A Formally Verified, Optimized Monitor for Metric First-Order Dynamic Logic
Ontology highlight
ABSTRACT:
SUBMITTER: Peltier N
PROVIDER: S-EPMC7324294 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:MotivationThe availability of more data of dynamic gene expression under multiple experimental conditions provides new information that makes the key goal of identifying not only the transcriptional regulators of a gene but also the underlying logical structure attainable.ResultsWe propose a novel method for inferring transcriptional regulation using a simple, yet biologically interpretable, model to find the logic by which a set of candidate genes and their associated transcription factors (TFs) regulate the transcriptional process of a gene of interest. Our dynamic model links the mRNA transcription rate of the target gene to the activation states of the TFs assuming that these interactions are consistent across multiple experiments and over time. A trans-dimensional Markov Chain Monte Carlo (MCMC) algorithm is used to efficiently sample the regulatory logic under different combinations of parents and rank the estimated models by their posterior probabilities. We demonstrate and compare our methodology with other methods using simulation examples and apply it to a study of transcriptional regulation of selected target genes of Arabidopsis Thaliana from microarray time series data obtained under multiple biotic stresses. We show that our method is able to detect complex regulatory interactions that are consistent under multiple experimental conditions.Availability and implementationPrograms are written in MATLAB and Statistics Toolbox Release 2016b, The MathWorks, Inc., Natick, Massachusetts, United States and are available on GitHub https://github.com/giorgosminas/TRS and at http://www2.warwick.ac.uk/fac/sci/systemsbiology/research/software.Contactgiorgos.minas@warwick.ac.uk or b.f.finkenstadt@warwick.ac.uk.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC5860162 | biostudies-literature
Project description:In their classical work (Proc. Natl. Acad. Sci. USA, 1981, 78:6840-6844), Goldbeter and Koshland mathematically analyzed a reversible covalent modification system which is highly sensitive to the concentration of effectors. Its signal-response curve appears sigmoidal, constituting a biochemical switch. However, the switch behavior only emerges in the 'zero-order region', i.e. when the signal molecule concentration is much lower than that of the substrate it modifies. In this work we showed that the switching behavior can also occur under comparable concentrations of signals and substrates, provided that the signal molecules catalyze the modification reaction in cooperation. We also studied the effect of dynamic disorders on the proposed biochemical switch, in which the enzymatic reaction rates, instead of constant, appear as stochastic functions of time. We showed that the system is robust to dynamic disorder at bulk concentration. But if the dynamic disorder is quasi-static, large fluctuations of the switch response behavior may be observed at low concentrations. Such fluctuation is relevant to many biological functions. It can be reduced by either increasing the conformation interconversion rate of the protein, or correlating the enzymatic reaction rates in the network.
| S-EPMC2374878 | biostudies-literature
Project description:Layer 6 (L6) is the sole purveyor of corticothalamic (CT) feedback to first-order thalamus and also sends projections to higher-order thalamus, yet how it engages the full corticothalamic circuit to contribute to sensory processing in an awake animal remains unknown. We sought to elucidate the functional impact of L6CT projections from the primary visual cortex to the dorsolateral geniculate nucleus (first-order) and pulvinar (higher-order) using optogenetics and extracellular electrophysiology in awake mice. While sustained L6CT photostimulation suppresses activity in both visual thalamic nuclei in vivo, moderate-frequency (10 Hz) stimulation powerfully facilitates thalamic spiking. We show that each stimulation paradigm differentially influences the balance between monosynaptic excitatory and disynaptic inhibitory corticothalamic pathways to the dorsolateral geniculate nucleus and pulvinar, as well as the prevalence of burst versus tonic firing. Altogether, our results support a model in which L6CTs modulate first- and higher-order thalamus through parallel excitatory and inhibitory pathways that are highly dynamic and context-dependent.
