A report on the 6th European Conference on Structural Control

A short report is provided on the 6th European Conference on Structural Control which took place in Sheffield from 11–13 July 201

iPSCs-Based Neural 3D Systems: A Multidimensional Approach for Disease Modeling and Drug Discovery

Induced pluripotent stem cells (iPSCs)-based two-dimensional (2D) protocols have offered invaluable insights into the pathophysiology of neurological diseases. However, these systems are unable to reproduce complex cytoarchitectural features, cell-cell and tissue-tissue interactions like their in vivo counterpart. Three-dimensional (3D)-based culture protocols, though in their infancy, have offered new insights into modeling human diseases. Human neural organoids try to recapitulate the cellular diversity of complex tissues and can be generated from iPSCs to model the pathophysiology of a wide spectrum of pathologies. The engraftment of iPSCs into mice models and the improvement of differentiation protocols towards 3D cultures has enabled the generation of more complex multicellular systems. Consequently, models of neuropsychiatric disorders, infectious diseases, brain cancer and cerebral hypoxic injury can now be investigated from new perspectives. In this review, we consider the advancements made in modeling neuropsychiatric and neurological diseases with iPSC-derived organoids and their potential use to develop new drugs

Fully-resolved simulations of coal particle combustion using a detailed multi-step approach for heterogeneous kinetics

Fully-resolved simulations of the heating, ignition, volatile flame combustion and char conversion of single coal particles in convective gas environments are conducted and compared to experimental data (Molina and Shaddix, 2007). This work extends a previous computational study (Tufano et al., 2016) by adding a significant level of model fidelity and generality, in particular with regard to the particle interior description and hetero- geneous kinetics. The model considers the elemental analysis of the given coal and interpolates its properties by linear superposition of a set of reference coals. The improved model description alleviates previously made assumptions of single-step pyrolysis, fixed volatile composition and simplified particle interior properties, and it allows for the consideration of char conversion. The results show that the burning behavior is affected by the oxygen concentration, i.e. for enhanced oxygen levels ignition occurs in a single step, whereas decreasing the oxygen content leads to a two-stage ignition process. Char conversion becomes dominant once the volatiles have been depleted, but also causes noticeable deviations of temperature, released mass, and overall particle con- version during devolatilization already, indicating an overlap of the two stages of coal conversion which are usually considered to be consecutive. The complex pyrolysis model leads to non-monotonous profiles of the combustion quantities which introduce a minor dependency of the ignition delay time $τ_{ign}$ on its definition. Regardless of the chosen extraction method, the simulations capture the measured values of $τ_{ign}$ very well

Life events, anxious depression and personality: a prospective and genetic study.

Background: The association between life events and anxious depression might be due to causality or to gene-environment correlation. We examined unidirectional and reciprocal causality and a gene-environment correlation model, in which genes that influence the vulnerability for anxious depression also increase the risk of exposure to life events. The effect of genes that influence environmental exposure might be mediated through personality and we therefore also examined the association between life events and personality (neuroticism and extraversion). Method: Information on life events, anxious depression, neuroticism and extraversion was collected in 5782 monozygotic (MZ) and dizygotic (DZ) twins who participated in a longitudinal survey study of the Netherlands Twin Register. To examine causality, data were analysed longitudinally. To examine gene-environment correlation, the co-twin control method was used. Results: Anxious depression and, to a lesser extent, neuroticism scores increased after exposure to life events. Anxious depression and neuroticism also predicted the experience of life events. Prospectively, extraversion was not associated with life events. Anxious depression, neuroticism and extraversion scores did not differ between the non-exposed subjects of MZ and DZ twin pairs and unrelated subjects discordant for life events. Conclusions: Our findings suggest that reciprocal causation explains the relationship between life events and anxious depression and between life events and neuroticism. Extraversion is not related to life events. No evidence was found for gene-environment correlation, i.e. the genes that influence anxious depression, neuroticism or extraversion do not overlap with the genes that increase the risk of exposure to life events

C. elegans expressing D76N β2-microglobulin: a model for in vivo screening of drug candidates targeting amyloidosis

The availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of β2-microglobulin (D76N β2-m) is associated with a fatal familial form of systemic amyloidosis. Hitherto, no animal model has been available for studying in vivo the pathogenicity of this protein. We have established a transgenic C. elegans line, expressing the human D76N β2-m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N β2-m expressing worms. We also demonstrated the specificity of the β2-m variant in determining the pathological phenotype by rescuing the wild type phenotype when β2-m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. In future, this C. elegans model, in conjunction with the INVAPP/Paragon system, offers the prospect of high-throughput chemical screening in the search for new drug candidates

Comparative study of the stabilities of synthetic in vitro and natural ex vivo transthyretin amyloid fibrils

Systemic amyloidosis caused by extracellular deposition of insoluble fibrils derived from the pathological aggregation of circulating proteins, such as transthyretin, is a severe and usually fatal condition. Elucidation of the molecular pathogenic mechanism of the disease and discovery of effective therapies still represents a challenging medical issue. The in vitro preparation of amyloid fibrils that exhibit structural and biochemical properties closely similar to those of natural fibrils is central to improving our understanding of the biophysical basis of amyloid formation in vivo and may offer an important tool for drug discovery. Here, we compared the morphology and thermodynamic stability of natural transthyretin fibrils with those of fibrils generated in vitro using either the common acidification procedure or primed by limited selective cleavage by plasmin. The free energies for fibril formation were -12.36 kcal mol-1, -8.10 kcal mol-1 and -10.61 kcal mol-1, respectively. The fibrils generated via plasmin cleavage were more stable than those prepared at low pH and were thermodynamically and morphologically similar to natural fibrils extracted from human amyloidotic tissue. Determination of thermodynamic stability is an important tool that is complementary to other methods for structural comparison between ex vivo fibrils and fibrils generated in vitro Our finding that fibrils created via an in vitro amyloidogenic pathway are structurally similar to ex vivo human amyloid fibrils does not necessarily establish that the fibrillogenic pathway is the same for both, but it narrows the current knowledge gap between in vitro models and in vivo pathophysiology