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Fast and reliable NMR-based fragment scoring for drug discovery
No full textTwo Bruker data files are provided that were acquired using three NMR experiments for the determination of KDs of protein-ligand interactions. One used 40uM naproxen and the other 40uM naproxen and 1uM HSA.
The abstract of the associated publication is provided below:
Fragment-Based Drug Discovery (FBDD) is a powerful strategy used in the development of new therapeutics. Molecular fragments are screened against a target protein, where interactions are typically characterized by a low affinity. Nuclear Magnetic Resonance (NMR) spectroscopy is well-suited to detect weak protein-ligand interactions and is therefore often used in FBDD. However, while NMR is very effective in initial screening, follow-up NMR experiments to measure binding affinities (i.e., KDs) are labor-intensive and time-consuming. To address this challenge, we have developed an innovative SHARPER NMR fragment scoring technique. The high sensitivity of SHARPER NMR dramatically reduces the data acquisition times, allowing faster and more accurate quantification of fragment KDs from ligand titration curves. To further accelerate fragment scoring, a machine learning model was developed that accurately ranks fragment affinities from only two SHARPER titration points. The resulting integrated method, termed “ML-boosted 1H LB SHARPER NMR”, produced signifi-cant time savings; using a 600 MHz QCI cryoprobe, KD values of up to 144 ligands in a day could be determined under our conditions, compared with only a handful achievable by traditional approaches. The proposed methodology will shorten the transition from hits to lead compounds, accelerating the drug discovery process by rapidly and reliably evaluating fragment binding, providing informed decision-making in the early stages of FBDD.The data are described in the SHARPER_for_KD_determination fil
Harvesting Atmospheres Dataset
No full textAbstract: The atmosphere of an interior space within an architectural built form can be defined by the interactions between the material and immaterial elements surrounding the in-habitant of a space, expressed through our own responding embodied experience. These psychologically tangible yet often immaterial experiences are deeply embodied, realised through our inter-connected visual perception, haptic engagement, auditory characteristics, temporal movement and thermal comfort. The study questions how we can harvest useful data to explore atmosphere as an ‘in-between’ state between perceiver and surroundings, through aligning physical environmental recordings with felt personal responses over parallel time-based studies. The approach explored analyses a set of existing spaces through harvesting of sensory elements using on-site, temporal recordings and participatory haptic engagement. Physical presence is recorded through measured environmental data, and audited through a theoretical stance of ‘conservation of mass’, as each extracted element is replaced and balanced by the other sensorial elements, supporting a holistic experience. Evolving thinking around design approaches promoting awareness of atmospheric sensibilities can ensure we do not lose the rich opportunities that sensory design can provide for contemporary architectural design practice. Harvesting atmospheres seeks to describe the broad, elemental nature of sensory design, defining examples of real-time temporary, elusive boundaries and fluid domains, that shift spaces between atmospheric experiences, whilst supporting the interconnected collage of the ‘in-between’ complexity of designing with this realm.'Documentation Information Harvesting Atmospheres.txt
Effect of movement goal on countermovement jump performance: An exploratory analysis of different sporting demands
