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61.
62.
Huipeng?Li Lakshmi?Venkatraman Balakrishnan?Chakrapani?Narmada Jacob?K.?White Hanry?YuEmail author 《BMC systems biology》2017,11(7):136
Background
Bistable behaviors are prevalent in cell signaling and can be modeled by ordinary differential equations (ODEs) with kinetic parameters. A bistable switch has recently been found to regulate the activation of transforming growth factor-β1 (TGF-β1) in the context of liver fibrosis, and an ordinary differential equation (ODE) model was published showing that the net activation of TGF-β1 depends on the balance between two antagonistic sub-pathways.Results
Through modeling the effects of perturbations that affect both sub-pathways, we revealed that bistability is coupled with the signs of feedback loops in the model. We extended the model to include calcium and Krüppel-like factor 2 (KLF2), both regulators of Thrombospondin-1 (TSP1) and Plasmin (PLS). Increased levels of extracellular calcium, which alters the TSP1-PLS balance, would cause high levels of TGF-β1, resembling a fibrotic state. KLF2, which suppresses production of TSP1 and plasminogen activator inhibitor-1 (PAI1), would eradicate bistability and preclude the fibrotic steady-state. Finally, the loop PLS???TGF-β1???PAI1 had previously been reported as negative feedback, but the model suggested a stronger indirect effect of PLS down-regulating PAI1 to produce positive (double-negative) feedback in a fibrotic state. Further simulations showed that activation of KLF2 was able to restore negative feedback in the PLS???TGF-β1???PAI1 loop.Conclusions
Using the TGF-β1 activation model as a case study, we showed that external factors such as calcium or KLF2 can induce or eradicate bistability, accompanied by a switch in the sign of a feedback loop (PLS???TGF-β1???PAI1) in the model. The coupling between bistability and positive/negative feedback suggests an alternative way of characterizing a dynamical system and its biological implications.63.
64.
Xue Y Davis AV Balakrishnan G Stasser JP Staehlin BM Focia P Spiro TG Penner-Hahn JE O'Halloran TV 《Nature chemical biology》2008,4(2):107-109
Methionine-rich motifs have an important role in copper trafficking factors, including the CusF protein. Here we show that CusF uses a new metal recognition site wherein Cu(I) is tetragonally displaced from a Met2His ligand plane toward a conserved tryptophan. Spectroscopic studies demonstrate that both thioether ligation and strong cation-pi interactions with tryptophan stabilize metal binding. This novel active site chemistry affords mechanisms for control of adventitious metal redox and substitution chemistry. 相似文献
65.
66.
Shim da J Nemeria NS Balakrishnan A Patel H Song J Wang J Jordan F Farinas ET 《Biochemistry》2011,50(35):7705-7709
The first component (E1o) of the Escherichia coli 2-oxoglutarate dehydrogenase complex (OGDHc) was engineered to accept substrates lacking the 5-carboxylate group by subjecting H260 and H298 to saturation mutagenesis. Apparently, H260 is required for substrate recognition, but H298 could be replaced with hydrophobic residues of similar molecular volume. To interrogate whether the second component would allow synthesis of acyl-coenzyme A derivatives, hybrid complexes consisting of recombinant components of OGDHc (o) and pyruvate dehydrogenase (p) enzymes were constructed, suggesting that a different component is the "gatekeeper" for specificity for these two multienzyme complexes in bacteria, E1p for pyruvate but E2o for 2-oxoglutarate. 相似文献
67.
Bottom-up engineering of microscale tissue ("microtissue") constructs to recapitulate partially the complex structure-function relationships of liver parenchyma has been realized through the development of sophisticated biomaterial scaffolds, liver-cell sources, and in vitro culture techniques. With regard to in vivo applications, the long-lived stem/progenitor cell constructs can improve cell engraftment, whereas the short-lived, but highly functional hepatocyte constructs stimulate host liver regeneration. With regard to in vitro applications, microtissue constructs are being adapted or custom-engineered into cell-based assays for testing acute, chronic and idiosyncratic toxicities of drugs or pathogens. Systems-level methods and computational models that represent quantitative relationships between biomaterial scaffolds, cells and microtissue constructs will further enable their rational design for optimal integration into specific biomedical applications. 相似文献
68.
Adrenomedullin2 (ADM2), also referred to as Intermedin (IMD) is expressed in trophoblast cells in human placenta and enhances the invasion and migration of first trimester HTR-8/SV-neo cells. Recently we demonstrated that infusion of IMD antagonist in pregnant rats causes feto-placental growth restriction suggesting a role for IMD in maintaining a successful pregnancy. Therefore, this study was undertaken to assess if IMD has a functional role in embryo implantation in a rat model. We show that IMD mRNA is expressed in rat implantation sites and its expression is significantly higher on day 15 in placenta compared to days 18-22. Infusion of IMD antagonist IMD????? from day 3 of pregnancy causes a significant decrease in the weights of day 9 implantation sites as well as serum levels of 17β-estradiol, progesterone, nitric oxide and serum MMP2 and MMP9 gelatinase activity. Further, expression of MMP2, MMP9, VEGF and PLGF protein levels are significantly downregulated in the implantation sites of IMD antagonist treated rats. This study suggests a potential involvement of IMD in regulating the factors that are critical for implantation and growth of the embryo and thus in establishment of normal rat pregnancy. 相似文献
69.
Datsen George Wei Vicki Chiang Elizabeth Fyne Mini Balakrishnan Tiffany Barnes Michael Graupe Joseph Hesselgesser Alivelu Irrinki Jeffrey P. Murry George Stepan Kirsten M. Stray Angela Tsai Helen Yu Jonathan Spindler Mary Kearney Celsa A. Spina Deborah McMahon Jacob Lalezari Derek Sloan John Mellors Romas Geleziunas Tomas Cihlar 《PLoS pathogens》2014,10(4)
Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART. 相似文献
70.
Arun Kumar Somavarapu Satish Balakrishnan Amit Kumar Singh Gautam David S Palmer Prasanna Venkatraman 《BMC structural biology》2014,14(1):1-14