A circuit for secretion-coupled cellular autonomy in multicellular eukaryotic cells.

Cancers represent complex autonomous systems, displaying self-sufficiency in growth signaling. Autonomous growth is fueled by a cancer cell's ability to "secrete-and-sense" growth factors (GFs): a poorly understood phenomenon. Using an integrated computational and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled autonomy. The circuit is assembled when the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Giαßγ and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed-loop control, allow the two GTPases to coregulate each other, and convert the expected switch-like behavior of Arf1-dependent secretion into an unexpected dose-response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self-sustained by stimulus-proportionate secretion. Proteomic studies and protein-protein interaction network analyses pinpoint GFs (e.g., the epidermal GF) as key stimuli for such self-sustenance. Findings highlight how the enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion-coupled autonomy of growth factors.

Design principles of improving the dose-response alignment in coupled GTPase switches.

"Dose-response alignment" (DoRA), where the downstream response of cellular signaling pathways closely matches the fraction of activated receptor, can improve the fidelity of dose information transmission. The negative feedback has been experimentally identified as a key component for DoRA, but numerical simulations indicate that negative feedback is not sufficient to achieve perfect DoRA, i.e., perfect match of downstream response and receptor activation level. Thus a natural question is whether there exist design principles for signaling motifs within only negative feedback loops to improve DoRA to near-perfect DoRA. Here, we investigated several model formulations of an experimentally validated circuit that couples two molecular switches-mGTPase (monomeric GTPase) and tGTPase (heterotrimeric GTPases) - with negative feedback loops. In the absence of feedback, the low and intermediate mGTPase activation levels benefit DoRA in mass action and Hill-function models, respectively. Adding negative feedback has versatile roles on DoRA: it may impair DoRA in the mass action model with low mGTPase activation level and Hill-function model with intermediate mGTPase activation level; in other cases, i.e., the mass action model with a high mGTPase activation level or the Hill-function model with a non-intermediate mGTPase activation level, it improves DoRA. Furthermore, we found that DoRA in a longer cascade (i.e., tGTPase) can be obtained using Hill-function kinetics under certain conditions. In summary, we show how ranges of activity of mGTPase, reaction kinetics, the negative feedback, and the cascade length affect DoRA. This work provides a framework for improving the DoRA performance in signaling motifs with negative feedback.

Coactivation of antagonistic genes stabilizes polarity patterning during shoot organogenesis.

Spatiotemporal patterns of gene expression are instrumental to morphogenesis. A stable pattern interface, often between reciprocal-inhibiting morphogens, must be robustly maintained after initial patterning cues diminish, organ growth, or organ geometry changes. In plants, floral and leaf primordia obtain the adaxial-abaxial pattern at the shoot apical meristem periphery. However, it is unknown how the pattern is maintained after primordia have left the shoot apex. Here, through a combination of computational simulations, time-lapse imaging, and genetic analysis, we propose a model in which auxin simultaneously promotes both adaxial and abaxial domains of expression. Furthermore, we identified multilevel feedback regulation of auxin signaling to refine the spatiotemporal patterns. Our results demonstrate that coactivation by auxin determines and stabilizes antagonistic adaxial-abaxial patterning during aerial organ formation.

Network design principle for robust oscillatory behaviors with respect to biological noise.

Oscillatory behaviors, which are ubiquitous in transcriptional regulatory networks, are often subject to inevitable biological noise. Thus, a natural question is how transcriptional regulatory networks can robustly achieve accurate oscillation in the presence of biological noise. Here, we search all two- and three-node transcriptional regulatory network topologies for those robustly capable of accurate oscillation against the parameter variability (extrinsic noise) or stochasticity of chemical reactions (intrinsic noise). We find that, no matter what source of the noise is applied, the topologies containing the repressilator with positive autoregulation show higher robustness of accurate oscillation than those containing the activator-inhibitor oscillator, and additional positive autoregulation enhances the robustness against noise. Nevertheless, the attenuation of different sources of noise is governed by distinct mechanisms: the parameter variability is buffered by the long period, while the stochasticity of chemical reactions is filtered by the high amplitude. Furthermore, we analyze the noise of a synthetic human nuclear factor κB (NF-κB) signaling network by varying three different topologies and verify that the addition of a repressilator to the activator-inhibitor oscillator, which leads to the emergence of high-robustness motif-the repressilator with positive autoregulation-improves the oscillation accuracy in comparison to the topology with only an activator-inhibitor oscillator. These design principles may be applicable to other oscillatory circuits.

Mathematical modeling of histone modifications reveals the formation mechanism and function of bivalent chromatin.

Bivalent chromatin is characterized by occupation of both activating and repressive histone modifications. Here, we develop a mathematical model that involves antagonistic histone modifications H3K4me3 and H3K27me3 to capture the key features of bivalent chromatin. Three necessary conditions for the emergence of bivalent chromatin are identified, including advantageous methylating activity over demethylating activity, frequent noise conversions of modifications, and sufficient nonlinearity. The first condition is further confirmed by analyzing the existing experimental data. Investigation of the composition of bivalent chromatin reveals that bivalent nucleosomes carrying both H3K4me3 and H3K27me3 account for no more than half of nucleosomes at the bivalent chromatin domain. We identify that bivalent chromatin not only allows transitions to multiple states but also serves as a stepping stone to facilitate a stepwise transition between repressive chromatin state and activating chromatin state and thus elucidate crucial roles of bivalent chromatin in mediating phenotypical plasticity during cell fate determination.

Study on arsenic, selenium, and lead produced in coal combustion: bibliometric method.

The literature on trace element pollutants (arsenic, selenium, lead) produced during coal burning from 2007 to 2020 was summarized by the bibliometric method, and the characteristics of published articles and research trends were analyzed. Taking 2007 as the starting point for statistics on articles in this research direction, there was a process of rapid growth in the total number of published articles by 2015, and it was increased over time. In the last 5 years of statistics, it is found that the number of articles published in China is the largest, accounting for almost half of the total. Most of the articles are published in the fields of energy, environmental protection, etc. Among them, the research on arsenic, selenium, and lead is mainly related to the use of adsorbents. At the same time, the effects of temperature, catalyst, material, and other conditions on the removal efficiency of arsenic, selenium, and lead in coal were considered. Application of photocatalysis, preparation of new adsorption materials, and mining of the properties of existing materials under different experimental conditions are a good development prospect.

Network Topologies That Can Achieve Dual Function of Adaptation and Noise Attenuation.

Many signaling systems execute adaptation under circumstances that require noise attenuation. Here, we identify an intrinsic trade-off existing between sensitivity and noise attenuation in the three-node networks. We demonstrate that although fine-tuning timescales in three-node adaptive networks can partially mediate this trade-off in this context, it prolongs adaptation time and imposes unrealistic parameter constraints. By contrast, four-node networks can effectively decouple adaptation and noise attenuation to achieve dual function without a trade-off, provided that these functions are executed sequentially. We illustrate ideas in seven biological examples, including Dictyostelium discoideum chemotaxis and the p53 signaling network and find that adaptive networks are often associated with a noise attenuation module. Our approach may be applicable to finding network design principles for other dual and multiple functions.