Delays induce novel stochastic effects in negative feedback gene circuits

AbstractStochastic models of reaction networks are widely used to depict gene expression dynamics. However, stochastic does not necessarily imply accurate, as subtle assumptions can yield erroneous results, masking key discrete effects. For instance, transcription and translation are not instantaneous processes—explicit delays separate their initiation from the appearance of their functional products. However, delays are often ignored in stochastic, single-gene expression models. By consequence, effects such as delay-induced stochastic oscillations at the single-cell level have remained relatively unexplored. Here, we present a systematic study of periodicity and multimodality in a simple gene circuit with negative feedback, analyzing the influence of negative feedback strength and transcriptional/translational delays on expression dynamics. We demonstrate that an oscillatory regime emerges through a Hopf bifurcation in both deterministic and stochastic frameworks. Of importance, a shift in the stochastic Hopf bifurcation evidences inaccuracies of the deterministic bifurcation analysis. Furthermore, noise fluctuations within stochastic oscillations decrease alongside increasing values of transcriptional delays and within a specific range of negative feedback strengths, whereas a strong feedback is associated with oscillations triggered by bursts. Finally, we demonstrate that explicitly accounting for delays increases the number of accessible states in the multimodal regime, and also introduces features typical of excitable systems

The long and viscous road: uncovering nuclear diffusion barriers in closed mitosis.

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Diffusion barriers are effective means for constraining protein lateral exchange in cellular membranes. In Saccharomyces cerevisiae, they have been shown to sustain parental identity through asymmetric segregation of ageing factors during closed mitosis. Even though barriers have been extensively studied in the plasma membrane, their identity and organization within the nucleus remains poorly understood. Based on different lines of experimental evidence, we present a model of the composition and structural organization of a nuclear diffusion barrier during anaphase. By means of spatial stochastic simulations, we propose how specialised lipid domains, protein rings, and morphological changes of the nucleus may coordinate to restrict protein exchange between mother and daughter nuclear lobes. We explore distinct, plausible configurations of these diffusion barriers and offer testable predictions regarding their protein exclusion properties and the diffusion regimes they generate. Our model predicts that, while a specialised lipid domain and an immobile protein ring at the bud neck can compartmentalize the nucleus during early anaphase; a specialised lipid domain spanning the elongated bridge between lobes would be entirely sufficient during late anaphase. Our work shows how complex nuclear diffusion barriers in closed mitosis may arise from simple nanoscale biophysical interactions.OIST funding

Non-Laboratory-Based Risk Factors for Automated Heart Disease Detection

© 2018 IEEE. Developing a heart disease detection model using simple non-laboratory risk factors plays an important role in preventive care, especially for high risk subjects. The model allows physicians/epidemiologists to effectively diagnose a person as having heart disease. In this work, we aim to develop a non-invasive risk prediction model for automated heart disease detection that involves age, gender, rest blood pressure, maximum heart rate, and rest electrocardiography. We examine four public datasets from 1071 participants who were referred for a special X-ray of the heart's arteries (i.e., to see if they are narrowed or blocked). The subjects also undertook a physical examination and three non-invasive tests. To estimate the heart disease status, we apply a generalized linear model with regularization paths via coordinate descent. Even without laboratory-based data (e.g., serum cholesterol, fasting blood sugar), we observed a prediction accuracy as high as 72%, compared with 76% of other comprehensive models. This observation suggests that few non-invasive factors utilizing recent advances in data analytics can replace the current practices of heart disease risk assessment

Offloading Energy Efficiency with Delay Constraint for Cooperative Mobile Edge Computing Networks

© 2018 IEEE. We propose a novel edge computing network architecture that enables edge nodes to cooperate in sharing computing and radio resources to minimize the total energy consumption of mobile users while meeting their delay requirements. To find the optimal task offloading decisions for mobile users, we first formulate the joint task offloading and resource allocation optimization problem as a mixed integer non-linear programming (MINLP). The optimization involves both binary (offloading decisions) and real variables (resource allocations), making it an NP-hard and computational intractable problem. To circumvent, we relax the binary decision variables to transform the MINLP to a relaxed optimization problem with real variables. After proving that the relaxed problem is a convex one, we propose two solutions namely ROP and IBBA. ROP is adopted from the interior point method and IBBA is developed from the branch and bound algorithm. Through the numerical results, we show that our proposed approaches allow minimizing the total energy consumption and meet all delay requirements for mobile users

