Terplindgren5377

Our findings provide insights into how the original recognized antifungal drug target-calcineurin regulates intracellular calcium homeostasis for cell survival and may have important implications for antifungal therapy and clinical drug administration.The multifaceted roles of metabolism in invasion have been investigated across many cancers. The brain tumor glioblastoma (GBM) is a highly invasive and metabolically plastic tumor with an inevitable recurrence. The neuronal glucose transporter 3 (GLUT3) was previously reported to correlate with poor glioma patient survival and be upregulated in GBM cells to promote therapeutic resistance and survival under restricted glucose conditions. It has been suggested that the increased glucose uptake mediated by GLUT3 elevation promotes survival of circulating tumor cells to facilitate metastasis. Here we suggest a more direct role for GLUT3 in promoting invasion that is not dependent upon changes in cell survival or metabolism. Analysis of glioma datasets demonstrated that GLUT3, but not GLUT1, expression was elevated in invasive disease. In human xenograft derived GBM cells, GLUT3, but not GLUT1, elevation significantly increased invasion in transwell assays, but not growth or migration. Further, there were no changes in glycolytic metabolism that correlated with invasive phenotypes. We identified the GLUT3 C-terminus as mediating invasion substituting the C-terminus of GLUT1 for that of GLUT3 reduced invasion. RNA-seq analysis indicated changes in extracellular matrix organization in GLUT3 overexpressing cells, including upregulation of osteopontin. Together, our data suggest a role for GLUT3 in increasing tumor cell invasion that is not recapitulated by GLUT1, is separate from its role in metabolism and survival as a glucose transporter, and is likely broadly applicable since GLUT3 expression correlates with metastasis in many solid tumors.The recombinant human keratinocyte growth factor (rhKGF) is a highly aggregation-prone therapeutic protein. The high aggregation liability of rhKGF is manifested by loss of the monomeric state, and accumulation of the aggregated species even at moderate temperatures. Here, we analyzed the rhKGF for its vulnerability toward aggregation by detection of aggregation-prone regions (APRs) using several sequence-based computational tools including TANGO, ZipperDB, AGGRESCAN, Zyggregator, Camsol, PASTA, SALSA, WALTZ, SODA, Amylpred, AMYPDB, and structure-based tools including SolubiS, CamSol structurally corrected, Aggrescan3D and spatial aggregation propensity (SAP) algorithm. The sequence-based prediction of APRs in rhKGF indicated that they are mainly located at positions 10-30, 40-60, 61-66, 88-120, and 130-140. Mapping on the rhKGF structure revealed that most of these residues including F16-R25, I43, E45, R47-I56, F61, Y62, N66, L88-E91, E108-F110, A112, N114, T131, and H133-T140 are surface-exposed in the native state which can promote aggregation without major unfolding event, or the conformational change may occur in the oligomers. The other regions are buried in the native state and their contribution to non-native aggregation is mediated by a preceding unfolding event. The structure-based prediction of APRs using the SAP tool limited the number of identified APRs to the dynamically-exposed hydrophobic residues including V12, A50, V51, L88, I89, L90, I118, L135, and I139 mediating the native-state aggregation. Our analysis of APRs in rhKGF identified the regions determining the intrinsic aggregation propensity of the rhKGF which are the candidate positions for engineering the rhKGF to reduce its aggregation tendency.Communicated by Ramaswamy H. Sarma.Kaposi Sarcoma (KS) is the most common AIDS-defining cancer, even as HIV-positive people live longer. Like other herpesviruses, human herpesvirus-8 (HHV-8) establishes a lifelong infection of the host that in association with HIV infection may develop at any time during the illness. With the increasing global incidence of KS, there is an urgent need of designing optimal therapeutic strategies for HHV-8-related infections. Here we formulate two models with innate and adaptive immune mechanisms, relevant for non-AIDS KS (NAKS) and AIDS-KS, where the initial condition of the second model is given by the equilibrium state of the first one. For the model with innate mechanism (MIM), we define an infectivity resistance threshold that will determine whether the primary HHV-8 infection of B-cells will progress to secondary infection of progenitor cells, a concept relevant for viral carriers in the asymptomatic phase. The optimal control strategy has been employed to obtain treatment efficacy in case of a combined antiretroviral therapy (cART). For the MIM we have shown that KS therapy alone is capable of reducing the HHV-8 load. In the model with adaptive mechanism (MAM), we show that if cART is administered at optimal levels, that is, 0.48 for protease inhibitors, 0.79 for reverse transcriptase inhibitors and 0.25 for KS therapy, both HIV-1 and HHV-8 can be reduced. The predictions of these mathematical models have the potential to offer more effective therapeutic interventions in the treatment of NAKS and AIDS-KS.Fouling mechanisms are mainly caused by the deposition of organic compounds that reduce the removal efficiency on reverse osmosis (RO) membranes. It can be described by mathematical models. selleck chemicals llc The aim of this study was to evaluate the membrane fouling and rejection mechanisms when aqueous solutions containing 17α-ethinylestradiol (EE2) in different concentrations are permeated at 5 and 10 bar in a bench-scale dead-end RO system. Adsorption tests were performed and the fouling mechanism was assessed by Hermia's model for solutions of EE2 at concentrations typically found in the environment (µg L-1). Fourier transform infrared spectroscopy (FTIR) has indicated the presence of EE2 on the fouled membrane surface. Membrane rejection of EE2 ranged from 90% to 98% and the main rejection mechanism was size exclusion at all experimental conditions. However, for the higher concentration of EE2 permeated at 5 and 10 bar, adsorption of 7 and 32 mg m-2, respectively, also took place. The rejection was influenced by fouling and concentration polarisation.