Anti-inflammatory effects of reticuline on the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathway in a mouse model of obesity-associated asthma.

BACKGROUND: Asthma associated with obesity is a chronic disease characterized by earlier airway remodeling, severe wheezing, and increased insensitivity to hormone therapy. Reticuline, a bioactive compound of Magnoliae Flos, exerts anti-inflammatory activity and can inhibit neutrophil recruitment. Thus, this study investigated the role of reticuline in obesity-related asthma. METHODS: The BALB/c mice fed a low-fat diet (LFD) and high-fat diet (HFD) were intranasally challenged with house dust mites (HDMs) or ovalbumin (OVA). Reticuline (0.25 mg/kg) was administrated into mice by intragastrical gavage. Airway hyper-responsiveness was examined after the final challenge. Body weight was measured, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The number of inflammatory cells in BALF was estimated. Histological changes were assessed by performing hematoxylin-eosin staining, and production of proinflammatory cytokines and IgE was examined by ELISA kits. Related pathways were studied with western blotting. RESULTS: Reticuline suppressed airway resistance and inflammatory infiltration in lung tissue and reduced inflammatory cell recruitment in BALF in obesity mice with asthma. Additionally, the levels of IL-17A, IL-1ß, IL-5, macrophage inflammatory protein 2, and regulated on activation, normal T cell expressed and secreted in the lung were reduced by reticuline. Mechanistically, reticuline inactivated the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathways in obesity-related asthma. CONCLUSION: Reticuline alleviates airway inflammation in obesity-related asthma by inactivating the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathways.

The role of the Patient-Generated Subjective Global Assessment (PG-SGA) and biochemical markers in predicting anemia patients with cancer.

PURPOSE: The causes of anemia and the common side effects of cancer are multifactorial. Malnutrition is one of the alleged components of the aforementioned complications. This study planned to investigate the relationship among biochemical markers, Patient-Generated Subjective Global Assessment (PG-SGA), and anemia in cancer patients. METHODS: This analysis consisted of 234 patients who were enlisted in the Department of Oncology of the First Hospital of Shanxi Medical University between December 2016 and October 2017. The groups were divided into anemic and non-anemic patients. The gathered data primarily discussed the patients' basic information, specifically the age, gender, smoking, alcohol consumption, and nutritional status based on levels of serum biochemical markers and PG-SGA scores. RESULTS: Among the participants, 31.2% of the cancer patients were diagnosed with anemia whereas, according to the scores of PG.SGA, 65.0% of patients experienced malnourishment. The anemia was significantly associated with biochemical markers, expecting a transferrin in univariable analyses. Binary logistic regression analysis between anemic cancer patients and non-anemic cancer patients suggested that high PG-SGA score (odds ratio 1.082; 95% CI 1.027-1.141) implied the risk factor for anemia, and high PG-SGA scores could potentially increase the risk of anemia. The multiple regression analysis showed that hemoglobin concentration (OR 0.575; 95% CI 0.450-0.736) and PG-SGA score (OR 1.231; 95% CI 1.013-1.496) were linked to anemia. However, total protein, albumin, prealbumin, serum iron, transferrin, and transferrin saturation lacked a strong relationship with anemia. CONCLUSION: Anemia prevailed in cancer patients, as nutritionally assessed by PG-SGA, while hemoglobin established a linkage with anemia as they could provide extra predictive information about anemia in patients diagnosed with cancer.

High codimensional bifurcation analysis to a six-neuron BAM neural network.

In this article, the high codimension bifurcations of a six-neuron BAM neural network system with multiple delays are addressed. We first deduce the existence conditions under which the origin of the system is a Bogdanov-Takens singularity with multiplicities two or three. By choosing the connection coefficients as bifurcation parameters and using the formula derived from the normal form theory and the center manifold, the normal forms of Bogdanov-Takens and triple zero bifurcations are presented. Some numerical examples are shown to support our main results.

Bifurcation-based approach reveals synergism and optimal combinatorial perturbation.

Cells accomplish the process of fate decisions and form terminal lineages through a series of binary choices in which cells switch stable states from one branch to another as the interacting strengths of regulatory factors continuously vary. Various combinatorial effects may occur because almost all regulatory processes are managed in a combinatorial fashion. Combinatorial regulation is crucial for cell fate decisions because it may effectively integrate many different signaling pathways to meet the higher regulation demand during cell development. However, whether the contribution of combinatorial regulation to the state transition is better than that of a single one and if so, what the optimal combination strategy is, seem to be significant issue from the point of view of both biology and mathematics. Using the approaches of combinatorial perturbations and bifurcation analysis, we provide a general framework for the quantitative analysis of synergism in molecular networks. Different from the known methods, the bifurcation-based approach depends only on stable state responses to stimuli because the state transition induced by combinatorial perturbations occurs between stable states. More importantly, an optimal combinatorial perturbation strategy can be determined by investigating the relationship between the bifurcation curve of a synergistic perturbation pair and the level set of a specific objective function. The approach is applied to two models, i.e., a theoretical multistable decision model and a biologically realistic CREB model, to show its validity, although the approach holds for a general class of biological systems.

