DNA as a universal substrate for chemical kinetics

Molecular programming aims to systematically engineer molecular and chemical systems of autonomous function and ever-increasing complexity. A key goal is to develop embedded control circuitry within a chemical system to direct molecular events. Here we show that systems of DNA molecules can be constructed that closely approximate the dynamic behavior of arbitrary systems of coupled chemical reactions. By using strand displacement reactions as a primitive, we construct reaction cascades with effectively unimolecular and bimolecular kinetics. Our construction allows individual reactions to be coupled in arbitrary ways such that reactants can participate in multiple reactions simultaneously, reproducing the desired dynamical properties. Thus arbitrary systems of chemical equations can be compiled into real chemical systems. We illustrate our method on the Lotka–Volterra oscillator, a limit-cycle oscillator, a chaotic system, and systems implementing feedback digital logic and algorithmic behavior

SUSTAIN drilling at Surtsey volcano, Iceland, tracks hydrothermal and microbiological interactions in basalt 50 years after eruption

The 2017 Surtsey Underwater volcanic System for Thermophiles, Alteration processes and INnovative concretes (SUSTAIN) drilling project at Surtsey volcano, sponsored in part by the International Continental Scientific Drilling Program (ICDP), provides precise observations of the hydrothermal, geochemical, geomagnetic, and microbiological changes that have occurred in basaltic tephra and minor intrusions since explosive and effusive eruptions produced the oceanic island in 1963–1967. Two vertically cored boreholes, to 152 and 192 m below the surface, were drilled using filtered, UV-sterilized seawater circulating fluid to minimize microbial contamination. These cores parallel a 181 m core drilled in 1979. Introductory investigations indicate changes in material properties and whole-rock compositions over the past 38 years. A Surtsey subsurface observatory installed to 181 m in one vertical borehole holds incubation experiments that monitor in situ mineralogical and microbial alteration processes at 25–124 ∘C. A third cored borehole, inclined 55∘ in a 264∘ azimuthal direction to 354 m measured depth, provides further insights into eruption processes, including the presence of a diatreme that extends at least 100 m into the seafloor beneath the Surtur crater. The SUSTAIN project provides the first time-lapse drilling record into a very young oceanic basaltic volcano over a range of temperatures, 25–141 ∘C from 1979 to 2017, and subaerial and submarine hydrothermal fluid compositions. Rigorous procedures undertaken during the drilling operation protected the sensitive environment of the Surtsey Natural Preserve

O-GlcNAc modifications regulate cell survival and epiboly during zebrafish development

<p>Abstract</p> <p>Background</p> <p>The post-translational addition of the monosaccharide O-linked β-<it>N</it>-acetylglucosamine (O-GlcNAc) regulates the activity of a wide variety of nuclear and cytoplasmic proteins. The enzymes O-GlcNAc Transferase (Ogt) and O-GlcNAcase (Oga) catalyze, respectively, the attachment and removal of O-GlcNAc to target proteins. In adult mice, Ogt and Oga attenuate the response to insulin by modifying several components of the signal transduction pathway. Complete loss of <it>ogt </it>function, however, is lethal to mouse embryonic stem cells, suggesting that the enzyme has additional, unstudied roles in development. We have utilized zebrafish as a model to determine role of O-GlcNAc modifications in development. Zebrafish has two <it>ogt </it>genes, encoding six different enzymatic isoforms that are expressed maternally and zygotically.</p> <p>Results</p> <p>We manipulated O-GlcNAc levels in zebrafish embryos by overexpressing zebrafish <it>ogt</it>, human <it>oga </it>or by injecting morpholinos against <it>ogt </it>transcripts. Each of these treatments results in embryos with shortened body axes and reduced brains at 24 hpf. The embryos had 23% fewer cells than controls, and displayed increased rates of cell death as early as the mid-gastrula stages. An extensive marker analysis indicates that derivatives of three germ layers are reduced to variable extents, and the embryos are severely disorganized after gastrulation. Overexpression of Ogt and Oga delayed epiboly and caused a severe disorganization of the microtubule and actin based cytoskeleton in the extra-embryonic yolk syncytial layer (YSL). The cytoskeletal defects resemble those previously reported for embryos lacking function of the Pou5f1/Oct4 transcription factor <it>spiel ohne grenzen</it>. Consistent with this, Pou5f1/Oct4 is modified by O-GlcNAc in human embryonic stem cells.</p> <p>Conclusion</p> <p>We conclude that O-GlcNAc modifications control the activity of proteins that regulate apoptosis and epiboly movements, but do not seem to regulate germ layer specification. O-GlcNAc modifies the transcription factor Spiel ohne grenzen/Pou5f1 and may regulate its activity.</p

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Methods of model reduction for large-scale biological systems: a survey of current methods and trends

Complex models of biochemical reaction systems have become increasingly common in the systems biology literature. The complexity of such models can present a number of obstacles for their practical use, often making problems difficult to intuit or computationally intractable. Methods of model reduction can be employed to alleviate the issue of complexity by seeking to eliminate those portions of a reaction network that have little or no effect upon the outcomes of interest, hence yielding simplified systems that retain an accurate predictive capacity. This review paper seeks to provide a brief overview of a range of such methods and their application in the context of biochemical reaction network models. To achieve this, we provide a brief mathematical account of the main methods including timescale exploitation approaches, reduction via sensitivity analysis, optimisation methods, lumping, and singular value decomposition-based approaches. Methods are reviewed in the context of large-scale systems biology type models, and future areas of research are briefly discussed

The route of priming influences the ability of respiratory virus–specific memory CD8+ T cells to be activated by residual antigen

After respiratory virus infections, memory CD8+ T cells are maintained in the lung airways by a process of continual recruitment. Previous studies have suggested that this process is controlled, at least in the initial weeks after virus clearance, by residual antigen in the lung-draining mediastinal lymph nodes (MLNs). We used mouse models of influenza and parainfluenza virus infection to show that intranasally (i.n.) primed memory CD8+ T cells possess a unique ability to be reactivated by residual antigen in the MLN compared with intraperitoneally (i.p.) primed CD8+ T cells, resulting in the preferential recruitment of i.n.-primed memory CD8+ T cells to the lung airways. Furthermore, we demonstrate that the inability of i.p.-primed memory CD8+ T cells to access residual antigen can be corrected by a subsequent i.n. virus infection. Thus, two independent factors, initial CD8+ T cell priming in the MLN and prolonged presentation of residual antigen in the MLN, are required to maintain large numbers of antigen-specific memory CD8+ T cells in the lung airways

Definitions and classification of malformations of cortical development: Practical guidelines

Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide