Coupled positive feedback loops regulate the biological behavior

Boolean Dynamics of Biological Networks with Multiple Coupled Feedback Loops

Coupled positive and negative feedback loops form an essential building block of cellular signaling pathways, but the dynamics of such a system remain to be fully explored. Here, we systematically analyze a two-component circuit with interlinked positive and negative feedback loops, focusing on feedback-induced dynamics and their mechanisms. We show that feedbacks can induce monostability, oscillation, and excitability as well as the coexistence of two attractors (including that of two different stable steady states (called Type-I bistability) and that of both a stable steady state and a stable limit cycle (called Type-II bistability)). In particular for Type-II bistability, we find that feedback-controlled molecular noise can induce stochastic switching between two different attractors, and that the first passage time between them exhibits a multi-peak distribution. These investigations provide insights for understanding the biological functions of coupled positive and negative feedback circuits from the viewpoint of dynamics.

Analysis of coupled two-phase natural circulation loops by developing HEM and DFM based numerical models

Peroxiredoxins (Prxs) are a family of multifunctional antioxidant thioredoxin-dependent peroxidases that have been identified in a large variety of organisms. The major functions of Prxs comprise cellular protection against oxidative stress, modulation of intracellular signaling cascades that apply hydrogen peroxide as a second messenger molecule, and regulation of cell proliferation. In the present review, we discuss pertinent findings on the protein structure, the cell- and tissue-specific distribution, as well as the subcellular localization of Prxs. A particular emphasis is put on Prx I, which is the most abundant and ubiquitously distributed member of the mammalian Prxs. Major transcriptional and posttranslational regulatory mechanisms and signaling pathways that control Prx gene expression and activity are summarized. The interaction of Prx I with the oncogene products c-Abl and c-Myc and the regulatory role of Prx I for cell proliferation and apoptosis are highlighted. Recent findings on phenotypical alterations of mouse models with targeted disruptions of Prx genes are discussed, confirming the physiological functions of Prxs for antioxidant cell and tissue protection along with an important role as tumor suppressors.

Studying Evolution of Multiple Myeloma with CanEvolve

Black phosphorus (BP) is a newly discovered two-dimensional material that has promising applications from bioelectronics to biomedicine. However, facile oxidation of BP leads to changes in surface ...

In toxicogenomics, functional annotation is an important step to gain additional insights into genes with aberrant expression that drive pathophysiological mechanisms. Nevertheless, there exists a gap on annotation of these genes which often hampers the interpretation of results and limits their applicability in translational medicine. In this study, we evaluated the coverage of functional annotations of differentially expressed genes (DEGs) induced by 10 selected compounds from the TG-GATEs database identified as high- or no-risk in causing drug-induced liver injury (most-DILI or no-DILI, respectively) using in vitro human data. Functional roles of DEGs not present in the most common biological annotation databases – termed “dark genes” – were unveiled via literature mining and via the identification of shared regulatory transcription factors or signaling pathways. Our results demonstrated that there were approximately 13% of dark genes induced by these compounds in vitro and we were able to obtain additional relevant information for up to 76% of those. Using interactome data from several sources, we have uncovered genes such as LRBA, and WDR26 as highly connected in the protein network that play roles in drug response. Genes such as MALAT1, H19, and MIR29C – whose links to hepatotoxicity have been confirmed – were identified as markers for the most-DILI group and appeared as top hits across all literature-based mining methods. Furthermore, we investigated the potential impact of dark genes on liver toxicity by identifying their rat orthologs in combination with their correlation to drug-induced liver pathologies observed in vivo following chemical exposure. We identified a set of important regulatory transcription factors of dark genes for all most-DILI compounds including E2F1 and JUND with supporting evidences in literature and we found Magee1 correlated with chemically induced bile duct hyperplasia and adverse responses at 29 days in rats in vivo. In conclusion, in this study we show the potential role of these poorly annotated genes in mechanisms underlying hepatotoxicity and offer a number of computational approaches that may help to minimize current gaps in gene annotation and highlight their values as potential biomarkers in toxicological studies.

ABSTRACTProstate cancer is one of the most common cancers in men over the age of sixty. Lysine acetyltransferase 5 (KAT5) is a histone acetyltransferase involved in transcriptional regulation, DNA repair, and cell signaling pathways. Previous studies have shown that KAT5 expression is reduced in the cytoplasm of the prostate cancer cell line LNCaP when exposed to androgen. Moreover, KAT5 has been reported to have a role in the molecular pathway leading to androgen-independent prostate cancer after long-term androgen deprivation therapy. Here, we showed that KAT5 expression was significantly reduced in prostate cancer tissues and cell lines by using the public databases Oncomine and Human Protein Atlas. Reduced KAT5 expression was significantly associated with high mortality in prostate cancer patients. Furthermore, KAT5 overexpression increased the level of apoptotic markers, such as cleaved-caspase 3, in LNCaP cells, thus enhancing the apoptotic death of LNCaP cells. Taken together, KAT5 induced apoptosis in prostate cancer cells via the caspase-3 pathway, indicating that KAT5 could be a gene therapy target for prostate cancer.

