Synthetic associative learning in engineered multicellular consortia

Associative learning is one of the key mechanisms displayed by living organisms in order to adapt to their changing environments. It was early recognized to be a general trait of complex multicellular organisms but also found in "simpler" ones. It has also been explored within synthetic biology using molecular circuits that are directly inspired in neural network models of conditioning. These designs involve complex wiring diagrams to be implemented within one single cell and the presence of diverse molecular wires become a challenge that might be very difficult to overcome. Here we present three alternative circuit designs based on two-cell microbial consortia able to properly display associative learning responses to two classes of stimuli and displaying long and short-term memory (i. e. the association can be lost with time). These designs might be a helpful approach for engineering the human gut microbiome or even synthetic organoids, defining a new class of decision-making biological circuits capable of memory and adaptation to changing conditions. The potential implications and extensions are outlined.Comment: 5 figure

Modulation of Arabidopsis and monocot root architecture by CLAVATA3/EMBRYO SURROUNDING REGION 26 peptide

Plant roots are important for a wide range of processes, including nutrient and water uptake, anchoring and mechanical support, storage functions, and as the major interface with the soil environment. Several small signalling peptides and receptor kinases have been shown to affect primary root growth, but very little is known about their role in lateral root development. In this context, the CLE family, a group of small signalling peptides that has been shown to affect a wide range of developmental processes, were the focus of this study. Here, the expression pattern during lateral root initiation for several CLE family members is explored and to what extent CLE1, CLE4, CLE7, CLE26, and CLE27, which show specific expression patterns in the root, are involved in regulating root architecture in Arabidopsis thaliana is assessed. Using chemically synthesized peptide variants, it was found that CLE26 plays an important role in regulating A. thaliana root architecture and interacts with auxin signalling. In addition, through alanine scanning and in silico structural modelling, key residues in the CLE26 peptide sequence that affect its activity are pinpointed. Finally, some interesting similarities and differences regarding the role of CLE26 in regulating monocot root architecture are presented

A carboxylesterase, Esterase-6, modulates sensory physiological and behavioral response dynamics to pheromone in Drosophila

Conclusions: Our study presents evidence that Est-6 plays a role in the physiological and behavioral dynamics of sex pheromone response in Drosophila males and supports a role of Est-6 as an odorant-degrading enzyme (ODE) in male antennae. Our results also expand the role of Est-6 in Drosophila biology, from reproduction to olfaction, and highlight the role of ODEs in insect olfaction

Essential guidelines for computational method benchmarking

In computational biology and other sciences, researchers are frequently faced with a choice between several computational methods for performing data analyses. Benchmarking studies aim to rigorously compare the performance of different methods using well-characterized benchmark datasets, to determine the strengths of each method or to provide recommendations regarding suitable choices of methods for an analysis. However, benchmarking studies must be carefully designed and implemented to provide accurate, unbiased, and informative results. Here, we summarize key practical guidelines and recommendations for performing high-quality benchmarking analyses, based on our experiences in computational biology.Comment: Minor update

Improved Network Performance via Antagonism: From Synthetic Rescues to Multi-drug Combinations

Recent research shows that a faulty or sub-optimally operating metabolic network can often be rescued by the targeted removal of enzyme-coding genes--the exact opposite of what traditional gene therapy would suggest. Predictions go as far as to assert that certain gene knockouts can restore the growth of otherwise nonviable gene-deficient cells. Many questions follow from this discovery: What are the underlying mechanisms? How generalizable is this effect? What are the potential applications? Here, I will approach these questions from the perspective of compensatory perturbations on networks. Relations will be drawn between such synthetic rescues and naturally occurring cascades of reaction inactivation, as well as their analogues in physical and other biological networks. I will specially discuss how rescue interactions can lead to the rational design of antagonistic drug combinations that select against resistance and how they can illuminate medical research on cancer, antibiotics, and metabolic diseases.Comment: Online Open "Problems and Paradigms" articl

Synthetic microbial ecosystems : an exciting tool to understand and apply microbial communities

Many microbial ecologists have described the composition of microbial communities in a plenitude of environments, which has greatly improved our basic understanding of microorganisms and ecosystems. However, the factors and processes that influence the behaviour and functionality of an ecosystem largely remain black boxes when using conventional approaches. Therefore, synthetic microbial ecology has gained a lot of interest in the last few years. Because of their reduced complexity and increased controllability, synthetic communities are often preferred over complex communities to examine ecological theories. They limit the factors that influence the microbial community to a minimum, allowing their management and identifying specific community responses. However, besides their use for basic research, synthetic ecosystems also found their way towards different applications, like industrial fermentation and bioremediation. Here, we review why and how synthetic microbial communities are applied for research purposes and for which applications they have been and could be successfully used

Dissecting the sharp response of a canonical developmental enhancer reveals multiple sources of cooperativity.

Developmental enhancers integrate graded concentrations of transcription factors (TFs) to create sharp gene expression boundaries. Here we examine the hunchback P2 (HbP2) enhancer which drives a sharp expression pattern in the Drosophila blastoderm embryo in response to the transcriptional activator Bicoid (Bcd). We systematically interrogate cis and trans factors that influence the shape and position of expression driven by HbP2, and find that the prevailing model, based on pairwise cooperative binding of Bcd to HbP2 is not adequate. We demonstrate that other proteins, such as pioneer factors, Mediator and histone modifiers influence the shape and position of the HbP2 expression pattern. Comparing our results to theory reveals how higher-order cooperativity and energy expenditure impact boundary location and sharpness. Our results emphasize that the bacterial view of transcription regulation, where pairwise interactions between regulatory proteins dominate, must be reexamined in animals, where multiple molecular mechanisms collaborate to shape the gene regulatory function

Designing stem cell niches for differentiation and self-renewal

Mesenchymal stem cells, characterized by their ability to differentiate into skeletal tissues and self-renew, hold great promise for both regenerative medicine and novel therapeutic discovery. However, their regenerative capacity is retained only when in contact with their specialized microenvironment, termed the stem cell niche. Niches provide structural and functional cues that are both biochemical and biophysical, stem cells integrate this complex array of signals with intrinsic regulatory networks to meet physiological demands. Although, some of these regulatory mechanisms remain poorly understood or difficult to harness with traditional culture systems. Biomaterial strategies are being developed that aim to recapitulate stem cell niches, by engineering microenvironments with physiological-like niche properties that aim to elucidate stem cell-regulatory mechanisms, and to harness their regenerative capacity in vitro. In the future, engineered niches will prove important tools for both regenerative medicine and therapeutic discoveries

Essential guidelines for computational method benchmarking

In computational biology and other sciences, researchers are frequently faced with a choice between several computational methods for performing data analyses. Benchmarking studies aim to rigorously compare the performance of different methods using well-characterized benchmark datasets, to determine the strengths of each method or to provide recommendations regarding suitable choices of methods for an analysis. However, benchmarking studies must be carefully designed and implemented to provide accurate, unbiased, and informative results. Here, we summarize key practical guidelines and recommendations for performing high-quality benchmarking analyses, based on our experiences in computational biology