1, which compare to US values of 0.030 and 13.9 m2 (g SO42?)?1. Radiative transport is computed, first for a base case having no aerosol and then for the two global fields corresponding to the US and LS of the hysteresis loop. Regional, global, seasonal, and annual averages of top-of-the-atmosphere aerosol radiative forcing on the LS and US (FL and FU, respectively, in W m2?) are calculated. Including both anthropogenic and natural emissions, we obtain global annual averages of FL = ?0.750, FU = ?0.930, and ?FU,L = 24% for full sky calculations without clouds and FL = ?0.485, FU = ?0.605, and ?FU,L = 25% when clouds are included. Regionally, ?FU,L = 48% over the USA, 55% over Europe, and 34% over East Asia. Seasonally, ?FU,L varies from 18% in DJF to 75% in SON over the USA. The global annual average contribution from anthropogenic aerosol is FL = ?0.314 and FU = ?0.404, which yield normalized direct radiative forcings (G) of GL = ?205 W (g SO42?)?1 and GU = ?264 W (g SO42?)?1

Effects of the physical state of tropospheric ammonium-sulfate-nitrate particles on global aerosol direct radiative forcing

International audienceThe effect of aqueous versus crystalline sulfate-nitrate-ammonium tropospheric particles on global aerosol direct radiative forcing is assessed. A global three-dimensional chemical transport model predicts sulfate, nitrate, and ammonium aerosol mass. An aerosol thermodynamics model is called twice, once for the upper side (US) and once for lower side (LS) of the hysteresis loop of particle phase. On the LS, the sulfate mass budget is 40% solid ammonium sulfate, 12% letovicite, 11% ammonium bisulfate, and 37% aqueous. The LS nitrate mass budget is 26% solid ammonium nitrate, 7% aqueous, and 67% gas-phase nitric acid release due to increased volatility upon crystallization. The LS ammonium budget is 45% solid ammonium sulfate, 10% letovicite, 6% ammonium bisulfate, 4% ammonium nitrate, 7% ammonia release due to increased volatility, and 28% aqueous. LS aerosol water mass partitions as 22% effloresced to the gas-phase and 78% remaining as aerosol mass. The predicted US/LS global fields of aerosol mass are employed in a Mie scattering model to generate global US/LS aerosol optical properties, including scattering efficiency, single scattering albedo, and asymmetry parameter. Global annual average LS optical depth and mass scattering efficiency are, respectively, 0.023 and 10.7 m2 (g SO4-2)-1, which compare to US values of 0.030 and 13.9 m2 (g SO4-2)-1. Radiative transport is computed, first for a base case having no aerosol and then for the two global fields corresponding to the US and LS of the hysteresis loop. Regional, global, seasonal, and annual averages of top-of-the-atmosphere aerosol radiative forcing on the LS and US (FL and FU, respectively, in W m-2) are calculated. Including both anthropogenic and natural emissions, we obtain global annual averages of FL=-0.750, FU=-0.930, and DFU,L=24% for full sky calculations without clouds and FL=-0.485, FU=-0.605, and DFU,L=25% when clouds are included. Regionally, DFU,L=48% over the USA, 55% over Europe, and 34% over East Asia. Seasonally, DFU,L varies from 18% in DJF to 75% in SON over the USA. The global annual average contribution from anthropogenic aerosol is FL=-0.314 and FU=-0.404, which yield normalized direct radiative forcings (G) of GL=-205 W (g SO4-2)-1 and GU=-264 W (g SO4-2)-1

Global patterns of the double mutualism phenomenon

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordData deposition: Data available from the Dryad Digital Repository: (Fuster et al. 2018).A double mutualism (DM) occurs when two interacting species benefit each other in two different functions, e.g. when an animal species acts both as pollinator and seed disperser of the same plant. Besides the double benefit, a DM also imposes a larger risk to both functions if the performance of one partner declines. We conducted the first global review of DMs involving pollinators and seed dispersers, aiming to: 1) assess their prevalence across ecosystems and biogeographical regions; 2) identify the main plant and animal taxa, and their traits, implicated in DMs; and 3) evaluate the conservation status of double mutualist species. We compiled published and unpublished DM records using specific search terms, noting the species involved, their conservation status and geographic location, as well as the type of study (species vs community‐level) in which the DM was detected. We identified 302 DM cases involving 207 plant and 92 animal species from 16 mainland and 17 island areas. Most records come from tropical regions and islands. Animals included birds (62%), mammals (22%), and reptiles (16%), mostly opportunist species; only 18% were nectarivores. Plants were mainly fleshy‐fruited shrub or tree species (59%) with actinomorphic flowers that were visited by several or many pollinator species (87%). Most (56%) DMs were detected in community‐level studies. DMs are mostly prevalent in ecosystems with limited food resources and mutualist partners, and with high generalization levels. Nearly 30% of the species involved in DMs are threatened according to IUCN criteria, 68% of which are found on islands. The high prevalence of DM on islands paired with the threat status of island species suggest that the loss of a double mutualists and its cascading consequences may have a severe impact on community composition and functioning of fragile island ecosystems.Spanish Governmen

