ncRNA-mediated bistability in the synthesis of hundreds of distinct mRNAs and proteins

The kinetics of gene expression can be bistable due to the feedback between the mRNA and protein formation. In eukaryotic cells, the interplay between mRNAs and proteins can be influenced by non-coding RNAs. Some of these RNAs, e.g., microRNAs, may target hundreds of distinct mRNAs. The model presented here shows how a non-coding RNA can be used as a mediator in order to involve numerous mRNAs and proteins into a bistable network.     

Oscillatory dynamics in a simple gene regulatory network mediated by small RNAs

More and more experiments show that small RNAs regulate gene expression by repressing translation of messenger RNAs (mRNAs) or degrading mRNAs. In this paper, we incorporate the small RNAs into a simple gene regulatory network and investigate its dynamical behaviors. In addition, we also derive the theoretical results of globally asymptotic stability and provide the sufficient conditions for the oscillation of the simple gene regulatory network, and further demonstrate that the amplitudes against the change of delay in the gene regulatory network are robust.     

Non-coding RNAs and a layered architecture of genetic networks

In eukaryotic cells, protein-coding sequences constitute a relatively small part of the genome. The rest of the genome is transcribed to non-coding RNAs (ncRNAs). Such RNAs form the cornerstone of a regulatory network that operates in parallel with the protein network. Their biological functions are based primarily on the ability to pair with and deactivate target messenger RNAs (mRNAs). To clarify the likely role of ncRNAs in complex genetic networks, we present and comprehensively analyze a kinetic model of one of the key counterparts of the network architectures. Specifically, the genes transcribed to ncRNAs are considered to interplay with a hierarchical two-layer set of genes transcribed to mRNAs. The genes forming the bottom layer are regulated from the top and negatively self-regulated. If the former regulation is positive, the dependence of the RNA populations on the governing parameters is found to be often non-monotonous. Specifically, the model predicts bistability. If the regulation is negative, the dependence of the RNA populations on the governing parameters is monotonous. In particular, the population of the mRNAs, corresponding to the genes forming the bottom layer, is nearly constant.     

Interplay of noncoding RNAs,mRNAs, and proteins during the growth of eukaryotic cells

Numerous biological functions of noncoding RNAs (ncRNAs) in eukaryotic cells are based primarily on their ability to pair with target mRNAs and then either to prevent translation or to result in rapid degradation of the mRNA-ncRNA complex. Using a general model describing this scenario, we show that ncRNAs may help to maintain constant mRNA and protein concentrations during the growth of cells. The possibility of observation of this effect on the global scale is briefly discussed.     

Hierarchical genetic networks and noncoding RNAs

In eukaryotic cells, many genes are transcribed into noncoding RNAs. Such RNAs may associate with mRNAs and inhibit their translation and facilitate degradation. To clarify what may happen in this case, we propose a kinetic model describing the effect of noncoding RNAs on a mRNA-protein network with the hierarchical three-layer architecture. For positive regulation of the layers, our model predicts either bistability with a fairly narrow hysteresis loop or a unique steady state. For negative or mixed regulation, the steady state is found to be unique.     

Interplay of viral miRNAs and host mRNAs and proteins

Recent experiments indicate that several viruses may encode microRNAs (miRNAs) in cells. Such RNAs may interfere with the host mRNAs and proteins. We present a kinetic analysis of this interplay. In our treatment, the viral miRNA is considered to be able to associate with the host mRNA with subsequent degradation. This process may result in a decline of the mRNA population and also in a decline of the population of the protein encoded by this mRNA. With these ingredients, we first show the types of the corresponding steady-state kinetics in the cases of positive and negative regulation of the miRNA synthesis by the protein. In addition, we scrutinize the situation when the protein regulates the virion replication or, in other words, provides a feedback for the replication. For the negative feedback, the replication rate is found to increase with increasing the intracellular virion population. For the positive feedback, the replication rate first increases and then drops. These features may determine the stability of steady states.     

Non-coding RNAs and complex distributed genetic networks

In eukaryotic cells, the mRNA-protein interplay can be dramatically influenced by non-coding RNAs (ncRNAs). Although this new paradigm is now widely accepted, an understanding of the effect of ncRNAs on complex genetic networks is lacking. To clarify what may happen in this case, we propose a mean-field kinetic model describing the influence of ncRNA on a complex genetic network with a distributed architecture including mutual protein-mediated regulation of many genes transcribed into mRNAs. ncRNA is considered to associate with mRNAs and inhibit their translation and/or facilitate degradation. Our results are indicative of the richness of the kinetics under consideration. The main complex features are found to be bistability and oscillations. One could expect to find kinetic chaos as well. The latter feature has however not been observed in our calculations. In addition, we illustrate the difference in the regulation of distributed networks by mRNA and ncRNA.     

