02510nas a2200205   4500008004100000022001400041245017400055210006900229260010600298300001200404490000700416520161600423653002602039653002302065653001002088653003602098100002102134700002302155856012602178       2015                        eng d  a1355-838200aMathematical modeling of combinatorial regulation suggests that apparent positive regulation of targets by miRNA could be an artifact resulting from competition for mRNA0 aMathematical modeling of combinatorial regulation suggests that   a1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USAbCOLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPTcMAR  a307-3190 v213 a<p>MicroRNAs bind to and regulate the abundance and activity of target messenger RNA through sequestration, enhanced degradation, and suppression of translation. Although miRNA have a predominantly negative effect on the target protein concentration, several reports have demonstrated a positive effect of miRNA, i.e., increase in target protein concentration on miRNA overexpression and decrease in target concentration on miRNA repression. miRNA-target pair-specific effects such as protection of mRNA degradation owing to miRNA binding can explain some of these effects. However, considering such pairs in isolation might be an oversimplification of the RNA biology, as it is known that one miRNA interacts with several targets, and conversely target mRNA are subject to regulation by several miRNAs. We formulate a mathematical model of this combinatorial regulation of targets by multiple miRNA. Through mathematical analysis and numerical simulations of this model, we show that miRNA that individually have a negative effect on their targets may exhibit an apparently positive net effect when the concentration of one miRNA is experimentally perturbed by repression/overexpression in such a multi-miRNA multitarget situation. We show that this apparent unexpected effect is due to competition and will not be observed when miRNA interact noncompetitively with the target mRNA. This result suggests that some of the observed unusual positive effects of miRNA may be due to the combinatorial complexity of the system rather than due to any inherently unusual positive effect of the miRNA on its target.</p>10acombinatorial binding10amathematical model10amiRNA10apost-transcriptional regulation1 aNyayanit, Dimpal1 aGadgil, Chetan, J.  uhttps://library.ncl.res.in/content/mathematical-modeling-combinatorial-regulation-suggests-apparent-positive-regulation-002958nas a2200277   4500008004100000022001400041245016700055210006900222260000800291300001100299490000700310520197300317653002502290653002202315653002002337653001102357653002302368653001802391100002602409700002002435700002402455700002102479700003302500700001802533856012902551       2021                        eng d  a2234-943X00aStudy of combinatorial drug synergy of novel acridone derivatives with temozolomide using in-silico and in-vitro methods in the treatment of drug-resistant glioma0 aStudy of combinatorial drug synergy of novel acridone derivative  cMAR  a6258990 v113 a<p>Drug resistance is one of the critical challenges faced in the treatment of Glioma. There are only limited drugs available in the treatment of Glioma and among them Temozolomide (TMZ) has shown some effectiveness in treating Glioma patients, however, the rate of recovery remains poor due to the inability of this drug to act on the drug resistant tumor sub-populations. Hence, in this study three novel Acridone derivative drugs AC2, AC7, and AC26 have been proposed. These molecules when combined with TMZ show major tumor cytotoxicity that is effective in suppressing growth of cancer cells in both drug sensitive and resistant sub-populations of a tumor. In this study a novel mathematical model has been developed to explore the various drug combinations that may be useful for the treatment of resistant Glioma and show that the combinations of TMZ and Acridone derivatives have a synergistic effect. Also, acute toxicity studies of all three acridone derivatives were carried out for 14 days and were found safe for oral administration of 400 mg/kg body weight on albino Wistar rats. Molecular Docking studies of acridone derivatives with P-glycoprotein (P-gp), multiple resistant protein (MRP), and O6-methylguanine-DNA methyltransferase (MGMT) revealed different binding affinities to the transporters contributing to drug resistance. It is observed that while the Acridone derivatives bind with these drug resistance causing proteins, the TMZ can produce its cytotoxicity at a much lower concentration leading to the synergistic effect. The in silico analysis corroborate well with our experimental findings using TMZ resistant (T-98) and drug sensitive (U-87) Glioma cell lines and we propose three novel drug combinations (TMZ with AC2, AC7, and AC26) and dosages that show high synergy, high selectivity and low collateral toxicity for the use in the treatment of drug resistant Glioma, which could be future drugs in the treatment of Glioblastoma.</p>10aacridone derivatives10adrug combinations10adrug resistance10aGlioma10amathematical model10asynergy index1 aChakravarty, Malobika1 aGanguli, Piyali1 aMurahari, Manikanta1 aSarkar, Ram, Rup1 aPeters, Godefridus, Johannes1 aMayur, Y., C.  uhttps://library.ncl.res.in/content/study-combinatorial-drug-synergy-novel-acridone-derivatives-temozolomide-using-silico-and02195nas a2200229   4500008004100000022001400041245010600055210006900161260000800230300001000238490000800248520141500256653002501671653001301696653001401709653002301723653002601746100002001772700001901792700002301811856013101834       2022                        eng d  a0168-165600aMathematical model of the multi-amino acid multi-transporter system predicts uptake flux in CHO cells0 aMathematical model of the multiamino acid multitransporter syste  cJAN  a40-490 v3443 aSupply and uptake of amino acids is of great importance to mammalian cell culture processes. Mammalian cells such as Chinese hamster ovary (CHO) cells express several amino acid (AA) transporters including uniporters and exchangers. Each transporter transports multiple AAs, making prediction of the effect of changed medium composition or transporter levels on individual AA transport rate challenging. A general kinetic model for such combinatorial amino acid transport, and a simplified analytical expression for the uptake rate as a function of amino acid concentrations and transporter levels is presented. From this general model, a CHO cell-specific AA transport model, to our knowledge the first such network model for any cell type, is constructed. The model is validated by its prediction of reported uptake flux and dependencies from experiments that were not used in model construction or parameter estimation. The model defines theoretical conditions for synergistic/repressive effect on the uptake rates of other AAs upon external addition of one AA. The ability of the CHO-specific model to predict amino acid interdependencies experimentally observed in other mammalian cell types suggests its robustness. This model will help formulate testable hypotheses of the effect of process changes on AA initial uptake, and serve as the AA transport component of kinetic models for cellular metabolism.10aAmino acid transport10aCHO cell10aExchanger10amathematical model10aMultiple transporters1 aSreejan, Ashley1 aGadgil, Mugdha1 aGadgil, Chetan, J.  uhttps://library.ncl.res.in/content/mathematical-model-multi-amino-acid-multi-transporter-system-predicts-uptake-flux-cho-cells