Modular Composition of Gene Transcription Networks

Predicting the dynamic behavior of a large network from that of the composing modules is a central problem in systems and synthetic biology. Yet, this predictive ability is still largely missing because modules display context-dependent behavior. One cause of context-dependence is retroactivity, a phenomenon similar to loading that influences in non-trivial ways the dynamic performance of a module upon connection to other modules. Here, we establish an analysis framework for gene transcription networks that explicitly accounts for retroactivity. Specifically, a module's key properties are encoded by three retroactivity matrices: internal, scaling, and mixing retroactivity. All of them have a physical interpretation and can be computed from macroscopic parameters (dissociation constants and promoter concentrations) and from the modules' topology. The internal retroactivity quantifies the effect of intramodular connections on an isolated module's dynamics. The scaling and mixing retroactivity establish how intermodular connections change the dynamics of connected modules. Based on these matrices and on the dynamics of modules in isolation, we can accurately predict how loading will affect the behavior of an arbitrary interconnection of modules. We illustrate implications of internal, scaling, and mixing retroactivity on the performance of recurrent network motifs, including negative autoregulation, combinatorial regulation, two-gene clocks, the toggle switch, and the single-input motif. We further provide a quantitative metric that determines how robust the dynamic behavior of a module is to interconnection with other modules. This metric can be employed both to evaluate the extent of modularity of natural networks and to establish concrete design guidelines to minimize retroactivity between modules in synthetic systems.United States. Air Force Office of Scientific Research (FA9550-12-1-0129

Complementary intestinal mucosa and microbiota responses to caloric restriction

The intestine is key for nutrient absorption and for interactions between the microbiota and its host. Therefore, the intestinal response to caloric restriction (CR) is thought to be more complex than that of any other organ. Submitting mice to 25% CR during 14 days induced a polarization of duodenum mucosa cell gene expression characterised by upregulation, and downregulation of the metabolic and immune/inflammatory pathways, respectively. The HNF, PPAR, STAT, and IRF families of transcription factors, particularly the Pparα and Isgf3 genes, were identified as potentially critical players in these processes. The impact of CR on metabolic genes in intestinal mucosa was mimicked by inhibition of the mTOR pathway. Furthermore, multiple duodenum and faecal metabolites were altered in CR mice. These changes were dependent on microbiota and their magnitude corresponded to microbial density. Further experiments using mice with depleted gut bacteria and CR-specific microbiota transfer showed that the gene expression polarization observed in the mucosa of CR mice is independent of the microbiota and its metabolites. The holistic interdisciplinary approach that we applied allowed us to characterize various regulatory aspects of the host and microbiota response to CR

Microbiome to Brain:Unravelling the Multidirectional Axes of Communication

The gut microbiome plays a crucial role in host physiology. Disruption of its community structure and function can have wide-ranging effects making it critical to understand exactly how the interactive dialogue between the host and its microbiota is regulated to maintain homeostasis. An array of multidirectional signalling molecules is clearly involved in the host-microbiome communication. This interactive signalling not only impacts the gastrointestinal tract, where the majority of microbiota resides, but also extends to affect other host systems including the brain and liver as well as the microbiome itself. Understanding the mechanistic principles of this inter-kingdom signalling is fundamental to unravelling how our supraorganism function to maintain wellbeing, subsequently opening up new avenues for microbiome manipulation to favour desirable mental health outcome

Shear-strength behavior of saturated clays and the role of the effective stress concept

This Paper discusses the mechanisms controlling the shear strength behaviour of saturated kaolinite and montmorrillonite clays from a detailed experimental programme based on certain theoretical consid'rations. In the light of the modified effective stress concept, which takes into consideration the interparticle electrical attractive and repulsive forces, an attempt has been made to explain the behaviour of the clays. Eight organic fluids of different dielectric properties, air and water have been used as pore media to vary the inter-particle forces in the conventional box shear apparatus. The experimental results are in qualitative conformity with the modified effective stress concept and the soil strength is significantly influenced by the dielectric properties of the pore discussed in detail

Mechanisms Controlling Volume Change Of Saturated Clays And Role Effective Stress Concept

This investigation deals with the mechanisms con- trolling the one-dimensional volume change beha- viour of saturated kaolinite and montmorillonitic clays. An attempt has been made to explain the behaviour of the clays in the light of the modified effective stress concept which takes into considera- tion the interparticle electrical attractive and repul- sive forces. Eight organic pore fluids of different dielectric properties and water have been used to vary the interparticle forces in the one-dimensional consolidation tests. In order to further confirm the nature of the mechanisms, tests have also been con- ducted in which the existing pore fluid was replaced by another of different dielectric properties, to change the force system at interparticle level. The experimental results clearly indicate that the volume change behaviour of these clays is controlled basi- cally by two mechanisms which are governed by the modified effective stress concept. In mechanism 1, the volume change is controlled by the shearing resistance at interparticle level and in mechanism 2, primarily by the long range diffuse double layer repulsive forces. Although these effects operate simultaneously, the results indicate that mechanism 1 primarily governs the volume change behaviour of non-expanding lattice type clays like kaolinite, and mechanism 2, that of the expanding lattice type clays like montmorillonite