Integrating microRNA and mRNA expression profiles of neuronal progenitors to identify regulatory networks underlying the onset of cortical neurogenesis

Background  

Cortical development is a complex process that includes sequential generation of neuronal progenitors, which proliferate and migrate to form the stratified layers of the developing cortex. To identify the individual microRNAs (miRNAs) and mRNAs that may regulate the genetic network guiding the earliest phase of cortical development, the expression profiles of rat neuronal progenitors obtained at embryonic day 11 (E11), E12 and E13 were analyzed.     

Polymeric‐Micelle‐Based Nanomedicine for siRNA Delivery

Small interfering RNAs (siRNAs) are a rapidly emerging class of innovative nucleic acid medicines for the treatment of diseases such as cancer. However, significant hurdles hamper their clinical application, including poor cellular uptake, instability under physiological conditions, off‐target effects, and possible immunogenicity. The development of suitable delivery systems that protect and efficiently transport siRNA to targeted cells has been pursued. Nanoparticle‐based vectors have been widely investigated as potential candidates for effective siRNA delivery. Among the different nanoparticles, polymeric micelles, which are self‐assembled nanoparticles composed of amphiphilic materials with a core‐shell structure, have attracted great attention in recent years. Polymeric micelles in the range of several tens to hundreds of nanometers can be prepared, regulated, and modified relatively easily. The outer hydrophilic segments can prolong the in vivo lifetime of siRNA to achieve effective accumulation in tumors and can also be modified with cationic charges that interact electrostatically with siRNA and be introduced with different moieties to target specific cells. The inner cores can improve the stability of micelles and serve as payloads for hydrophobic drugs. Here, the barriers impeding siRNA delivery, the different polymeric micelles of siRNA developed to date, their gene silencing or therapeutic activity, and advanced applications for the co‐delivery of drugs and siRNA by these delivery systems are reviewed.     

长链非编码RNA XR_923426参与调控电离辐射诱导的微丝骨架变化

细胞微丝骨架是多功能亚细胞结构,是电离辐射的感受器也是效应器。为了明确长链非编码RNA(lncRNA)是否参与调控电离辐射引起的微丝骨架动力学变化,采用Swinholide A处理诱导细胞微丝骨架解聚之后,进行lncRNA组学分析并验证差异表达的lncRNA;采用鬼笔环肽染色和微丝网络结构分析等方法评价电离辐射引起微丝骨架动力学变化的程度。结果发现,微丝骨架解聚后,lncRNA XR_923426的表达下调;人为上调lncRNA XR_923426的表达水平能够显著缓解辐射导致的微丝骨架结构异常和微丝网络连接减少。这些发现为微丝通过lncRNA调控辐射导致细胞死亡或肿瘤转移的机制提供了新的研究思路,有望成为肿瘤治疗和正常组织辐射防护的新靶点。     

Localized mRNA translation and protein association

Recent direct observations of localization of mRNAs and proteins both in prokaryotic and eukaryotic cells can be related to slowdown of diffusion of these species due to macromolecular crowding and their ability to aggregate and form immobile or slowly mobile complexes. Here, a generic kinetic model describing both these factors is presented and comprehensively analyzed. Although the model is non-linear, an accurate self-consistent analytical solution of the corresponding reaction-diffusion equation has been constructed, the types of localized protein distributions have been explicitly shown, and the predicted kinetic regimes of gene expression have been classified.     

Fermionic Quantization and Configuration Spaces for the Skyrme and Faddeev-Hopf Models

The fundamental group and rational cohomology of the configuration spaces of the Skyrme and Faddeev-Hopf models are computed. Physical space is taken to be a compact oriented 3-manifold, either with or without a marked point representing an end at infinity. For the Skyrme model, the codomain is any Lie group, while for the Faddeev-Hopf model it is S². It is determined when the topology of configuration space permits fermionic and isospinorial quantization of the solitons of the model within generalizations of the frameworks of Finkelstein-Rubinstein and Sorkin. Fermionic quantization of Skyrmions is possible only if the target group contains a symplectic or special unitary factor, while fermionic quantization of Hopfions is always possible. Geometric interpretations of the results are given. The first author was partially supported by NSF grant DMS-0204651 The second author was partially supported by EPSRC grant GR/R66982/01     

非结构多面体二阶局部保界全局重映算法

提出一种三维非结构多面体二阶保界全局重映算法.在旧网格上选取模板利用最小二乘构造插值多项式,采用凸包算法计算多面体相交部分,最后使用局部保界修正技术修补重映后的越界量.多项数值实验表明这种格式同时具有高精度、高分辨率和高效率的特点.