Circadian (∼24 h) timekeeping is essential for the lives of many organisms. To understand the biochemical mechanisms of this timekeeping, we have developed a detailed mathematical model of the ...mammalian circadian clock. Our model can accurately predict diverse experimental data including the phenotypes of mutations or knockdown of clock genes as well as the time courses and relative expression of clock transcripts and proteins. Using this model, we show how a universal motif of circadian timekeeping, where repressors tightly bind activators rather than directly binding to DNA, can generate oscillations when activators and repressors are in stoichiometric balance. Furthermore, we find that an additional slow negative feedback loop preserves this stoichiometric balance and maintains timekeeping with a fixed period. The role of this mechanism in generating robust rhythms is validated by analysis of a simple and general model and a previous model of the Drosophila circadian clock. We propose a double‐negative feedback loop design for biological clocks whose period needs to be tightly regulated even with large changes in gene dosage.
An accurate mathematical model of the mammalian circadian clock provides novel insights into the mechanisms that generate 24‐h rhythms. A double‐negative feedback loop design is proposed for biological clocks whose period needs to be tightly regulated.
Synopsis
An accurate mathematical model of the mammalian circadian clock provides novel insights into the mechanisms that generate 24‐h rhythms. A double‐negative feedback loop design is proposed for biological clocks whose period needs to be tightly regulated.
A 1–1 stoichiometric balance and tight binding between activators (PER–CRY) and repressors (BMAL1–CLOCK/NPAS2) is required for sustained rhythmicity.
Stoichiometry is balanced by an additional negative feedback loop consisting of a stable activator.
Our detailed model can explain more experimental data than previous models.
Mathematical analysis of a simple model supports our claims.
Biochemical systems consist of numerous elementary reactions governed by the law of mass action. However, experimentally characterizing all the elementary reactions is nearly impossible. Thus, over a ...century, their deterministic models that typically contain rapid reversible bindings have been simplified with non-elementary reaction functions (e.g., Michaelis-Menten and Morrison equations). Although the non-elementary reaction functions are derived by applying the quasi-steady-state approximation (QSSA) to deterministic systems, they have also been widely used to derive propensities for stochastic simulations due to computational efficiency and simplicity. However, the validity condition for this heuristic approach has not been identified even for the reversible binding between molecules, such as protein-DNA, enzyme-substrate, and receptor-ligand, which is the basis for living cells. Here, we find that the non-elementary propensities based on the deterministic total QSSA can accurately capture the stochastic dynamics of the reversible binding in general. However, serious errors occur when reactant molecules with similar levels tightly bind, unlike deterministic systems. In that case, the non-elementary propensities distort the stochastic dynamics of a bistable switch in the cell cycle and an oscillator in the circadian clock. Accordingly, we derive alternative non-elementary propensities with the stochastic low-state QSSA, developed in this study. This provides a universally valid framework for simplifying multiscale stochastic biochemical systems with rapid reversible bindings, critical for efficient stochastic simulations of cell signaling and gene regulation. To facilitate the framework, we provide a user-friendly open-source computational package, ASSISTER, that automatically performs the present framework.
Tomato yellow leaf curl virus (TYLCV) is one of the most well-known tomato-infecting begomoviruses and transmitted by Bemisia tabaci. Seed transmission has previously been reported for some RNA ...viruses, but TYLCV has not previously been described as a seed-borne virus. In 2013 and 2014, without whitefly-mediated transmission, TYLCV was detected in young tomato plants germinated from fallen fruits produced from TYLCV-infected tomato plants in the previous cultivation season. In addition, TYLCV-Israel (TYLCV-IL) was also detected in seeds and their seedlings of TYLCV-infected tomato plants that were infected by both viruliferous whitefly-mediated transmission and agro-inoculation. The seed infectivity was 20-100%, respectively, and the average transmission rate to seedlings was also 84.62% and 80.77%, respectively. TYLCV-tolerant tomatoes also produced TYLCV-infected seeds, but the amount of viral genome was less than seen in TYLCV-susceptible tomato plants. When tomato plants germinated from TYLCV-infected seeds, non-viruliferous whiteflies and healthy tomato plants were placed in an insect cage together, TYLCV was detected from whiteflies as well as receiver tomato plants six weeks later. Taken together, TYLCV-IL can be transmitted via seeds, and tomato plants germinated from TYLCV-infected seeds can be an inoculum source of TYLCV. This is the first report about TYLCV seed transmission in tomato.
