ABSTRACT
The T-cell receptor (TCR) is a crucial molecule in cellular immunity. The single-chain T-cell receptor (scTCR) is a potential format in TCR therapeutics because it eliminates the possibility of αß-TCR mispairing. However, its poor stability and solubility impede the in vitro study and manufacturing of therapeutic applications. In this study, some conserved structural motifs are identified in variable domains regardless of germlines and species. Theoretical analysis helps to identify those unfavored factors and leads to a general strategy for stabilizing scTCRs by substituting residues at exact IMGT positions with beneficial propensities on the consensus sequence of germlines. Several representative scTCRs are displayed to achieve stability optimization and retain comparable binding affinities with the corresponding αß-TCRs in the range of µM to pM. These results demonstrate that our strategies for scTCR engineering are capable of providing the affinity-enhanced and specificity-retained format, which are of great value in facilitating the development of TCR-related therapeutics.
Subject(s)
Receptors, Antigen, T-Cell , Humans , Receptors, Antigen, T-Cell/chemistry , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell/immunology , Protein Stability , Receptors, Antigen, T-Cell, alpha-beta/chemistry , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Amino Acid Sequence , Models, Molecular , Protein Engineering , Protein BindingABSTRACT
This study aimed to explore the risk factors for acute myocardial injury (AMI) caused by acute organophosphorus pesticide poisoning (AOPP).The clinical data of 98 patients, who were treated in our hospital due to oral AOPP from April 2013 to April 2017, were retrospectively analyzed. These patients were divided into two groups: AMI group and control group. The incidence of AMI was analyzed. Furthermore, the dosage forms and dose of the pesticide, and the interval between pesticide taking and doctor visit were compared between these two groups. Moreover, their clinical symptoms were observed; the serum cholinesterase levels, myocardial injury, and heart failure markers were detected, and the occurrence of arrhythmia and the structure and function of the heart were investigated through continuous electrocardiographic monitoring and transthoracic echocardiography.Among these 98 AOPP patients, 51 patients were complicated with AMI, and the incidence was 52.0%. The main manifestations of these 51 patients with AMI were as follows: the serum levels of myocardial injury markers (creatine kinase-Mb [CK-Mb] and cardiac troponin I [cTnI]) and heart failure markers (N-terminal pro B-type natriuretic peptide [NT-pro BNP]) were significantly higher, when compared with the control group (Pâ<â.001), and the incidence of arrhythmia (FVPB, Pâ=â.02; RAA, Pâ=â.03; RVA, Pâ=â.02; ST-T changes, Pâ=â.01) and heart failure (Pâ=â.04) was also significantly higher when compared with the control group. With regard to dosage forms of the pesticides, the number of patients taking the pesticides with solvents containing aromatic hydrocarbons was significantly higher in the AMI group than in the control group (Pâ=â.001). And the number of patients taking over 100âmL of pesticides was also significantly higher in the AMI group than in the control group (Pâ<â.001). Significantly more patients in the AMI group had an interval of over 1âh between pesticide taking and doctor visit than in the control group (Pâ<â.001).Risk factors for AMI after AOPP may include the dose and dosage form of the pesticide, and the interval between pesticide taking and doctor visit.