Effect of Organic Fertilizers on Avocado Trees (Cvs. Fuerte, Hass, Lamb Hass) in Western Crete, a Cool Subtropical Region

The market for avocado is one of the fastest expanding worldwide, inclduing the Mediterranean basin. Organic farming systems cannot make use of synthetic fertilizers and therefore rely on several cultural techniques to maintain vigorous young trees and for quick shoot development, satisfactory yield, and fruit quality. We studied the effect of three different organic products (Terra Insecta (R) (Aeiphoria-Sustainable products of Crete, Chania, Greece), Fruit-Fix (R), and AMINO-16 (R) (both products manufactured by EVYP, Sindos, Thessaloniki, Greece) on avocado plants in the cool subtropical area of southern Greece. Three experiments were carried out, two of them on young avocado trees, and the third one on mature, fully productive trees. The establishment success (ES) (%), plants with shoot induction (SI) (%), plants with shoot growth >= 3 cm (SG) (%), number of sprouted buds >= 3 cm per plant (SB), mean shoot length (cm) per plant (SL), total shoot length (cm) per plant (TSL), mean leaf number per plant (LN), and total leaf number per plant (TLN) were measured in the first and second experiments, while in the third experiment, fruit growth parameters (length, width, fruit weight, fruit weight increase (FWI)) and fruit quality parameters (dry matter, oil concentration, dry matter, and oil concentration increase) were measured. The application of 0.2 K of Terra Insecta (R) to the planting hole did not have any statistically significant effect on plant growth, but when added around the trunk, statistically higher values were observed for SB, SL, LN, TSL, and TLN in the Terra Insecta (R) treatment compared to the control. Fruit-Fix (R) application to Lamb Hass avocado trees resulted in significant differences in ES, SI, SG, SL, TSL, LN, and TLN, and in the Hass variety, in SB. In the AMINO-16 (R) experiment, the fruit dimensions, quality parameters, and yield of the Hass variety were not recorded as significantly different. However, in the Fuerte variety, FW increased by 119.3% in the AMINO-16 (R) treatment. The effect of the organic fertilizers used in this research showed noticeable results requiring studies to be carried out over more seasons, different tree ages, cultivation methods, and stress conditions

Pressure-dependent EPANET extension

In water distribution systems (WDSs), the available flow at a demand node is dependent on the pressure at that node. When a network is lacking in pressure, not all consumer demands will be met in full. In this context, the assumption that all demands are fully satisfied regardless of the pressure in the system becomes unreasonable and represents the main limitation of the conventional demand driven analysis (DDA) approach to WDS modelling. A realistic depiction of the network performance can only be attained by considering demands to be pressure dependent. This paper presents an extension of the renowned DDA based hydraulic simulator EPANET 2 to incorporate pressure-dependent demands. This extension is termed “EPANET-PDX” (pressure-dependent extension) herein. The utilization of a continuous nodal pressure-flow function coupled with a line search and backtracking procedure greatly enhance the algorithm’s convergence rate and robustness. Simulations of real life networks consisting of multiple sources, pipes, valves and pumps were successfully executed and results are presented herein. Excellent modelling performance was achieved for analysing both normal and pressure deficient conditions of the WDSs. Detailed computational efficiency results of EPANET-PDX with reference to EPANET 2 are included as well

Cx43 regulates mechanotransduction mechanisms in human preterm amniotic membrane defects

Objective: The effects of mechanical stimulation in preterm amniotic membrane (AM) defects were explored. Methods: Preterm AM was collected from women undergoing planned preterm caesarean section (CS) due to fetal growth restriction or emergency CS after spontaneous preterm prelabour rupture of the membranes (sPPROM). AM explants near the cervix or placenta were subjected to trauma and/or mechanical stimulation with the Cx43 antisense. Markers for nuclear morphology (DAPI), myofibroblasts (αSMA), migration (Cx43), inflammation (PGE2) and repair (collagen, elastin and transforming growth factor β [TGFβ1]) were examined by confocal microscopy, second harmonic generation, qPCR and biochemical assays. Results: In preterm AM defects, myofibroblast nuclei were highly deformed and contractile and expressed αSMA and Cx43. Mechanical stimulation increased collagen fibre polarisation and the effects on matrix markers were dependent on tissue region, disease state, gestational age and the number of fetuses. PGE2 levels were broadly similar but reduced after co-treatment with Cx43 antisense in late sPPROM AM defects. TGFβ1 and Cx43 gene expression were significantly increased after trauma and mechanical stimulation but this response dependent on gestational age. Conclusion: Mechanical stimulation affects Cx43 signalling and cell/collagen mechanics in preterm AM defects. Establishing how Cx43 regulates mechanosignalling could be an approach to repair tissue integrity after trauma