Neural fate decisions mediated by combinatorial regulation of Hes1 and miR-9.

In the nervous system, Hes1 shows an oscillatory manner in neural progenitors but a persistent one in neurons. Many models involving Hes1 have been provided for the study of neural differentiation but few of them take the role of microRNA into account. It is known that a microRNA, miR-9, plays crucial roles in modulating Hes1 oscillations. However, the roles of miR-9 in controlling Hes1 oscillations and inducing transition between different cell fates still need to be further explored. Here we provide a mathematical model to show the interaction between miR-9 and Hes1, with the aim of understanding how the Hes1 oscillations are produced, how they are controlled, and further, how they are terminated. Based on the experimental findings, the model demonstrates the essential roles of Hes1 and miR-9 in regulating the dynamics of the system. In particular, the model suggests that the balance between miR-9 and Hes1 plays important roles in the choice between progenitor maintenance and neural differentiation. In addition, the synergistic (or antagonistic) effects of several important regulations are investigated so as to elucidate the effects of combinatorial regulation in neural decision-making. Our model provides a qualitative mechanism for understanding the process in neural fate decisions regulated by Hes1 and miR-9.

Mean field theory for biology inspired duplication-divergence network model.

The duplication-divergence network model is generally thought to incorporate key ingredients underlying the growth and evolution of protein-protein interaction networks. Properties of the model have been elucidated through numerous simulation studies. However, a comprehensive theoretical study of the model is lacking. Here, we derived analytic expressions for quantities describing key characteristics of the network-the average degree, the degree distribution, the clustering coefficient, and the neighbor connectivity-in the mean-field, large-N limit of an extended version of the model, duplication-divergence complemented with heterodimerization and addition. We carried out extensive simulations and verified excellent agreement between simulation and theory except for one partial case. All four quantities obeyed power-laws even at moderate network size ( N∼10(4)), except the degree distribution, which had an additional exponential factor observed to obey power-law. It is shown that our network model can lead to the emergence of scale-free property and hierarchical modularity simultaneously, reproducing the important topological properties of real protein-protein interaction networks.

Bifurcation dynamics and determination of alternate cell fates in bipotent progenitor cells.

The gene regulatory networks in which two lineage-affiliated transcription factors, such as GATA1 and PU.1, inhibit each other but activate themselves so as to regulate the choice between alternative cell fates have been extensively studied. These simple networks can generate bistability and explain the transitions between the alternative cell fates. The commitment of a progenitor cell to a new fate corresponds to the occurrence of different types of bifurcations, depending on if a system is symmetrical and how perturbations affect the system. Here we take a general modeling and analyzing approach and show that the lateral inhibition with symmetry and asymmetry can lead to different bifurcation dynamics. Especially, if cell fate decision-making is initiated with asymmetry or symmetry-breaking perturbations, a progenitor cell pre-patterns itself into a polarized cell, depending on the asymmetry or symmetry-breaking perturbations. This study may help us understand the fundamental features of binary cell fate decisions more clearly and further apply to a wider range of decision-making processes.

Pinning synchronization of hybrid-coupled directed delayed dynamical network via intermittent control.

This paper concerns the problem of exponential synchronization for a class of general delayed dynamical networks with hybrid coupling via pinning periodically intermittent control. Both the internal delay and coupling delay are taken into account in the network model. Meanwhile, the transmission delay and self-feedback delay are involved in the delayed coupling term. By establishing a new differential inequality, several simple and useful exponential synchronization criteria are derived analytically. It is shown that the controlled synchronization state can vary in comparison with the conventional synchronized solution, and the degree of the node and the inner delayed coupling matrix play important roles in the controlled synchronization state. By choosing different inner delayed coupling matrices and the degrees of the node, different controlled synchronization states can be obtained. Furthermore, the detail pinning schemes deciding what nodes should be chosen as pinned candidates and how many nodes are needed to be pinned for a fixed coupling strength are provided. The simple procedures illuminating how to design suitable intermittent controllers in real application are also given. Numerical simulations, including an undirected scale-free network and a directed small-world network, are finally presented to demonstrate the effectiveness of the theoretical results.

