Development and use of databases for ligand-protein interaction studies

This project applies structure-activity relationship (SAR), structure-based and database mining approaches to study ligand-protein interactions. To support these studies, we have developed a relational database system called EDinburgh University Ligand Selection System (EDULISS 2.0) which stores the structure-data files of +5.5 million commercially available small molecules (+4.0 million are recognised as unique) and over 1,500 various calculated molecular properties (descriptors) for each compound. A user-friendly web-based interface for EDULISS 2.0 has been established and is available at http://eduliss.bch.ed.ac.uk/. We have utilised PubChem bioassay data from an NMR based screen assay for a human FKBP12 protein (PubChem AID: 608). A prediction model using a Logistic Regression approach was constructed to relate the assay result with a series of molecular descriptors. The model reveals 38 descriptors which are found to be good predictors. These are mainly 3D-based descriptors, however, the presence of some predictive functional groups is also found to give a positive contribution to the binding interaction. The application of a neural network technique called Self Organising Maps (SOMs) succeeded in visualising the similarity of the PubChem compounds based on the 38 descriptors and clustering the 36 % of active compounds (16 out of 44) in a cluster and discriminating them from 95 % of inactive compounds. We have developed a molecular descriptor called the Atomic Characteristic Distance (ACD) to profile the distribution of specified atom types in a compound. ACD has been implemented as a pharmacophore searching tool within EDULISS 2.0. A structure-based screen succeeded in finding inhibitors for pyruvate kinase and the ligand-protein complexes have been successfully crystallised. This study also discusses the interaction of metal-binding sites in metalloproteins. We developed a database system and web-based interface to store and apply geometrical information of these metal sites. The programme is called MEtal Sites in Proteins at Edinburgh UniverSity (MESPEUS; http://eduliss.bch.ed.ac.uk/MESPEUS/). MESPEUS is an exceptionally versatile tool for the collation and abstraction of data on a wide range of structural questions. As an example we carried out a survey using this database indicating that the most common protein types which contain Mg-OATP-phosphate site are transferases and the most common pattern is linkage through the β- and γ-phosphate groups

Taiwanese parents’ perspectives on young children’s use of information communication technology

IntroductionHow parents think and feel about their children’s use of technology can influence how their kids behave online. The family’s socioeconomic status (SES) may also affect this influence. In light of this, this research emphasizes the need for more investigation into parental attitudes and the role of SES in shaping how children consume media.MethodsThis study surveyed 629 Taiwanese parents to explore their attitudes toward their young children’s use of information communication technology (ICT), usage patterns, and the interplay with socioeconomic status.ResultsThe findings revealed a significant disconnect: although approximately 50% of parents considered above six years old to be a suitable age for children to start ICT, over 80% of children had already engaged with ICT before that age, indicating a large disparity between parental expectations and actual initiation. Furthermore, parents highlighted “learning interest” and “various content” as the most positive impacts of children’s ICT use, while “addiction and overreliance” emerged as their primary concern. Notably, parents, as a whole, tended to perceive their child’s ICT use more negative than positively, with fathers displaying greater acceptance of negative viewpoints than mothers. Parental attitudes toward children’s ICT use were categorized into five clusters, ranging from balanced and optimistic views to value emphasis, conservatism, and negative doubts. This classification underscores the intricate and multifaceted nature of parental perspectives, encompassing both positive and negative outlooks on children’s ICT utilization.DiscussionThe findings underscore the nuanced character of parents’ attitudes toward technology, shaped by the intricacies and challenges posed by the digital era. These insights emphasize that parental attitudes go beyond a simplistic positive-negative divide, reflecting a comprehensive response to the opportunities and complexities inherent in the digital age

An in situ study on the coalescence of monolayer-protected Au-Ag nanoparticle deposits upon heating