Feature Analysis for Discrimination of Motor Unit Action Potentials

© 2018 IEEE. In electrophysiological signal processing for intramuscular electromyography data (nEMG), single motor unit activity is of great interest. The changes of action potential (MUAP) morphology, motor unit (MU) activation, and recruitment provide the most informative part to study the nature causality in neuromuscular disorders. In practice, for a single nEMG recording, more than one motor unit activities (in the surrounding area of a needle electrode) are usually collected. Such a fact makes the MUAP discrimination that separates single unit activities a crucial task. Most neurology laboratories worldwide still recruit specialists who spend hours to manually or semi-automatically sort MUAPs. From a machine learning perspective, this task is analogous to the clustering-based classification problem in which the number of classes and other class information are unfortunately missing. In this paper, we present a feature analysis strategy to help better utilize unsupervised (i.e., totally automated) methods for MUAP discrimination. To that end, we extract a large pool of features from each MUAP. Then we select the top ranked candidates using clusterability scores as selection criteria. We found spectrograms of wavelet decomposition as a top-ranking feature, highly correlated to the motor unit reference and was more separable than existing features. Using a correlation-based clustering technique, we demonstrate the sorting performance with this feature set. Compared with the reference produced by human experts, our method obtained a comparable result (e.g., equivalent number of classes was found, identical MUAP morphology in each pair of corresponding MU class, and similar histograms of MUs). Taking the manual labels as references, our method got a much higher sensitivity and accuracy than the compared unsupervised sorting method. We obtained a similar result in MUAP classification to the reference

Neuropsychiatric Features of Punding and Hobbyism in Parkinson's Disease

BACKGROUND: Little is known about the cognitive and neuropsychiatric profile associated with punding and hobbyism in Parkinson's disease (PD). OBJECTIVE: To compare the clinical and neuropsychological features of PD patients with punding and hobbyism to PD controls. METHODS: The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) was used as a screening tool, and a structured interview was used to diagnose punding/hobbyism. Clinical and neuropsychological assessment was conducted with validated questionnaires/scales. RESULTS: Twenty-one patients with PD and punding (PD + pu) were compared to 26 with hobbyism (PD + h) and 25 PD controls. PD + pu patients showed higher levels of anxiety, non-motor symptoms and motor symptoms, and lower Frontal Assessment Battery scores. The PD + h group exhibited similar levels of anxiety and motor fluctuations to the PD + pu group. CONCLUSION: PD + pu showed increased anxiety and frontal lobe dysfunction, similar to PD + h. Hobbyism could be a prodromal phase with increased risk of leading to punding

A profiling analysis of contributions of cigarette smoking, dietary calcium intakes, and physical activity to fragility fracture in the elderly

© 2018 The Author(s). Fragility fracture and bone mineral density (BMD) are influenced by common and modifiable lifestyle factors. In this study, we sought to define the contribution of lifestyle factors to fracture risk by using a profiling approach. The study involved 1683 women and 1010 men (50+ years old, followed up for up to 20 years). The incidence of new fractures was ascertained by X-ray reports. A "lifestyle risk score" (LRS) was derived as the weighted sum of effects of dietary calcium intake, physical activity index, and cigarette smoking. Each individual had a unique LRS, with higher scores being associated with a healthier lifestyle. Baseline values of lifestyle factors were assessed. In either men or women, individuals with a fracture had a significantly lower age-adjusted LRS than those without a fracture. In men, each unit lower in LRS was associated with a 66% increase in the risk of total fracture (non-adjusted hazard ratio [HR] 1.66; 95% CI, 1.26 to 2.20) and still significant after adjusting for age, weight or BMD. However, in women, the association was uncertain (HR 1.30; 95% CI, 1.11 to 1.53). These data suggest that unhealthy lifestyle habits are associated with an increased risk of fracture in men, but not in women, and that the association is mediated by BMD