Clonal chromosome abnormalities and somatic gene mutations are the hallmarks of many leukemia and lymphoma, such as t(9;22)/BCR/ABL1 fusions in chronic myeloid leukemia (CML) and t(8;14)/IGH/MYC fusions in Burkitt leukemia and lymphoma. Nonrandom chromosome translocations, inversion and insertion, loss and gain of chromosomes, and deletions and amplifications of parts of chromosomes and gene mutations are readily detected by chromosome analysis, FISH and microarray tests, and next-generation sequencing (NGS) techniques. Chromosome translocation and/or inversion in myeloid and lymphoid leukemia and lymphoma frequently involve the genes that are functionally related to transcriptional regulation, epigenetic regulation, cell cycling, apoptosis regulation, and cytokine signaling pathways. Detecting certain chromosome abnormalities greatly helps in establishing a precise diagnosis and differential diagnosis and also in selecting appropriate treatment. Moreover, chromosome abnormalities are the most significant prognostic factors for patients with de novo acute leukemia and lymphoma. With novel molecular techniques, particularly next-generation sequencing, more genetic biomarkers are being discovered, many of which are genetic-based therapeutic targets that allow various clinical trials with promising novel treatment options, such as immune checkpoint inhibitors targeting PDL1/PDL2 in classical Hodgkin lymphoma (cHL). This progress from new genetic findings will further enable us better to understand the genetic mechanisms of relevant genes and novel fusions in various leukemo- and lymphogenesis, define new disease entities, and allow us to study on treatment resistance in many patients even with novel genetic-based treatment.

Network motifs hold a very important status in genetic regulatory networks. This paper aims to analyse the dynamical property of the network motifs in genetic regulatory networks. The main result we obtained is that the dynamical property of a single motif is very simple with only an asymptotically stable equilibrium point, but the combination of several motifs can make more complicated dynamical properties emerge such as limit cycles. The above-mentioned result shows that network motif is a stable substructure in genetic regulatory networks while their combinations make the genetic regulatory network more complicated.

We studied interactions between the mitogen-activated protein kinase (MAPK) signalling pathway and cAMP-protein kinase (PKA) signaling pathway in regulation of mitogenesis of mesangial cells (MC) determined by [3H]thymidine incorporation, with or without added EGF. Forskolin or dibutyryl cAMP strongly (by 60-70%) inhibited [3H]thymidine incorporation into MC. Cilostamide, lixazinone or cilostazol selective inhibitors of cAMP-phosphodiesterase (PDE) isozyme PDE-III, inhibited mitogenesis to similar extent as forskolin and DBcAMP and activated in situ PKA, but without detectable increase in cAMP levels. Cilostamide and cilostazol were more than three times more effective at inhibiting mesangial mitogenesis than rolipram and denbufylline, inhibitors of isozyme PDE-IV, even though PDE-IV was two times more abundant in MC than was PDE-III. On the other hand, when incubated with forskolin, rolipram-enhanced cAMP accumulation was far greater (10-100x) than with cilostamide. EGF increased MAPK activity (+300%); PDE isozyme inhibitors which suppressed mitogenesis also inhibited MAPK. PDE isozyme inhibitors also suppressed PDGF-stimulated MC proliferation. We conclude that cAMP inhibits the mitogen-dependent MAPK-signaling pathway probably by decreasing the activity of Raf-1 due to PKA-catalyzed phosphorylation. Further, we surmise that minor increase in the cAMP pool metabolized by PDE-III is intimately related to regulation of mesangial proliferation. Thus, PDE isozyme inhibitors have the potential to suppress MC proliferation by a focused effect upon signaling pathways.

Skeletal musle disuse has been shown to induce muscle atrophy rapidly in both young and old human individuals (1) as well as extracellular matrix (ECM) remodeling in young individuals (2). However, little is known about the effect of immobilization on ECM remodeling in older individuals. PURPOSE: To study the effect of aging on transcriptional regulatory signaling pathways involved in ECM remodeling with short-term immobilization. METHODS: Myofiber atrophy was induced by application of a knee-brace for a total period of 4 days in young (Y∼20 yrs, n=11) and aged (O∼70 yrs, n=11) individuals. Muscle biopsies of the vastus lateralis (VL) muscle were collected 1 week prior to immobilization and after 24h, 48h and 96h of immobilization. Expression levels of Col1A1, Col3A1, MMP2 and MMP9 mRNAs were determined using real-time RT-PCR and normalized to the Ribosomal Protein Large P0 (RPLP0) mRNA. RESULTS: In both age groups an increase in expression levels of Col1A1, Col3A1, MMP2 and MMP9 mRNA was observed after 24h. In contrast, expression levels of Col1A1 and Col3A1 mRNA were up regulated at 48h and 96h primarily in old individuals and an overall effect of age was observed. The expression level of MMP2 mRNA was not changed from pre at 48h and 96h. The expression level of MMP9 mRNA was up regulated in both age groups at all three time points. CONCLUSIONS: The present data demonstrates early (post 24h) signs of ECM remodeling in both young and old individuals. Moreover, the results point toward an age specific regulation of ECM in response to muscle disuse, with an up regulation of collagen I and III in old only after 48h and 96h of immobilisation. REFERENCES 1) Suetta C et al. Aging affects the transcriptional regulation of human skeletal muscle disuse atrophy. PLoS One. 2012;7(12) 2) Reich KA et al. Forty-eight hours of unloading and 24 h of reloading lead to changes in global gene expression patterns related to ubiquination and oxidative stress in humans. J Appl Physiol 109: 1404-1415, 2010.