The structural evolution of thiolate-protected nanoparticles of gold, silver, and their alloys with various Au/Ag ratios (3:1, 1:1, and 1:3) upon heating was investigated by means of in situ synchrotron radiation X-ray diffraction. The relationships between the coalescence and composition of nanoparticles, as well as the surfactant reactions, were clarified. Experimental results show that there existed a critical temperature ranging from 120°C to 164°C, above which the tiny broad X-ray diffraction peaks became sharp and strong due to particle coalescence. The coalescence temperatures for alloy nanoparticle deposits were clearly lower than those for pure metals, which can be ascribed to the rivalry between the thermodynamic effect due to alloying and the interactions between surface-assembled layers and the surface atoms of the nanoparticles. The strong affinity of thiolates to Ag and thus complex interactions give rise to a greater energy barrier for the coalescence of nanoparticles into the bulk and subsequent high coalescence temperature. The influences of particle coalescence on the optical and electrical properties of the nanoparticle deposits were also explored

Preparation of Bismuth Oxide Photocatalyst and Its Application in White-light LEDs

Bismuth oxide photocatalysts were synthesized and coated on the front surface of phosphor-converted white light-emitting diodes to produce a safe and environmentally benign lighting source. Bismuth oxide photocatalyst powders were synthesized with a spray pyrolysis method at 500°C, 600°C, 700°C, and 800°C. Using the absorption spectrum in the blue and UV regions of the bismuth oxide photocatalysts, the blue light and UV leakage problems of phosphor-converted white LEDs can be significantly reduced. The experimental results showed that bismuth oxide photocatalyst synthesized at 700°C exhibited the most superior spectrum inhibiting ability. The suppressed ratio reached 52.33% in the blue and UV regions from 360 to 420 nm. Related colorimetric parameters and the photocatalyst decomposition ability of fabricated white-light LEDs were tested. The CIE chromaticity coordinates (x,y) were (0.349, 0.393), and the correlated color temperature was 4991 K. In addition, the coating layer of photocatalyst can act as an air purifier and diffuser to reduce glare. A value of 66.2±0.60 ppmv of molecular formaldehyde gas can be decomposed in 120 mins

Targeting F-Box Protein Fbxo3 Attenuates Lung Injury Induced by Ischemia-Reperfusion in Rats

Background: Increasing evidence suggests that Fbxo3 signaling has an important impact on the pathophysiology of the inflammatory process. Fbxo3 protein inhibition has reduced cytokine-driven inflammation and improved disease severity in animal model of Pseudomonas-induced lung injury. However, it remains unclear whether inhibition of Fbxo3 protein provides protection in acute lung injury induced by ischemia-reperfusion (I/R). In this study, we investigated the protective effects of BC-1215 administration, a Fbxo3 inhibitor, on acute lung injury induced by I/R in rats.Methods: Lung I/R injury was induced by ischemia (40 min) followed by reperfusion (60 min). The rats were randomly assigned into one of six experimental groups (n = 6 rats/group): the control group, control + BC-1215 (Fbxo3 inhibitor, 0.5 mg/kg) group, I/R group, or I/R + BC-1215 (0.1, 0.25, 0.5 mg/kg) groups. The effects of BC-1215 on human alveolar epithelial cells subjected to hypoxia-reoxygenation (H/R) were also examined.Results: BC-1215 significantly attenuated I/R-induced lung edema, indicated by a reduced vascular filtration coefficient, wet/dry weight ratio, lung injury scores, and protein levels in bronchoalveolar lavage fluid (BALF). Oxidative stress and the level of inflammatory cytokines in BALF were also significantly reduced following administration of BC-1215. Additionally, BC-1215 mitigated I/R-stimulated apoptosis, NF-κB, and mitogen-activated protein kinase activation in the injured lung tissue. BC-1215 increased Fbxl2 protein expression and suppressed Fbxo3 and TNFR associated factor (TRAF)1–6 protein expression. BC-1215 also inhibited IL-8 production and NF-κB activation in vitro in experiments with alveolar epithelial cells exposed to H/R.Conclusions: Our findings demonstrated that Fbxo3 inhibition may represent a novel therapeutic approach for I/R-induced lung injury, with beneficial effects due to destabilizing TRAF proteins

Dominance of Tau Burden in Cortical Over Subcortical Regions Mediates Glymphatic Activity and Clinical Severity in PSP