For a self-sustaining wireless communication system in the Internet-of-Things (IoT) networks, energy harvesting (EH) can be implemented at each user node as a constant renewable power supply source. ...Hence, an investigation into the use of wireless-powered communication network (WPCN) protocols to facilitate communication between an access point (AP) and multiple mobile users (MUs) is presented in this article. The AP has multiple antennas and operates in the full-duplex (FD) mode. The MUs, on the other hand, have single antennas and works in the half-duplex (HD) mode. Each MU communicating with the FD-AP is assigned to one of two groups, based on the time allocation and channel access for either uplink (UL) or downlink (DL) communication. The channel assignment, time resource, and power resource allocations are optimized to maximize the UL weighted sum rate. The sum-rate optimization problem is found to be nonconvex. Therefore, an iterative algorithm is investigated to optimize the UL weighted sum rate of the proposed FD-WPCN system. Next, the proposed FD-WPCN algorithm is modified for HD-WPCN-enabled communication between the AP and multiple MUs. Extensive simulations are conducted to verify the proposed algorithm for FD-WPCN and compare its performance with the HD-WPCN counterpart. From the simulation results, FD-WPCN outperformed HD-WPCN at a low AP transmit signal-to-noise ratio (SNR) region. The opposite behavior is observed for high AP transmit SNR due to increasing residual self-interference at the FD-AP.
Autophagy, a catabolic process to remove unnecessary or dysfunctional organelles, is triggered by various signals including nutrient starvation. Depending on the types of the nutrient deficiency, ...diverse sensing mechanisms and signaling pathways orchestrate for transcriptional and epigenetic regulation of autophagy. However, our knowledge about nutrient type-specific transcriptional regulation during autophagy is limited. To understand nutrient type-dependent transcriptional mechanisms during autophagy, we performed single cell RNA sequencing (scRNAseq) in the mouse embryonic fibroblasts (MEFs) with or without glucose starvation (GS) as well as amino acid starvation (AAS). Trajectory analysis using scRNAseq identified sequential induction of potential transcriptional regulators for each condition. Gene regulatory rules inferred using TENET newly identified CCAAT/enhancer binding protein γ (C/EBPγ) as a regulator of autophagy in AAS, but not GS, condition, and knockdown experiment confirmed the TENET result. Cell biological and biochemical studies validated that activating transcription factor 4 (ATF4) is responsible for conferring specificity to C/EBPγ for the activation of autophagy genes under AAS, but not under GS condition. Together, our data identified C/EBPγ as a previously unidentified key regulator under AAS-induced autophagy.
ABSTRACT
A majority of existing studies on uncertainties in climate change impact assessments carried out the uncertainty analysis independently at each stage without quantifying the total ...uncertainty and thus it was seldom possible to assess the relative contribution of each stage to the total uncertainty and also to see how the uncertainty is propagated as the stage proceeds. To overcome these shortcomings, this study proposes a simple yet new approach, which can quantify the total uncertainty as well as the incremental uncertainty at each stage. Employing the maximum entropy as an uncertainty measure, the new approach was applied to a case study that consists of two emission scenarios, four global climate model GCM scenarios, two downscaling techniques, and two hydrological models. The difference was noteworthy: in case of the water streamflow projection, the conventional approach identified the GCM stage as the largest contributor (89.34%) to the total uncertainty while this new approach concluded the emission scenario stage the largest (58.66%). In case of the precipitation projection, the downscaling stage produced the largest uncertainty indicating that the relative uncertainty contribution of each assessment stage can vary depending on the projection variable which of uncertainty is examined. The case study also compared the projection uncertainty with the natural variability that exists in the observed data and concluded that the uncertainty generated by the future climate change projection is about two times larger than that of the past natural variability.
Abstract
Determination of the polytropic index of plasma in a magnetic field provides description of plasma physics ranging from laboratory plasma in the Earth to black hole in the Universe. ...Accordingly, a lot of efforts have been devoted to revealing the dependence of polytropic index of plasma on magnetic field. A recent experiment performed in a magnetic nozzle reported the dependency of the polytropic index on the magnetic field strength in that the polytropic index changes from 5/3 to unity with decreasing the magnetic field strength. In this letter, we show that the polytropic index of plasma does not depend on magnetic field if the radial electric field is sustained. The polytropic index is measured to be close to 2, higher than the previously reported value, regardless of the change in the strength and configuration of magnetic field.
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