Thermo-programmed synthetic DNA-based receptors

Herein, we present a generalizable and versatile strategy to engineer synthetic DNA ligand-binding devices that can be programmed to load and release a specific ligand at a defined temperature. We do so by re-engineering two model DNA-based receptors: a triplex-forming bivalent DNA-based receptor that recognizes a specific DNA sequence and an ATP-binding aptamer. The temperature at which these receptors load/release their ligands can be finely modulated by controlling the entropy associated with the linker connecting the two ligand-binding domains. The availability of a set of receptors with tunable and reversible temperature dependence allows achieving complex load/release behavior such as sustained ligand release over a wide temperature range. Similar programmable thermo-responsive synthetic ligand-binding devices can be of utility in applications such as drug delivery and production of smart materials

OpenWorm: an open-science approach to modeling Caenorhabditis elegans.

OpenWorm is an international collaboration with the aim of understanding how the behavior of Caenorhabditis elegans (C. elegans) emerges from its underlying physiological processes. The project has developed a modular simulation engine to create computational models of the worm. The modularity of the engine makes it possible to easily modify the model, incorporate new experimental data and test hypotheses. The modeling framework incorporates both biophysical neuronal simulations and a novel fluid-dynamics-based soft-tissue simulation for physical environment-body interactions. The project's open-science approach is aimed at overcoming the difficulties of integrative modeling within a traditional academic environment. In this article the rationale is presented for creating the OpenWorm collaboration, the tools and resources developed thus far are outlined and the unique challenges associated with the project are discussed

OpenWorm: overview and recent advances in integrative biological simulation of Caenorhabditis elegans

The adoption of powerful software tools and computational methods from the software industry by the scientific research community has resulted in a renewed interest in integrative, large-scale biological simulations. These typically involve the development of computational platforms to combine diverse, process-specific models into a coherent whole. The OpenWorm Foundation is an independent research organization working towards an integrative simulation of the nematode Caenorhabditis elegans, with the aim of providing a powerful new tool to understand how the organism's behaviour arises from its fundamental biology. In this perspective, we give an overview of the history and philosophy of OpenWorm, descriptions of the constituent sub-projects and corresponding open-science management practices, and discuss current achievements of the project and future directions. This article is part of a discussion meeting issue ‘Connectome to behaviour: modelling C. elegans at cellular resolution’

Open Source Brain: A Collaborative Resource for Visualizing, Analyzing, Simulating, and Developing Standardized Models of Neurons and Circuits

Computational models are powerful tools for exploring the properties of complex biological systems. In neuroscience, data-driven models of neural circuits that span multiple scales are increasingly being used to understand brain function in health and disease. But their adoption and reuse has been limited by the specialist knowledge required to evaluate and use them. To address this, we have developed Open Source Brain, a platform for sharing, viewing, analyzing, and simulating standardized models from different brain regions and species. Model structure and parameters can be automatically visualized and their dynamical properties explored through browser-based simulations. Infrastructure and tools for collaborative interaction, development, and testing are also provided. We demonstrate how existing components can be reused by constructing new models of inhibition-stabilized cortical networks that match recent experimental results. These features of Open Source Brain improve the accessibility, transparency, and reproducibility of models and facilitate their reuse by the wider community

Calibration-free measurement of phenylalanine levels in the blood using an electrochemical aptamer-based sensor suitable for point-of-care applications

By analogy to the revolution the “home glucose monitor” created in the treatment of diabetes, the availability of a modular, “platform” technology able to measure nearly any metabolite, biomarker, or drug “at-home” in unprocessed, finger-prick volumes of whole blood could revolutionize the monitoring and treatment of disease. Thus motivated, we have adapted here the electrochemical aptamer-based sensing platform to the problem of rapidly and conveniently measuring the level of phenylalanine in the blood, an ability that would aid the monitoring and management of phenylketonuria (PKU). To achieve this, we exploited a previously reported DNA aptamer that recognizes phenylalanine in complex with a rhodium-based “receptor” that improves affinity. We re-engineered this to undergo a large-scale, binding-induced conformational change before modifying it with a methylene blue redox reporter and attaching it to a gold electrode that supports the appropriate electrochemical interrogation. The resultant sensor achieves a useful dynamic range of 90 nM to 7 μM. When challenged with finger-prick-scale sample volumes of the whole blood (diluted 1000-fold to match the sensor’s dynamic range), the device achieves the accurate (±20%), calibration-free measurement of blood phenylalanine levels in minutes

Accuratezza diagnostica della ColonTC nello staging pre-operatorio della neoplasia del colon-retto: studio prospettico su 66 pazienti

No abstract availabl

Allosteric DNA nanoswitches for controlled release of a molecular cargo triggered by biological inputs

Here we demonstrate the rational design of a new class of DNA-based nanoswitches which are allosterically regulated by specific biological targets, antibodies and transcription factors, and are able to load and release a molecular cargo (i.e. doxorubicin) in a controlled fashion. In our first model system we rationally designed a stem-loop DNA-nanoswitch that adopts two mutually exclusive conformations: a “Load” conformation containing a doxorubicin-intercalating domain and a “Release” conformation containing a duplex portion recognized by a specific transcription-factor (here Tata Binding Protein). The binding of the transcription factor pushes this conformational equilibrium towards the “Release” state thus leading to doxorubicin release from the nanoswitch. In our second model system we designed a similar stem-loop DNAnanoswitch for which conformational change and subsequent doxorubicin release can be triggered by a specific antibody. Our approach augments the current tool kit of smart drug release mechanisms regulated by different biological inputs