No full textThis study explored the influence of different counter movement jump (CMJ) goals on performance, kinetic, and kinematic variables between 56 elite track and field (T&F), football, and futsal athletes. Within and between-sport difference were compared when using the goals: (a) “jump as high as possible” (CMJh) and (b) “jump as fast as possible” (CMJf), using a mixed MANOVA and follow-up univariate mixed ANOVAs. Movement goals had a significant main effect on all variables (p < .001). Compared to CMJh, CMJf elicited higher mean propulsive power normalized to body mass (MPPbm ) and reactive strength index (RSI), alongside lower jump height, contraction time (CT), propulsive displacement, and countermovement velocity (CMvelocity). Sport interaction analyses revealed that T&F athletes consistently outperformed the other sports in RSI across both movement goals. Significant differences in MPPbm and CT emerged between T&F and football. Additionally, a significant interaction between Movement goal and Sport was found for CMvelocity, indicated that T&F and football athletes increased their CM velocity under CMJh, while futsal players maintained similar downward velocities across both movement goals. In conclusion, movement goals significantly modify CMJ performance variables in elite athletes, and these effects are further influenced by sport specialization. Furthermore, adaptations in motor control processes according to the specific movement goals emphasize the need for task-specific and context-relevant communication. Coaches should align goal instructions with both the targeted task goals and the athletes’ sporting context to optimize training outcomes and athlete assessment
Trained neural networks and model data for `Online learning in idealized ocean gyres`
No full textCalculations performed using bt_ocean. bt_ocean is a differentiable finite difference solver for the barotropic vorticity equation on a beta-plane, for classic wind-forced barotropic ocean gyre simulations. The latest version of bt_ocean is available at https://github.com/jrmaddison/bt_ocean. For documentation and examples please visit https://jrmaddison.github.io/bt_ocean
Sex-dimorphic proteo-genetic architecture
No full textSex-stratified GWAS can help shed light on sexual differences in genetic architecture. In June et al (2025) we conducted sex-stratified Genome-wide association study across blood protein profiles and prevalence of disorders in UK Biobank data to assess the sex-dimorphic effect of genetics on protein level, in a search for genetic variants that presented significant differences in association to the traits considered. These are summary statistics of genome-wide association on protein levels and prevalences of disorders througth the study on sex-dimorphic proteo-genetic archtecture
Direct Observation of the Activation of MscL in Tethered Lipid Bilayers by an Antimicrobial Peptide
No full textData and Python code to support the manuscript "Direct Observation the Activation of MscL in Tethered Lipid Bilayers by an Antimicrobial Peptide". Abstract: Hypothesis Membrane proteins serve a wide range of vital roles in the functioning of living organisms. They account for approximately 20% to 30% of the genomes across bacterial, archaeal, and eukaryotic organisms. They are responsible for many cellular functions, such as signaling, ion and molecule transport, binding and catalytic reactions. Compared to other classes of proteins, determining membrane protein structures remains a challenge, in large part due to the difficulty in establishing experimental conditions that can preserve the correct conformation and function of the protein in isolation from its native environment. Many therapeutics target membrane proteins which are accessible on the surface of cells. Here we hypothesize that the observed efficacy of antimicrobial peptides (AMPs) that interact with bacterial membranes may in part be associated with their triggering of MscL (Mechansensitive Ion Channel of Large Conductance) gating. We further conjecture that the insertion of peptides into the membrane induces significant changes in membrane tension and/or curvature, leading to prolonged gating of the MscL channels.
Experiments We present realistic model membrane systems containing MscL. We investigated the ion channel in lipid vesicles and in a planar lipid bilayer. We developed a novel method for protein-lipid planar bilayer formation, avoiding the use of detergents. By using a polymeric tether our planar membrane mimetic was not constrained by the underlying solid substrate, making it sufficiently flexible to allow for increases in bilayer curvature and changes in membrane tension. We used quartz crystal microbalance with dissipation (QCM-D), and polarised neutron reflectivity (PNR) to show the formation of MscL containing phospholipid bilayers, tethered with a high density PEG layer onto gold substrates from vesicle rupture. The MscL containing vesicles were separately characterised with small angle neutron scattering (SANS).