Charge-signal multiplication mediated by urea wires inside Y-shaped carbon nanotubes.

In previous studies, we reported molecular dynamics (MD) simulations showing that single-file water wires confined inside Y-shaped single-walled carbon nanotubes (Y-SWNTs) held strong and robust capability to convert and multiply charge signals [Y. S. Tu, P. Xiu, R. Z. Wan, J. Hu, R. H. Zhou, and H. P. Fang, Proc. Natl. Acad. Sci. U.S.A. 106, 18120 (2009); Y. Tu, H. Lu, Y. Zhang, T. Huynh, and R. Zhou, J. Chem. Phys. 138, 015104 (2013)]. It is fascinating to see whether the signal multiplication can be realized by other kinds of polar molecules with larger dipole moments (which make the experimental realization easier). In this article, we use MD simulations to study the urea-mediated signal conversion and multiplication with Y-SWNTs. We observe that when a Y-SWNT with an external charge of magnitude 1.0 e (the model of a signal at the single-electron level) is solvated in 1 M urea solutions, urea can induce drying of the Y-SWNT and fill its interiors in single-file, forming Y-shaped urea wires. The external charge can effectively control the dipole orientation of the urea wire inside the main channel (i.e., the signal can be readily converted), and this signal can further be multiplied into 2 (or more) output signals by modulating dipole orientations of urea wires in bifurcated branch channels of the Y-SWNT. This remarkable signal transduction capability arises from the strong dipole-induced ordering of urea wires under extreme confinement. We also discuss the advantage of urea as compared with water in the signal multiplication, as well as the robustness and biological implications of our findings. This study provides the possibility for multiplying signals by using urea molecules (or other polar organic molecules) with Y-shaped nanochannels and might also help understand the mechanism behind signal conduction in both physical and biological systems.

Dynamics of posttranslational modifications of p53.

The latest experimental evidence indicates that acetylation of p53 at K164 (lysine 164) and K120 may induce directly cell apoptosis under severe DNA damage. However, previous cell apoptosis models only studied the effects of active and/or inactive p53, that is, phosphorylation/dephosphorylation of p53. In the present paper, based partly on Geva-Zatorsky et al. (2006) and Batchelor et al. (2008), we propose a new cell apoptosis network, in which p53 has three statuses, that is, unphosphorylated p53, phosphorylated p53, and acetylated p53. The time delay differential equations (DDEs) are formulated based on our network to investigate the dynamical insights of p53-induced cell apoptosis. In agreement with experiments (Loewer et al. (2010)), our simulations indicate that acetylated p53 accumulates gradually and then induces the proapoptotic protein Bax under enough DNA damage. Moreover, phosphorylated p53 oscillates and initiates cell repair during DNA damage.

Investigation of oscillation accumulation triggered genetic switch in gene regulatory networks.

Genetic oscillator motifs and genetic switch motifs are blocks of biochemical reaction networks, which are involved in the regulation of rhythms, cell cycle progression, signal processing and cell fate decision. These motifs often interact to constitute complex signal processing systems. There widely exists the oscillation accumulation triggered mechanism in gene regulatory networks, i.e., an oscillator promotes the accumulation of a signaling protein over a threshold value, and activates a switch. The structure can be fund in some important biological function switches, such as apoptosis and DNA repair. We propose the structure as an oscillation accumulation triggered genetic switch (OATGS). Through mathematical modeling and analysis, results show the OATGS with features of robustness to noise and triggered mode. In addition, we show the existence of OATGS features and triggered manner in p53 gene regulatory networks, and explain some of the p53 regulation process, such as counting mechanism and pulse shape. We speculate that OATGS with oscillation accumulation triggered manner is a new important biological function switch.

Overexpression of DCF1 inhibits glioma through destruction of mitochondria and activation of apoptosis pathway.

Gliomas are the most common brain tumors affecting the central nervous system and are associated with a high mortality rate. DCF1 is a membrane protein that was previously found to play a role in neural stem cell differentiation. In the present study, we found that overexpression of dcf1 significantly inhibited cell proliferation, migration, and invasion and dramatically promoted apoptosis in the glioblastoma U251 cell line. DCF1 deletion mutations in the functional region showed that the complete structure of DCF1 was necessary for apoptosis. Furthermore, significantly lower tumorigenicity was observed in athymic nude mice by transplanting U251 cells overexpressing dcf1. To decode the apoptosis induced by dcf1, mitochondrial structure and membrane potential in glioma cells were investigated and the results indicated obvious mitochondrial swelling, destruction of cristae, and a significant decline in membrane potential. Mechanismly, caspase-3 signaling was activated. Finally, endogenous dcf1 silence in U251 cells was investigated. Results showed a highly methylation at -1339 and -1322 position at dcf1 promoter sequence, revealing the causal relationship between dcf1 gene and tumorigencicity. The present study identified a previously unknown cancer apoptosis mechanism involving dcf1 overexpression and provided a novel approach to potentially treat glioma patients.

