Design of novel compounds with the potential of dual PPARγ/α modulation for the management of metabolic syndrome

This study sought to identify a single molecule capable of managing all three manifestations of metabolic syndrome–hyperglycaemia, dyslipidaemia and hypertension. Two Protein Data Bank (PDB) depositions were selected and used to establish the baseline affinity that any designed molecule in this study should ideally exceed in order to be considered for further optimisation. These were PDB depositions 3VN2 and 2P54 describing the bound co-ordinates of the Peroxisome Proliferator Activated Receptor (PPAR) partial agonist and Angiotensin II Receptor (Ang(II)R) blocker telmisartan and of the experimental PPAR fibrate agonist GW590735 bound to their respective cognate receptors. These small molecules were extracted from their cognate receptors, docked into their non-cognate counterparts, conformational analysis performed, and the optimal conformers were selected as template scaffolds in two parallel processes. The first was a fragment based de novo approach. Here, molecular moieties from the optimal telmisartan and GW590735 scaffolds modelled in their non-cognate targets and considered critical to binding were identified and modelled, in order to produce seed structures capable of sustaining molecular growth at user-directed sites designated as H.spc atoms subsequent to their being docked within the non-cognate Ligand Binding Pockets (LBPs). The second approach was a Virtual Screening (VS) exercise. Here, the optimal telmisartan and GW590735 conformers were submitted as query molecules to VS databases both individually and in the form of a consensus pharmacophore. This VS exercise identified structurally diverse molecules which were electronically and spatially similar to the queries and which were capable of modulating the target receptors. The molecular cohorts identified through both VS and the de novo approaches were filtered for Lipinski Rule compliance. The molecules that survived filtering were then re-docked into the non-cognate PPAR and/or _LBPs, conformational analysis re-performed and the affinity of the optimal conformer measured for its cognate receptor quantified. Comparison was made to the baseline and non-cognate receptor affinities previously established, and the molecules exhibiting dual affinities exceeding baseline values were selected for further optimisation. The use of the “tried and tested” Ang(II)R blocker and fibrate scaffolds as templates predisposes to the identification of novel structures devoid of unacceptable toxicity.peer-reviewe

Bridging the Gap Between Traditional Metadata and the Requirements of an Academic SDI for Interdisciplinary Research

Metadata has long been understood as a fundamental component of any Spatial Data Infrastructure, providing information relating to discovery, evaluation and use of datasets and describing their quality. Having good metadata about a dataset is fundamental to using it correctly and to understanding the implications of issues such as missing data or incorrect attribution on the results obtained for any analysis carried out. Traditionally, spatial data was created by expert users (e.g. national mapping agencies), who created metadata for the data. Increasingly, however, data used in spatial analysis comes from multiple sources and could be captured or used by nonexpert users – for example academic researchers ‐ many of whom are from non‐GIS disciplinary backgrounds, not familiar with metadata and perhaps working in geographically dispersed teams. This paper examines the applicability of metadata in this academic context, using a multi‐national coastal/environmental project as a case study. The work to date highlights a number of suggestions for good practice, issues and research questions relevant to Academic SDI, particularly given the increased levels of research data sharing and reuse required by UK and EU funders

Using Free and Open Source GIS to Automatically Create Standards-Based Spatial Metadata in Academia - First Investigations

The importance of understanding the quality of data used in any GIS operation has increased significantly as a result of the advent of Free and Open Source (FOSS) tools and Open Data, which in turn have encouraged non-specialists to make use of GIS. Metadata (data about data) traditionally provides a description of this quality information and permits data curation, but it is frequently deemed as complex to create and maintain. Additionally, it is generally stored separately from the data, leading to issues where updates to the data are not reflected in the metadata and to users not being aware that metadata exists. This paper describes an approach to address these issues in an academic context - tightly coupling data and metadata and automating elements of standards-based metadata creation and automating keyword generation and language detection. We describe research into the potential of the FOSS packages Quantum GIS and PostGIS to support this form of metadata generation and maintenance

Integrating expertises and ambitions for data-driven digital building permits - the EUNET4DBP