Findings MscL was expressed into vesicles using cell free protein expression. Analysing these vesicles with small angle neutron scattering, the radius of gyration of the protein was determined to be between 26-29~\AA{}, consistent with the crystal structure of individual MscL channels. The MscL composition of the formed bilayer was 14\%v/v, close to the initial volume composition of the vesicles at ~13.6% and a protein protrusion extending ca. 46~\AA{} into the solvent was determined by PNR. Addition of 1.6 and 3.2 uM pexiganan resulted in a decrease in the protrusion of MscL (from ~46 to ~38~\AA{}). To our knowledge, these findings represent the first direct experimental evidence of a structural change in the C-terminus containing protrusion of MscL, triggered by an antimicrobial peptide. This adds to our understanding of antimicrobial peptide action in therapeutic treatments.Jupyter notebooks containing code to fit polarized neutron reflectivity data
Tether_bilayer_only_model-RefNX_volumes_final-Copy3.ipynb
MscL_1p6_PXG_model-RefNX_volumes_final.ipynb
MscL_3p2_PXG_model-RefNX_volumes_final.ipynb
SANS model fits and data
LysoPC
LysoPCmodel_1level_GP.csv
SANS_LysoPC_D2O.txt
MscLVesicle
MscLVesicle_2levelGPmodelfit.csv
SANS_MscLVesicle_D2O.txt
MscLVesicle post Lyso-PC
MscLVesicle_model_2level_GP.csv
SANS_MscLVesicle_LysoPC_D2O.txt
MscLVesicle post PXG
MscLvesicleafterPXG_model_2levelGP.csv
SANS_MscLVesicleafterPXG_D2O.txt
MscLVesicle(pre-PXG)
MscLVesicle_model_2level_GP.csv
SANS_MscLVesicle_D2O.txt
Neutron reflectivity datafiles used in the Jupyter notebooks
IvsQ_26838_26839_26840_IvsQ_26838_1_IvsQ_26839_1_IvsQ_26840_1.dat.txt
IvsQ_26841_26842_26843_IvsQ_26841_1_IvsQ_26842_1_IvsQ_26843_1.dat.txt
IvsQ_26841_26842_26843_IvsQ_26841_2_IvsQ_26842_2_IvsQ_26843_2.dat.txt
IvsQ_26844_26845_26846_IvsQ_26844_1_IvsQ_26845_1_IvsQ_26846_1.dat.txt
IvsQ_26844_26845_26846_IvsQ_26844_2_IvsQ_26845_2_IvsQ_26846_2.dat.txt
POLLREFfinalIvsQ_26838_26839_26840_IvsQ_26838_1_IvsQ_26839_1_IvsQ_26840_1.dat
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POLLREFfinalIvsQ_26854_26855_26856_IvsQ_26854_1_IvsQ_26855_1_IvsQ_26856_1.dat.txt
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POLLREFfinalIvsQ_26860_26861_26862_IvsQ_26860_1_IvsQ_26861_1_IvsQ_26862_1.dat.txt
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POLLREFfinalIvsQ_26863_26864_26865_IvsQ_26863_1_IvsQ_26864_1_IvsQ_26865_1.dat.txt
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POLLREFfinalIvsQ_26875_26876_26877_IvsQ_26875_1_IvsQ_26876_1_IvsQ_26877_1.dat.txt
POLLREFfinalIvsQ_26875_26876_26877_IvsQ_26875_2_IvsQ_26876_2_IvsQ_26877_2.dat.txt
POLLREFfinalIvsQ_26878_26879_26880_IvsQ_26878_1_IvsQ_26879_1_IvsQ_26880_1.dat.txt
POLLREFfinalIvsQ_26878_26879_26880_IvsQ_26878_2_IvsQ_26879_2_IvsQ_26880_2.dat.txt
POLLREFfinalIvsQ_26881_26882_26883_IvsQ_26881_1_IvsQ_26882_1_IvsQ_26883_1.dat.txt
POLLREFfinalIvsQ_26881_26882_26883_IvsQ_26881_2_IvsQ_26882_2_IvsQ_26883_2.dat.tx
High Throughput, image based drug screening on patient derived, glioblastoma stem cell lines using Cell Painting staining for target agnostic, phenotypic readouts
No full text384w microplate format of high throughput, high content drug screening data from image based readouts. Screening was conducted against 6 glioma stem cell lines using multple drug libraries using approved and pre-clinical compounds. The dataset includes quantified image analysis from CellProfiler pipeline outputs: Raw data and processed data (feature re-scaling/transformation, removal of redundant features, normalisation to dmso), including metadata and related plate maps/informationRefer to README.txt file. Dataset will be split across each drug library screened
Anonymised transcripts from a research project on patient and transplant staff experiences with liver transplantation and the transplant benefit score