Background: Progressive supranuclear palsy (PSP) is a tauopathy that involves subcortical regions but also extends to cortical areas. The clinical impact of different tau protein sites and their influence on glymphatic dysfunction have not been investigated. Patients and Methods: Participants (n = 55; 65.6 ± 7.1 years; 29 women) with PSP (n = 32) and age-matched normal controls (NCs; n = 23) underwent 18F-Florzolotau tau PET, MRI, PSP Rating Scale (PSPRS), and Mini-Mental State Examination. Cerebellar gray matter (GM) and parametric estimation of reference signal intensity were used as references for tau burden measured by SUV ratios. Glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS). Results: Parametric estimation of reference signal intensity is a better reference than cerebellar GM to distinguish tau burden between PSP and NCs. PSP patients showed higher cortical and subcortical tau SUV ratios than NCs (P < 0.001 and <0.001). Cortical and subcortical tau deposition correlated with PSPRS, UPDRS, and Mini-Mental State Examination scores (all P’s < 0.05). Cortical tau deposition was further associated with the DTI-ALPS index and frontal-temporal-parietal GM atrophy. The DTI-ALPS indexes showed a significantly negative correlation with the PSPRS total scores (P < 0.01). Finally, parietal and occipital lobe tau depositions showed mediating effects between the DTI-ALPS index and PSPRS score. Conclusions: Cortical tau deposition is associated with glymphatic dysfunction and plays a role in mediating glymphatic dysfunction and clinical severity. Our results provide a possible explanation for the worsening of clinical severity in patients with PSP

Experimental evidence for Berry curvature multipoles in antiferromagnets

Berry curvature multipoles appearing in topological quantum materials have recently attracted much attention. Their presence can manifest in novel phenomena, such as nonlinear anomalous Hall effects (NLAHE). The notion of Berry curvature multipoles extends our understanding of Berry curvature effects on the material properties. Hence, research on this subject is of fundamental importance and may also enable future applications in energy harvesting and high-frequency technology. It was shown that a Berry curvature dipole can give rise to a 2nd order NLAHE in materials of low crystalline symmetry. Here, we demonstrate a fundamentally new mechanism for Berry curvature multipoles in antiferromagnets that are supported by the underlying magnetic symmetries. Carrying out electric transport measurements on the kagome antiferromagnet FeSn, we observe a 3rd order NLAHE, which appears as a transverse voltage response at the 3rd harmonic frequency when a longitudinal a.c. current drive is applied. Interestingly, this NLAHE is strongest at and above room temperature. We combine these measurements with a scaling law analysis, a symmetry analysis, model calculations, first-principle calculations, and magnetic Monte-Carlo simulations to show that the observed NLAHE is induced by a Berry curvature quadrupole appearing in the spin-canted state of FeSn. At a practical level, our study establishes NLAHE as a sensitive probe of antiferromagnetic phase transitions in other materials, such as moir\'e superlattices, two-dimensional van der Waal magnets, and quantum spin liquid candidates, that remain poorly understood to date. More broadly, Berry curvature multipole effects are predicted to exist for 90 magnetic point groups. Hence, our work opens a new research area to study a variety of topological magnetic materials through nonlinear measurement protocols

EDULISS: a small-molecule database with data-mining and pharmacophore searching capabilities

We present the relational database EDULISS (EDinburgh University Ligand Selection System), which stores structural, physicochemical and pharmacophoric properties of small molecules. The database comprises a collection of over 4 million commercially available compounds from 28 different suppliers. A user-friendly web-based interface for EDULISS (available at http://eduliss.bch.ed.ac.uk/) has been established providing a number of data-mining possibilities. For each compound a single 3D conformer is stored along with over 1600 calculated descriptor values (molecular properties). A very efficient method for unique compound recognition, especially for a large scale database, is demonstrated by making use of small subgroups of the descriptors. Many of the shape and distance descriptors are held as pre-calculated bit strings permitting fast and efficient similarity and pharmacophore searches which can be used to identify families of related compounds for biological testing. Two ligand searching applications are given to demonstrate how EDULISS can be used to extract families of molecules with selected structural and biophysical features