| S-EPMC7293611 | biostudies-literature
Project description:Multi-view clustering (MVC) is a mainstream task that aims to divide objects into meaningful groups from different perspectives. The quality of data representation is the key issue in MVC. A comprehensive meaningful data representation should be with the discriminant characteristics in a single view and the correlation of multiple views. Considering this, a novel framework called Dynamic Guided Metric Representation Learning for Multi-View Clustering (DGMRL-MVC) is proposed in this paper, which can cluster multi-view data in a learned latent discriminated embedding space. Specifically, in the framework, the data representation can be enhanced by multi-steps. Firstly, the class separability is enforced with Fisher Discriminant Analysis (FDA) within each single view, while the consistence among different views is enhanced based on Hilbert-Schmidt independence criteria (HSIC). Then, the 1st enhanced representation is obtained. In the second step, a dynamic routing mechanism is introduced, in which the location or direction information is added to fulfil the expression. After that, a generalized canonical correlation analysis (GCCA) model is used to get the final ultimate common discriminated representation. The learned fusion representation can substantially improve multi-view clustering performance. Experiments validated the effectiveness of the proposed method for clustering tasks.
| S-EPMC9044235 | biostudies-literature
Project description:PurposeTo validate metric optimized gating phase-contrast MR (MOG PC-MR) flow measurements for a range of fetal flow velocities in phantom experiments. 2) To investigate intra- and interobserver variability for fetal flow measurements at an imaging center other than the original site.MethodsMOG PC-MR was compared to timer/beaker measurements in a pulsatile flow phantom using a heart rate (?145 bpm), nozzle diameter (?6?mm), and flow range (?130-700?mL/min) similar to fetal imaging. Fifteen healthy fetuses were included for intra- and interobserver variability in the fetal descending aorta and umbilical vein.ResultsPhantom MOG PC-MR flow bias and variability was 2%?±?23%. Accuracy of MOG PC-MR was degraded for flow profiles with low velocity-to-noise ratio. Intra- and interobserver coefficients of variation were 6% and 19%, respectively, for fetal descending aorta; and 10% and 17%, respectively, for the umbilical vein.ConclusionPhantom validation showed good agreement between MOG and conventionally gated PC-MR, except for cases with low velocity-to-noise ratio, which resulted in MOG misgating and underestimated peak velocities and warranted optimization of sequence parameters to individual fetal vessels. Inter- and intraobserver variability for fetal MOG PC-MR imaging were comparable to previously reported values.
| S-EPMC6282515 | biostudies-literature
Project description:Animals from worms and insects to birds and mammals show distinct body plans; however, the embryonic development of diverse body plans with tissues and organs within is controlled by a surprisingly few signaling pathways. It is well recognized that combinatorial use of and dynamic interactions among signaling pathways follow specific logic to control complex and accurate developmental signaling and patterning, but it remains elusive what such logic is, or even, what it looks like.We have developed a computational model for Drosophila eye development with innovated methods to reveal how interactions among multiple pathways control the dynamically generated hexagonal array of R8 cells. We obtained two novel findings. First, the coupling between the long-range inductive signals produced by the proneural Hh signaling and the short-range restrictive signals produced by the antineural Notch and EGFR signaling is essential for generating accurately spaced R8s. Second, the spatiotemporal orders of key signaling events reveal a robust pattern of lateral inhibition conducted by Ato-coordinated Notch and EGFR signaling to collectively determine R8 patterning. This pattern, stipulating the orders of signaling and comparable to the protocols of communication, may help decipher the well-appreciated but poorly defined logic of developmental signaling.The model is available upon request.hao.zhu@ymail.comSupplementary data are available at Bioinformatics online.
| S-EPMC4965629 | biostudies-literature
Project description:Pulsed dynamic nuclear polarization (DNP) techniques can accomplish electron-nuclear polarization transfer efficiently with an enhancement factor that is independent of the Zeeman field. However, they often require large Rabi frequencies and, therefore, high-power microwave irradiation. Here, we propose a new low-power DNP sequence for static samples that is composed of a train of microwave pulses of length τp spaced with delays d. A particularly robust DNP condition using a period τm = τp + d set to ~1.25 times the Larmor period τLarmor is investigated which is a time-optimized pulsed DNP sequence (TOP-DNP). At 0.35 T, we obtained an enhancement of ~200 using TOP-DNP compared to ~172 with nuclear spin orientation via electron spin locking (NOVEL), a commonly used pulsed DNP sequence, while using only ~7% microwave power required for NOVEL. Experimental data and simulations at higher fields suggest a field-independent enhancement factor, as predicted by the effective Hamiltonian.