No full textThe Transplant Benefit Score (TBS) was introduced in the UK in March 2018 as a method of allocating DBD (donation after brain death) livers for transplantation. The TBS is both far more algorithmically complex than the previous system of allocation, and offers less clinician autonomy in allocation decisions, with livers being matched to particular patients from a national database. The TBS has been the subject of recent media attention, with pieces from BBC News and The Financial Times questioning its fairness and comprehensibility. This data set is the result of a qualitative empirical research project which interviewed 20 patients and 9 transplant staff on their perspectives on the TBS. The project considers the ethics of involving complex algorithmic systems in high stakes resource allocation. The data set includes participant perspectives on information disclosure and patient consent, trust, distributive justice, the staff-patient relationship, the clinical role, amongst other topics
Identification of an upper limit to the laser pulse duration in photonic band-edge liquid crystal lasers
No full textThe supplied data pertain to the graphs presented in "Identification of an upper limit to the laser pulse duration in photonic band-edge liquid crystal lasers". The data are accompanied by a README file which describe in further detail each of the data sets supplied in the Excel file
Investigating TRPM3 Modulation and Cyst Reversibility in Ex Vivo and Organoid Models of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
No full textAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, affecting approximately 1 in 1000 live births. It is characterised by multiple fluid-filled cysts in renal tubules. ADPKD is associated with mutations in the PKD1 and PKD2 genes, which encode the proteins polycystin 1 (PC1) and polycystin 2 (PC2). PC1 is a transmembrane protein that acts as a mechano-sensor, while PC2 is a non-selective cation channel that belongs to the transient receptor potential (TRP) superfamily. PC1 and PC2 form a heterodimer complex in the primary cilium, crucial for regulating intracellular calcium levels. Recent research suggests that TRPM3, another TRP family member, is necessary for PC2's ciliary function. Therefore, I analysed the impact of TRPM3 activators (nifedipine and CIM0216) and inhibitors (isosakuranetin, primidone, and diclofenac) on cyst formation in cultured E12.5 mouse kidneys which were exposed to various concentrations of forskolin, a compound known to induce cyst formation in kidney cultures. The results indicated that cyst formation occurred at lower forskolin concentrations in kidney rudiments treated with TRPM3 antagonists. In contrast, TRPM3 agonists significantly reduced cyst formation, especially at high forskolin concentrations, compared to kidneys treated with forskolin alone. Among the TRPM3 agonists tested, nifedipine—an FDA-approved antihypertensive drug—showed potential as a therapeutic for ADPKD.
Isosakuranetin was the TRPM3 antagonist that most significantly increased forskolin sensitivity. I generated a drug-induced PKD model by treating mouse kidney rudiments with isosakuranetin and forskolin to analyse cyst reversibility. Cysts in my PKD model originated from proximal tubules and showed disrupted apical-basal polarity. Upon isosakuranetin and forskolin withdrawal, cysts shrank and eventually disappeared with no detectable cell death.
I showed that siRNA-based downregulation was not a useful technique for designing a reversible cyst-forming organoid model, at least in my experimental conditions.
To test whether similar results in cyst reversibility could be achieved in mutant human systems, I developed a CRISPR/Cas13b-based reversible gene downregulation system for future studies. This tool has the potential for the analysis of cyst regression in human organoid studies by inducing cyst formation through controlled downregulation of PKD1 or PKD2 genes, followed by gene re-expression.
Overall, the study suggests that TRPM3 could be a viable target for ADPKD treatment, and nifedipine may be a promising therapeutic option. The findings also provide detailed findings into cyst regression in an early developmental stage. However, it should be noted that all results obtained in these studies were from ex vivo mouse kidney rudiments. To obtain more reliable results, the data here should be confirmed in human ADPKD models. In this context, nifedipine can be tested in ADPKD patient-derived organoids or PKD1 or PKD2 mutant human organoid models