Dynamic analysis of the combinatorial regulation involving transcription factors and microRNAs in cell fate decisions.

P53 and E2F1 are critical transcription factors involved in the choices between different cell fates including cell differentiation, cell cycle arrest or apoptosis. Recent experiments have shown that two families of microRNAs (miRNAs), p53-responsive miR34 (miRNA-34 a, b and c) and E2F1-inducible miR449 (miRNA-449 a, b and c) are potent inducers of these different fates and might have an important role in sensitizing cancer cells to drug treatment and tumor suppression. Identifying the mechanisms responsible for the combinatorial regulatory roles of these two transcription factors and two miRNAs is an important and challenging problem. Here, based in part on the model proposed in Tongli Zhang et al. (2007), we developed a mathematical model of the decision process and explored the combinatorial regulation between these two transcription factors and two miRNAs in response to DNA damage. By analyzing nonlinear dynamic behaviors of the model, we found that p53 exhibits pulsatile behavior. Moreover, a comparison is given to reveal the subtle differences of the cell fate decision process between regulation and deregulation of miR34 on E2F1. It predicts that miR34 plays a critical role in promoting cell cycle arrest. In addition, a computer simulation result also predicts that the miR449 is necessary for apoptosis in response to sustained DNA damage. In agreement with experimental observations, our model can account for the intricate regulatory relationship between these two transcription factors and two miRNAs in the cell fate decision process after DNA damage. These theoretical results indicate that miR34 and miR449 are effective tumor suppressors and play critical roles in cell fate decisions. The work provides a dynamic mechanism that shows how cell fate decisions are coordinated by two transcription factors and two miRNAs. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology and Clinical Implications. Guest Editor: Yudong Cai.

MicroRNA-mediated regulation in biological systems with oscillatory behavior.

As a class of small noncoding RNAs, microRNAs (miRNAs) regulate stability or translation of mRNA transcripts. Some reports bring new insights into possible roles of microRNAs in modulating cell cycle. In this paper, we focus on the mechanism and effectiveness of microRNA-mediated regulation in the cell cycle. We first describe two specific regulatory circuits that incorporate base-pairing microRNAs and show their fine-tuning roles in the modulation of periodic behavior. Furthermore, we analyze the effects of miR369-3 on the modulation of the cell cycle, confirming that miR369-3 plays a role in shortening the period of the cell cycle. These results are consistent with experimental observations.

Destructive extraction of phospholipids from Escherichia coli membranes by graphene nanosheets.

Understanding how nanomaterials interact with cell membranes is related to how they cause cytotoxicity and is therefore critical for designing safer biomedical applications. Recently, graphene (a two-dimensional nanomaterial) was shown to have antibacterial activity on Escherichia coli, but its underlying molecular mechanisms remain unknown. Here we show experimentally and theoretically that pristine graphene and graphene oxide nanosheets can induce the degradation of the inner and outer cell membranes of Escherichia coli, and reduce their viability. Transmission electron microscopy shows three rough stages, and molecular dynamics simulations reveal the atomic details of the process. Graphene nanosheets can penetrate into and extract large amounts of phospholipids from the cell membranes because of the strong dispersion interactions between graphene and lipid molecules. This destructive extraction offers a novel mechanism for the molecular basis of graphene's cytotoxicity and antibacterial activity.

Coupling-induced synchronization in multicellular circadian oscillators of mammals.

In mammals, circadian rhythms are controlled by the neurons located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Each neuron in the SCN contains an autonomous molecular clock. The fundamental question is how the individual cellular oscillators, expressing a wide range of periods, interact and assemble to achieve phase synchronization. Most of the studies carried out so far emphasize the crucial role of the periodicity imposed by the light-dark cycle in neuronal synchronization. However, in natural conditions, the interaction between the SCN neurons is non-negligible and coupling between cells in the SCN is achieved partly by neurotransmitters. In this paper, we use a model of nonidentical, globally coupled cellular clocks considered as Goodwin oscillators. We mainly study the synchronization induced by coupling from an analytical way. Our results show that the role of the coupling is to enhance the synchronization to the external forcing. The conclusion of this paper can help us better understand the mechanism of circadian rhythm.

Functional characteristics of a double negative feedback loop mediated by microRNAs.