| S-EPMC6357739 | biostudies-literature
Project description:Controlling gene expression during a bioprocess enables real-time metabolic control, coordinated cellular responses, and staging order-of-operations. Achieving this with small molecule inducers is impractical at scale and dynamic circuits are difficult to design. Here, we show that the same set of sensors can be integrated by different combinatorial logic circuits to vary when genes are turned on and off during growth. Three Escherichia coli sensors that respond to the consumption of feedstock (glucose), dissolved oxygen, and by-product accumulation (acetate) are constructed and optimized. By integrating these sensors, logic circuits implement temporal control over an 18-h period. The circuit outputs are used to regulate endogenous enzymes at the transcriptional and post-translational level using CRISPRi and targeted proteolysis, respectively. As a demonstration, two circuits are designed to control acetate production by matching their dynamics to when endogenous genes are expressed (pta or poxB) and respond by turning off the corresponding gene. This work demonstrates how simple circuits can be implemented to enable customizable dynamic gene regulation.
| S-EPMC6263354 | biostudies-literature
Project description:Platelets store a plethora of different molecules within their granules, modulating numerous pathways, not only in coagulation, but also in angiogenesis, wound healing, and inflammatory diseases. These molecules get rapidly released upon activation and therefore represent an easily accessible indirect marker for platelet activation. Accurate analysis of platelet-derived molecules in the plasma requires appropriate anticoagulation to avoid in vitro activation and subsequent degranulation of platelets, potentially causing artificially high levels and masking biologically relevant differences within translational research studies. However, there is still enormous heterogeneity among anticoagulants used to prevent unwanted platelet activation, so that plasma levels reported for platelet granule contents range over several orders of magnitude. To address this problem and to define the most robust method of plasma preparation to avoid in vitro platelet activation during processing, we compared plasma concentrations of the three platelet-stored factors thrombospondin (TSP-1), platelet factor 4 (PF4), and soluble P-selectin (sCD62P) between human blood samples anticoagulated with either citrate-theophylline-adenosine-dipyridamole (CTAD), acid-citrate-dextrose (ACD), citrate, ethylenediaminetetraacetic acid (EDTA) or heparin. Additionally, we assessed the effect of storage temperature and time between blood drawing and sample processing within the differentially anticoagulated samples. Our data strongly support the use of CTAD as anticoagulant for determining plasma concentrations of platelet-stored molecules, as anticoagulation with heparin or EDTA led to a 12.4- or 8.3-fold increase in plasma levels of PF4, respectively. Whereas ACD was similar effective as CTAD, citrate only showed comparable PF4 plasma levels when plasma was kept at 4°C. Moreover, blood sampling with CTAD as anticoagulant resulted in the most reproducible values, even when samples were processed at ambient temperature or after storage over 6 hours. In the latter case, anticoagulation with heparin or EDTA led to artificially high plasma levels indicative of in vitro platelet activation. Therefore, we want to raise scientific awareness for choosing CTAD as optimal anticoagulant for the detection of platelet-stored molecules in plasma.
| S-EPMC5722331 | biostudies-literature
Project description:The assembly of heteromeric protein complexes is an inherently stochastic process in which multiple genes are expressed separately into proteins, which must then somehow find each other within the cell. Here, we considered one of the ways by which prokaryotic organisms have attempted to maximize the efficiency of protein complex assembly: the organization of subunit-encoding genes into operons. Using structure-based assembly predictions, we show that operon gene order has been optimized to match the order in which protein subunits assemble. Exceptions to this are almost entirely highly expressed proteins for which assembly is less stochastic and for which precisely ordered translation offers less benefit. Overall, these results show that ordered protein complex assembly pathways are of significant biological importance and represent a major evolutionary constraint on operon gene organization.
| S-EPMC4742563 | biostudies-literature