VUS next in rare diseases? Deciphering genetic determinants of biomolecular condensation.

The diagnostic odysseys for rare disease patients are getting shorter as next-generation sequencing becomes more widespread. However, the complex genetic diversity and factors influencing expressivity continue to challenge accurate diagnosis, leaving more than 50% of genetic variants categorized as variants of uncertain significance.Genomic expression intricately hinges on localized interactions among its products.

Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson-Gilford Progeria.

Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson-Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1.

Coexistence of nestedness and modularity in host-pathogen infection networks.

The long-term coevolution of hosts and pathogens in their environment forms a complex web of multi-scale interactions. Understanding how environmental heterogeneity affects the structure of host-pathogen networks is a prerequisite for predicting disease dynamics and emergence. Although nestedness is common in ecological networks, and theory suggests that nested ecosystems are less prone to dynamic instability, why nestedness varies in time and space is not fully understood.

Population dynamics of synthetic terraformation motifs.

Ecosystems are complex systems, currently experiencing several threats associated with global warming, intensive exploitation and human-driven habitat degradation. Because of a general presence of multiple stable states, including states involving population extinction, and due to the intrinsic nonlinearities associated with feedback loops, collapse in ecosystems could occur in a catastrophic manner. It has been recently suggested that a potential path to prevent or modify the outcome of these transitions would involve designing synthetic organisms and synthetic ecological interactions that could push these endangered systems out of the critical boundaries.

Spatial dynamics of synthetic microbial mutualists and their parasites.

A major force contributing to the emergence of novelty in nature is the presence of cooperative interactions, where two or more components of a system act in synergy, sometimes leading to higher-order, emergent phenomena. Within molecular evolution, the so called hypercycle defines the simplest model of an autocatalytic cycle, providing major theoretical insights on the evolution of cooperation in the early biosphere. These closed cooperative loops have also inspired our understanding of how catalytic loops appear in ecological systems.

Spatial self-organization in hybrid models of multicellular adhesion.

Spatial self-organization emerges in distributed systems exhibiting local interactions when nonlinearities and the appropriate propagation of signals are at work. These kinds of phenomena can be modeled with different frameworks, typically cellular automata or reaction-diffusion systems. A different class of dynamical processes involves the correlated movement of agents over space, which can be mediated through chemotactic movement or minimization of cell-cell interaction energy.

Synthetic collective intelligence.

Intelligent systems have emerged in our biosphere in different contexts and achieving different levels of complexity. The requirement of communication in a social context has been in all cases a determinant. The human brain, probably co-evolving with language, is an exceedingly successful example.

Emergence of proto-organisms from bistable stochastic differentiation and adhesion.

The rise of multicellularity in the early evolution of life represents a major challenge for evolutionary biology. Guidance for finding answers has emerged from disparate fields, from phylogenetics to modelling and synthetic biology, but little is known about the potential origins of multicellular aggregates before genetic programmes took full control of developmental processes. Such aggregates should involve spatial organization of differentiated cells and the modification of flows and concentrations of metabolites within well-defined boundaries.

A morphospace for synthetic organs and organoids: the possible and the actual.

Efforts in evolutionary developmental biology have shed light on how organs are developed and why evolution has selected some structures instead of others. These advances in the understanding of organogenesis along with the most recent techniques of organotypic cultures, tissue bioprinting and synthetic biology provide the tools to hack the physical and genetic constraints in organ development, thus opening new avenues for research in the form of completely designed or merely altered settings. Here we propose a unifying framework that connects the concept of morphospace (i.

Synthetic circuit designs for earth terraformation.

Background: Mounting evidence indicates that our planet might experience runaway effects associated to rising temperatures and ecosystem overexploitation, leading to catastrophic shifts on short time scales. Remediation scenarios capable of counterbalancing these effects involve geoengineering, sustainable practices and carbon sequestration, among others. None of these scenarios seems powerful enough to achieve the desired restoration of safe boundaries.

MiR-2 family regulates insect metamorphosis by controlling the juvenile hormone signaling pathway.

In 2009 we reported that depletion of Dicer-1, the enzyme that catalyzes the final step of miRNA biosynthesis, prevents metamorphosis in Blattella germanica. However, the precise regulatory roles of miRNAs in the process have remained elusive. In the present work, we have observed that Dicer-1 depletion results in an increase of mRNA levels of Krüppel homolog 1 (Kr-h1), a juvenile hormone-dependent transcription factor that represses metamorphosis, and that depletion of Kr-h1 expression in Dicer-1 knockdown individuals rescues metamorphosis.

A bottom-up characterization of transfer functions for synthetic biology designs: lessons from enzymology.