Throughout evolution, plants have developed various strategies to tolerate water stress. Among them, the accumulation of proline has been reported in a wide range of species. The metabolic pathway of this compatible solute is relatively well characterized in Arabidopsis thaliana. However, the signaling cascades involved in its regulation remain largely unknown. Thellungiella halophila, which is a close relative of Arabidopsis, tolerates extreme salinity up to 500 mM NaCl. In this work, the involvement of lipid signaling pathways in the regulation of proline accumulation was investigated in these two species upon water stress. A pharmacological approach has been performed using specific inhibitors of key signaling elements. The effects of these inhibitors have been investigated on proline accumulation. The present data show that phospholipases D (PLDs) are negative regulators of proline anabolism under normal conditions inA. thaliana. When such PLD-mediated regulation is abolished by 1-butanol, plants show a higher proline responsiveness to osmotic stress. In contrast to Arabidopsis, 1-butanol does not have any effect on proline accumulation in T. halophila under non-stress conditions. However, upon water constraints, 1-butanol reduces rather than increase proline accumulation. Our data suggest the involvement of a PLD-mediated signaling pathway in the tight regulation of proline metabolism that acts in a opposite way in A. thaliana and T. halophila. On the other hand, phospholipases C exert a positive control on proline accumulation in A. thaliana upon salt stress and a negative control in T. halophila upon water stress and non-stress conditions. In conclusion, we provide experimental evidence that positive and negative regulators are involved in the fine regulation of proline metabolism upon moderate water stress. Our study has defined a critical role of lipid signaling pathways in proline accumulation in A. thaliana and in T. halophila. Thus, in Arabidopsis, our data indicate that PLC-based signaling is a committed step in proline biosynthesis upon salinity but not upon hyperosmotic stress.

Effects of Sijunzi decoction and Yupingfeng powder on expression of janus kinase-signal transducer and activator of transcription signal pathway in the brain of spleen-deficiency model rats

Much effort has been devoted to assess the importance of nodes in complex biological networks (such as gene transcriptional regulatory networks, protein interaction networks, and neural networks). Examples of commonly used measures of node importance include node degree, node centrality, and node vulnerability score (the effect of the node deletion on the network efficiency). Here, we present a new approach to compute and investigate the mutual dependencies between network nodes from the matrices of node-node correlations. To this end, we first define the dependency of node i on node j (or the influence of node j on node i), D(i, j) as the average over all nodes k of the difference between the i - k correlation and the partial correlations between these nodes with respect to node j. Note that the dependencies, D(i, j) define a directed weighted matrix, since, in general, D(i, j) differs from D( j, i). For this reason, many of the commonly used measures of node importance, such as node centrality, cannot be used. Hence, to assess the node importance of the dependency networks, we define the system level influence (SLI) of antigen j, SLI( j) as the sum of the influence of j on all other antigens i. Next, we define the system level influence or the influence score of antigen j, SLI( j) as the sum of D(i, j) over all nodes i. We introduce the new approach and demonstrate that it can unveil important biological information in the context of the immune system. More specifically, we investigated antigen dependency networks computed from antigen microarray data of autoantibody reactivity of IgM and IgG isotypes present in the sera of ten mothers and their newborns. We found that the analysis was able to unveil that there is only a subset of antigens that have high influence scores (SLI) common both to the mothers and newborns. Networks comparison in terms of modularity (using the Newman's algorithm) and of topology (measured by the divergence rate) revealed that, at birth, the IgG networks exhibit a more profound global reorganization while the IgM networks exhibit a more profound local reorganization. During immune system development, the modularity of the IgG network increases and becomes comparable to that of the IgM networks at adulthood. We also found the existence of several conserved IgG and IgM network motifs between the maternal and newborns networks, which might retain network information as our immune system develops. If correct, these findings provide a convincing demonstration of the effectiveness of the new approach to unveil most significant biological information. Whereas we have introduced the new approach within the context of the immune system, it is expected to be effective in the studies of other complex biological social, financial, and manmade networks.