MicroRNAs (miRNAs) are a class of small, noncoding RNAs that play crucial roles in almost all cellular processes. As key post-transcriptional regulators of gene expression, miRNAs mainly induce mRNA degradation or translational repression. Recently computational and experimental studies have identified an abundance of motifs involving miRNAs and transcriptional factors (TFs). Here, we study the functional characteristics of one such motif, a two-node miRNA-mediated double negative feedback loop (MDNFL) in which a TF suppresses an miRNA and the TF itself is negatively regulated by the miRNA. Several examples of this motif are described from the literature. We propose a general computational model for the MDNFL based on biochemical regulations and explore its dynamics by using bifurcation analysis. Our results show that the MDNFL can behave as a bistable switch. This functional feature is in agreement with experimental observations of the widespread appearance of miRNAs in fate decisions such as differentiation during development. Importantly, it is found that under the interplay of a TF and an miRNA, the MDNFL model can behave as switches for wide ranges of parameters even without cooperative binding of the TF. In addition, we also investigate how extrinsic noise affects dynamic behavior of the MDNFL. Interestingly, it is found that when the MDNFL is in the bistable region, by choosing the appropriate extrinsic noise source, the MDNFL system can switch from one steady state to the other and meanwhile the production of either miRNA or protein is amplified significantly. From an engineering perspective, this noise-based switch and amplifier for gene expression is very easy to control. It is hoped that the results presented here would provide a new insight on how gene expression is regulated by miRNAs and further guidance for experiments.

Dynamical behaviors of Rb-E2F pathway including negative feedback loops involving miR449.

MiRNAs, which are a family of small non-coding RNAs, regulate a broad array of physiological and developmental processes. However, their regulatory roles have remained largely mysterious. E2F is a positive regulator of cell cycle progression and also a potent inducer of apoptosis. Positive feedback loops in the regulation of Rb-E2F pathway are predicted and shown experimentally. Recently, it has been discovered that E2F induce a cluster of miRNAs called miR449. In turn, E2F is inhibited by miR449 through regulating different transcripts, thus forming negative feedback loops in the interaction network. Here, based on the integration of experimental evidence and quantitative data, we studied Rb-E2F pathway coupling the positive feedback loops and negative feedback loops mediated by miR449. Therefore, a mathematical model is constructed based in part on the model proposed in Yao-Lee et al. (2008) and nonlinear dynamical behaviors including the stability and bifurcations of the model are discussed. A comparison is given to reveal the implication of the fundamental differences of Rb-E2F pathway between regulation and deregulation of miR449. Coherent with the experiments it predicts that miR449 plays a critical role in regulating the cell cycle progression and provides a twofold safety mechanism to avoid excessive E2F-induced proliferation by cell cycle arrest and apoptosis. Moreover, numerical simulation and bifurcation analysis shows that the mechanisms of the negative regulation of miR449 to three different transcripts are quite distinctive which needs to be verified experimentally. This study may help us to analyze the whole cell cycle process mediated by other miRNAs more easily. A better knowledge of the dynamical behaviors of miRNAs mediated networks is also of interest for bio-engineering and artificial control.

Mechanisms generating bistability and oscillations in microRNA-mediated motifs.

The importance of post-transcriptional regulation by microRNAs (miRNAs) has recently been recognized in almost all cellular processes. When participating in cellular processes, miRNAs mainly mediate mRNA degradation or translational repression. Recently computational and experimental studies have identified an abundance of motifs involving miRNAs and transcriptional factors (TFs). The simplest motif is a two-node miRNA-mediated feedback loop (MFL) in which a TF regulates an miRNA and the TF itself is negatively regulated by the miRNA. In this paper we present a general computational model for the MFL based on biochemical regulations and explore its dynamics by using bifurcation analysis. Our results show that the MFL can behave either as switches or as oscillators, depending on the TF as a repressor or an activator. These functional features are consistent with the widespread appearance of miRNAs in fate decisions such as proliferation, differentiation, and apoptosis during development. We found that under the interplay of a TF and an miRNA, the MFL model can behave as switches for wide ranges of parameters even without cooperative binding of the TF. In addition, oscillations induced by the miRNA in the MFL model require neither an additional positive feedback loop, nor self-activation of the gene, nor cooperative binding of the TF, nor saturated degradation. Therefore, the MFL may provide a general network structure to induce bistability or oscillations. It is hoped that the results presented here will provide a new view on how gene expression is regulated by miRNAs and further guidance for experiments. Moreover, the insight gained from this study is also expected to provide a basis for the investigation of more complex networks assembled by simple building blocks.