The digitalization of the process for building permit (involving the use of 3D information systems) is seen as a priority in a wide part of the world. Since it is a very multidisciplinary use case, involving a variety of stakeholders tackling complex issues and topics, some of them joined their efforts and skills in the European Network for Digital Building Permit. The initial activity of the network, after a review of on-going experiences, was a workshop to share knowledge about the topics involved and to identify the main ambitions of the network with respect to three pillars (i.e. Process - Rules and Requirements - Technology) and the related requirements. It was achieved through a collective brainstorming activity guided by digital tools, whose results were further analysed in a post-processing phase. Such results are presented in this paper and will be the base for planning the future network activity. © Authors 2020

Dysbiosis in the gut microbiota in patients with inflammatory bowel disease during remission

Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder which comprises two main conditions: Crohn’s disease (CD) and ulcerative colitis (UC). Although the etiology of IBD has not been fully elucidated, the gut microbiota is hypothesized to play a vital role in its development. The aim of this cross-sectional study was to characterize the fecal microbiota in CD or UC patients in a state of remission to reveal potential factors sustaining residual levels of inflammation and triggering disease relapses. Ninety-eight IBD patients in a state of clinical remission (66 UC, 32 CD) and 97 controls were recruited, and stool samples, as well as detailed patient data, were collected. After DNA extraction, the variable regions V1 and V2 of the 16S rRNA gene were amplified and sequenced. Patients with IBD had a decrease in alpha diversity compared to that of healthy controls, and the beta diversity indices showed dissimilarity between the cohorts. Healthy controls were associated with the beneficial organisms unclassified Akkermansia species (Akkermansia uncl.), Oscillibacter uncl., and Coprococcus uncl., while flavonoid-degrading bacteria were associated with IBD. Network analysis identified highly central and influential disease markers and a strongly correlated network module of Enterobacteriaceae which was associated with IBD and could act as drivers for residual inflammatory processes sustaining and triggering IBD, even in a state of low disease activity. The microbiota in IBD patients is significantly different from that of healthy controls, even in a state of remission, which implicates the microbiota as an important driver of chronicity in IBD. IMPORTANCE Dysbiosis in inflammatory bowel disease (IBD) has been implicated as a causal or contributory factor to the pathogenesis of the disease. This study, done on patients in remission while accounting for various confounding factors, shows significant community differences and altered community dynamics, even after acute inflammation has subsided. A cluster of Enterobacteriaceae was linked with Crohn’s disease, suggesting that this cluster, which contains members known to disrupt colonization resistance and form biofilms, persists during quiescence and can lead to chronic inflammation. Flavonoid-degrading bacteria were also associated with IBD, raising the possibility that modification of dietary flavonoids might induce and maintain remission in IBD.peer-reviewe

Microbial dynamics in newly diagnosed and treatment naïve IBD patients in the Mediterranean

Background: Microbial communities have long been suspected to influence inflammatory processes in the gastrointestinal tract of patients with inflammatory bowel disease. However, these effects are often influenced by treatments and can rarely be analyzed in treatment-naïve onset cases. Specifically, microbial differences between IBD pathologies in new onset cases have rarely been investigated and can provide novel insight into the dynamics of the microbiota in Crohn’s disease (CD) and ulcerative colitis (UC). Methods: Fifty-six treatment-naïve IBD onset patients (67.3% CD, 32.7% UC) and 97 healthy controls were recruited from the Maltese population. Stool samples were collected after diagnosis but before administration of anti-inflammatory treatments. Fecal microbial communities were assessed via 16S rRNA gene sequencing and subjected to ecological analyses to determine disease-specific differences between pathologies and disease subtypes or to predict future treatment options. Results: We identified significant differences in community composition, variability, and diversity between healthy and diseased individuals—but only small to no differences between the newly diagnosed, treatment-naïve UC and CD cohorts. Network analyses revealed massive turn-over of bacterial interactions between healthy and diseased communities, as well as between CD and UC communities, as signs of disease-specific changes of community dynamics. Furthermore, we identified taxa and community characteristics serving as predictors for prospective treatments. Conclusion: Untreated and newly diagnosed IBD shows clear differences from healthy microbial communities and an elevated level of disturbance, but only the network perspective revealed differences between pathologies. Furthermore, future IBD treatment is to some extent predictable by microbial community characteristics.peer-reviewe

