24 research outputs found
The malarial exported PFA0660w is an Hsp40 co-chaperone of PfHsp70-x
Plasmodium falciparum, the human pathogen responsible for the most dangerous malaria infection, survives and develops in mature erythrocytes through the export of proteins needed for remodelling of the host cell. Molecular chaperones of the heat shock protein (Hsp) family are prominent members of the exportome, including a number of Hsp40s and a Hsp70. PFA0660w, a type II Hsp40, has been shown to be exported and possibly form a complex with PfHsp70-x in the infected erythrocyte cytosol. However, the chaperone properties of PFA0660w and its interaction with human and parasite Hsp70s are yet to be investigated. Recombinant PFA0660w was found to exist as a monomer in solution, and was able to significantly stimulate the ATPase activity of PfHsp70-x but not that of a second plasmodial Hsp70 (PfHsp70-1) or a human Hsp70 (HSPA1A), indicating a potential specific functional partnership with PfHsp70-x. Protein binding studies in the presence and absence of ATP suggested that the interaction of PFA0660w with PfHsp70-x most likely represented a co-chaperone/chaperone interaction. Also, PFA0660w alone produced a concentrationdependent suppression of rhodanese aggregation, demonstrating its chaperone properties. Overall, we have provided the first biochemical evidence for the possible role of PFA0660w as a chaperone and as co-chaperone of PfHsp70-x. We propose that these chaperones boost the chaperone power of the infected erythrocyte, enabling successful protein trafficking and folding, and thereby making a fundamental contribution to the pathology of malaria
Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment
We identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3+ T cell/myeloma cell crosslinking, followed by CD4+/CD8+ T cell activation, and secretion of interferon-Îł, granzyme B, and perforin. This effect is CD4 and CD8 T cell mediated. EM801 induced, at nanomolar concentrations, myeloma cell death by autologous T cells in 34 of 43 bone marrow aspirates, including those from high-risk patients and patients after multiple lines of treatment, tumor regression in six of nine mice in a myeloma xenograft model, and depletion of BCMA+ cells in cynomolgus monkeys. Pharmacokinetics and pharmacodynamics indicate weekly intravenous/subcutaneous administration
Response to âComment on âDetermination of Electrophoretic Mobilities and Hydrodynamic Radii of Three Humic Substances as a Function of pH and Ionic Strengthâ'
Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment
We identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3+ T cell/myeloma cell crosslinking, followed by CD4+/CD8+ T cell activation, and secretion of interferon-Îł, granzyme B, and perforin. This effect is CD4 and CD8 T cell mediated. EM801 induced, at nanomolar concentrations, myeloma cell death by autologous T cells in 34 of 43 bone marrow aspirates, including those from high-risk patients and patients after multiple lines of treatment, tumor regression in six of nine mice in a myeloma xenograft model, and depletion of BCMA+ cells in cynomolgus monkeys. Pharmacokinetics and pharmacodynamics indicate weekly intravenous/subcutaneous administration
PEGylation of a Maltose Biosensor Promotes Enhanced Signal Response When Immobilized in a Silica SolâGel
Hydrodynamic Modeling of NOM Transport in UF: Effects of Charge Density and Ionic Strength on Effective Size and Sieving
Use of DGT to measure cadmium speciation in solutions with synthetic and natural ligands : comparison with model predictions.
The performance of the technique of diffusive gradients in thin films (DGT) was characterized in well-defined systems containing cadmium with chloride and nitrate ions, simple organic ligands (nitrilotriacetic acid and diglycolic acid), and Suwannee river fulvic acid for the pH range 5â8. Cd was fully labile in all Cd, Cl-, and NO3- solutions tested (I = 0.1 and 0.01 M), even at very low Cd concentrations (10 nM), consistent with there being no binding of Cd to the diffusive gel. Diffusion coefficients of Cdânitritotriacetic acid (NTA) and Cdâdiglycolic acid (DGA) species were measured and found to be ca. 25â30% lower than the equivalent coefficient for free metal ions. These values were used to calculate concentrations of labile Cd from DGT measurements in solutions of Cd with NTA or DGA. CdâNTA and CdâDGA species were found to be fully DGT-labile. DGT devices that used a diffusive gel with a reduced pore size, which retarded the passage of fulvic acid species through the gel, were used to estimate the proportion of Cd complexed by fulvic acid. These results were compared with predictions of the solution speciation from models with default parameter values. ECOSAT, incorporating the NICAâDonnan model, correctly predicted the magnitude of the binding and its pH dependence, while predictions from WHAM V (with humic ion binding model V) and WHAM 6 (with humic ion binding model VI) were less satisfactory at predicting the pH dependence. Reasonable fits to the data could be obtained from WHAM 6 when the effective binding constant log KMA was changed from 1.6 to 1.5, the value of ÎLK1 from 2.8 to 1.0 to minimize the dependence on pH, and the value of ÎLK2 from 1.48 to1.0 to decrease the strength of the strong bidentate and tridentate binding sites