Within the field of synthetic biology, a rational design of genetic parts should include a causal understanding of their input-output responses-the so-called transfer function-and how to tune them. However, a commonly adopted strategy is to fit data to Hill-shaped curves without considering the underlying molecular mechanisms. Here we provide a novel mathematical formalization that allows prediction of the global behavior of a synthetic device by considering the actual information from the involved biological parts.

Regulation of atrophin by both strands of the mir-8 precursor.

In Drosophila melanogaster, miR-8-3p regulates mRNA levels of atrophin, a factor involved in neuromotor coordination, and we found that Blattella germanica with suppressed atrophin showed motor problems. Bionformatic predictions and luciferase-reporter tests indicated that B. germanica atrophin mRNA contains target sites for miR-8-3p and miR-8-5p.

Exploring and challenging the network of angiogenesis.

Angiogenesis is one of the hallmarks of cancer and, as such, one of the alternative general targets for anticancer therapy. Since angiogenesis is a complex process involving a high number of interconnected components, a network approach would be a convenient systemic way to analyse responses to directed drug attacks. Herein we show that, although the angiogenic network is easily broken by short combinations of directed attacks, it still remains essentially functional by keeping the global patterns and local efficiency essentially unaltered after these attacks.

A combined model of hepatic polyamine and sulfur amino acid metabolism to analyze S-adenosyl methionine availability.

Many molecular details remain to be uncovered concerning the regulation of polyamine metabolism. A previous model of mammalian polyamine metabolism showed that S-adenosyl methionine availability could play a key role in polyamine homeostasis. To get a deeper insight in this prediction, we have built a combined model by integration of the previously published polyamine model and one-carbon and glutathione metabolism model, published by different research groups.

When metabolism meets topology: Reconciling metabolite and reaction networks.

The search for a systems-level picture of metabolism as a web of molecular interactions provides a paradigmatic example of how the methods used to characterize a system can bias the interpretation of its functional meaning. Metabolic maps have been analyzed using novel techniques from network theory, revealing some non-trivial, functionally relevant properties. These include a small-world structure and hierarchical modularity.

Systems biology metabolic modeling assistant: an ontology-based tool for the integration of metabolic data in kinetic modeling.

Summary: We present Systems Biology Metabolic Modeling Assistant (SBMM Assistant), a tool built using an ontology-based mediator, and designed to facilitate metabolic modeling through the integration of data from repositories that contain valuable metabolic information. This software can be used for the visualization, design and management of metabolic networks; selection, integration and storage of metabolic information; and as an assistant for kinetic modeling.

Availability: SBMM Assistant for academic use is freely available at http://www.

AMMO-Prot: amine system project 3D-model finder.

Background: Amines are biogenic amino acid derivatives, which play pleiotropic and very important yet complex roles in animal physiology. For many other relevant biomolecules, biochemical and molecular data are being accumulated, which need to be integrated in order to be effective in the advance of biological knowledge in the field. For this purpose, a multidisciplinary group has started an ontology-based system named the Amine System Project (ASP) for which amine-related information is the validation bench.

Homocysteine is a potent modulator of plasma membrane electron transport systems.

The deregulation of homocysteine metabolism leads to hyperhomocysteinemia, a condition described as an independent cardiovascular disease risk factor. Ubiquitous plasma membrane redox systems can play a dual pro-oxidant and anti-oxidant role in defense. In this study, we test the hypothesis that homocysteine, as a redox active compound, could modulate the endothelial plasma membrane redox system.

Information integration of protein-protein interactions as essential tools for immunomics.

After a brief introduction to point out the necessity to advance for a global understanding of the macromolecular interactions occurring during the immune system development and responses, Section 2 will be devoted to analyse the current tools for an automatic location of information on these protein-protein interactions in the web. In the next section (Section 3), we will point out different action lines to improve these tools and, consequently, to increase the efficiency to establish (to understand) the "protein network skeleton" that controls our immune responses. Finally, we will briefly present our current strategy and work to advance towards this goal.

Mathematical modeling of polyamine metabolism in mammals.

Polyamines are considered as essential compounds in living cells, since they are involved in cell proliferation, transcription, and translation processes. Furthermore, polyamine homeostasis is necessary to cell survival, and its deregulation is involved in relevant processes, such as cancer and neurodegenerative disorders. Great efforts have been made to elucidate the nature of polyamine homeostasis, giving rise to relevant information concerning the behavior of the different components of polyamine metabolism, and a great amount of information has been generated.

Localization of StarD5 cholesterol binding protein.

Human StarD5 belongs to the StarD4 subfamily of START (for steroidogenic acute regulatory lipid transfer) domain proteins. We previously reported that StarD5 is located in the cytosolic fraction of human liver and binds cholesterol and 25-hydroxycholesterol. After overexpression of the gene encoding StarD5 in primary rat hepatocytes, free cholesterol accumulated in intracellular membranes.