Chemical and physical modifications of the surface of sisal agave fibre used as a reinforcement in epoxy resin : a review

A combination of sisal fibers and bio-based epoxy resin offers good potential for producing environmentally friendly bio-composites with improved or equivalent mechanical properties compared to those obtained using 100% synthetic resins. However, the poor interaction between the two materials caused by the different distribution of electrical charge over the atoms joined by the bond in the functional groups of the chemical structure (polarity) necessitates the modification of one of the surfaces of the constituents through various techniques. The paper discusses available literature on several treatments to improve the adhesion between sisal fibres and thermoset epoxy matrices by achieving favorable wettability, mechanical interlocking, and improved interaction through chemical bonding. It is shown that fiber washing in an NaOH solution followed by rinsing and drying is the prevalent chemical treatment. With NaOH treatments, researchers observed cleaner fibres and this promoted better adhesion with the epoxy matrix. Coupling agents such as silane treatments showed an improved resistance to fiber moisture absorption. Thermal treatments affect the fiber’s morphology by increasing the crystallinity of the cellulose leading to stiffer composites. It was also observed that the improvement in fiber-matrix adhesion had an adverse effect on the impact strength of the composite.peer-reviewe

ŽELJKO HOLJEVAC GOSPIĆ U VOJNOJ KRAJINI

A range of novel heterocyclic cations have been synthesized by the Rh­(III)-catalyzed oxidative C–N and C–C coupling of 1-phenylpyrazole, 2-phenylpyridine, and 2-vinylpyridine with alkynes (4-octyne and diphenylacetylene). The reactions proceed via initial C–H activation, alkyne insertion, and reductive coupling, and all three of these steps are sensitive to the substrates involved and the reaction conditions. Density functional theory (DFT) calculations show that C–H activation can proceed via a heteroatom-directed process that involves displacement of acetate by the neutral substrate to form charged intermediates. This step (which leads to cationic C–N coupled products) is therefore favored by more polar solvents. An alternative non-directed C–H activation is also possible that does not involve acetate displacement and so becomes favored in low polarity solvents, leading to C–C coupled products. Alkyne insertion is generally more favorable for diphenylacetylene over 4-octyne, but the reverse is true of the reductive coupling step. The diphenylacetylene moiety can also stabilize unsaturated seven-membered rhodacycle intermediates through extra interaction with one of the Ph substituents. With 1-phenylpyrazole this effect is sufficient to suppress the final C–N reductive coupling. A comparison of a series of seven-membered rhodacycles indicates the barrier to coupling is highly sensitive to the two groups involved and follows the trend C–N⁺ > C–N > C–C (i.e., involving the formation of cationic C–N, neutral C–N, and neutral C–C coupled products, respectively)

Pulmonary SARS-CoV-2 infection leads to para-infectious immune activation in the brain

Neurological complications, including encephalopathy and stroke, occur in a significant proportion of COVID-19 cases but viral protein is seldom detected in the brain parenchyma. To model this situation, we developed a novel low-inoculum K18-hACE2 mouse model of SARS-CoV-2 infection during which active viral replication was consistently seen in mouse lungs but not in the brain. We found that several mediators previously associated with encephalopathy in clinical samples were upregulated in the lung, including CCL2, and IL-6. In addition, several inflammatory mediations, including CCL4, IFNγ, IL-17A, were upregulated in the brain, associated with microglial reactivity. Parallel in vitro experiments demonstrated that the filtered supernatant from SARS-CoV-2 virion exposed brain endothelial cells induced activation of uninfected microglia. This model successfully recreates SARS-CoV-2 virus-associated para-infectious brain inflammation which can be used to study the pathophysiology of the neurological complications and the identification of potential immune targets for treatment