Dissipation of vibration in rough contact

The relationship which links the normal vibration occurring during the sliding of rough surfaces and the nominal contact area is investigated. Two regimes are found. In the first one, the vibrational level does not depend on the contact area, while in the second one, it is propor- tional to the contact area. A theoretical model is proposed. It is based on the assumption that the vibrational level results from a competition between two processes of vibration damping, the internal damping of the material and the contact damping occurring at the interface

Geophysical validation and long-term consistency between GOME-2/MetOp-A total ozone column and measurements from the sensors GOME/ERS-2, SCIAMACHY/ENVISAT and OMI/Aura

The main aim of the paper is to assess the consistency of five years of Global Ozone Monitoring Experiment-2/Metop-A [GOME-2] total ozone columns and the long-term total ozone satellite monitoring database already in existence through an extensive inter-comparison and validation exercise using as reference Brewer and Dobson ground-based measurements. The behaviour of the GOME-2 measurements is being weighed against that of GOME (1995–2011), Ozone Monitoring Experiment [OMI] (since 2004) and the Scanning Imaging Absorption spectroMeter for Atmospheric CartograpHY [SCIAMACHY] (since 2002) total ozone column products. Over the background truth of the ground-based measurements, the total ozone columns are inter-evaluated using a suite of established validation techniques; the GOME-2 time series follow the same patterns as those observed by the other satellite sensors. In particular, on average, GOME-2 data underestimate GOME data by about 0.80%, and underestimate SCIAMACHY data by 0.37% with no seasonal dependence of the differences between GOME-2, GOME and SCIAMACHY. The latter is expected since the three datasets are based on similar DOAS algorithms. This underestimation of GOME-2 is within the uncertainty of the reference data used in the comparisons. Compared to the OMI sensor, on average GOME-2 data underestimate OMI_DOAS (collection 3) data by 1.28%, without any significant seasonal dependence of the differences between them. The lack of seasonality might be expected since both the GOME data processor [GDP] 4.4 and OMI_DOAS are DOAS-type algorithms and both consider the variability of the stratospheric temperatures in their retrievals. Compared to the OMI_TOMS (collection 3) data, no bias was found. We hence conclude that the GOME-2 total ozone columns are well suitable to continue the long-term global total ozone record with the accuracy needed for climate monitoring studies

Effects of the physical state of tropospheric ammonium-sulfate-nitrate particles on global aerosol direct radiative forcing

The effect of aqueous versus crystalline sulfate-nitrate-ammonium tropospheric particles on global aerosol direct radiative forcing is assessed. A global three-dimensional chemical transport model predicts sulfate, nitrate, and ammonium aerosol mass. An aerosol thermodynamics model is called twice, once for the upper side (US) and once for lower side (LS) of the hysteresis loop of particle phase. On the LS, the sulfate mass budget is 40% solid ammonium sulfate, 12% letovicite, 11% ammonium bisulfate, and 37% aqueous. The LS nitrate mass budget is 26% solid ammonium nitrate, 7% aqueous, and 67% gas-phase nitric acid release due to increased volatility upon crystallization. The LS ammonium budget is 45% solid ammonium sulfate, 10% letovicite, 6% ammonium bisulfate, 4% ammonium nitrate, 7% ammonia release due to increased volatility, and 28% aqueous. LS aerosol water mass partitions as 22% effloresced to the gas-phase and 78% remaining as aerosol mass. The predicted US/LS global fields of aerosol mass are employed in a Mie scattering model to generate global US/LS aerosol optical properties, including scattering efficiency, single scattering albedo, and asymmetry parameter. Global annual average LS optical depth and mass scattering efficiency are, respectively, 0.023 and 10.7 m² (g SO₄^-2)^-1, which compare to US values of 0.030 and 13.9 m² (g SO₄^-2)^-1. Radiative transport is computed, first for a base case having no aerosol and then for the two global fields corresponding to the US and LS of the hysteresis loop. Regional, global, seasonal, and annual averages of top-of-the-atmosphere aerosol radiative forcing on the LS and US (<i>F_L </i> and <i>F_U</i>, respectively, in W m^-2) are calculated. Including both anthropogenic and natural emissions, we obtain global annual averages of <i>F_L</i>=-0.750, <i>F_U</i>=-0.930, and <font face='Symbol'>D</font><i>F_U,L</i>=24% for full sky calculations without clouds and <i>F_L</i>=-0.485, <i>F_U</i>=-0.605, and <font face='Symbol'>D</font><i>F_U,L</i>=25% when clouds are included. Regionally, <font face='Symbol'>D</font><i>F_U,L</i>=48% over the USA, 55% over Europe, and 34% over East Asia. Seasonally, <font face='Symbol'>D</font><i>F_U,L</i>varies from 18% in DJF to 75% in SON over the USA. The global annual average contribution from anthropogenic aerosol is <i>F_L</i>=-0.314 and <i>F_U</i>=-0.404, which yield normalized direct radiative forcings (<i>G</i>) of <i>G_L</i>=-205 W (g SO₄^-2)^-1 and <i>G_U</i>=-264 W (g SO₄^-2)^-1