Neurotransmitter receptors as glycoproteins

Summary Incubation of calf brain membrane preparations with the plant lectins, concanavalin A and wheat germ agglutinin did not inhibit neurotransmitter receptor binding sites directly. Plant lectins did however protect these sites against subsequent trypsin digestion suggesting that neurotransmitter binding sites may be associated with glycoprotein structures.     

The immunodominant site of a synthetic immunogen has a conformational preference in water for a type-II reverse turn

Many short synthetic peptides have now been shown to induce antibodies reactive with their cognate sequences in the intact folded protein. Aside from the usefulness of such antibodies as site-specific reagents, the frequency with which this recognition occurs has raised several theoretical issues, the central one being that of how an antibody to a short synthetic peptide, which represents one of the most disordered states of a site in a protein, can react with the more ordered version of the same sequence in the folded protein. This apparent paradox can be resolved if the target site on the protein approaches disorder or if the peptide in solution or on a carrier adopts, with significant frequency, a conformation compatible with that of the cognate site in the protein. Various studies already suggest that antigenic sites in proteins correspond to regions of high atomic mobility. We now show, using high-field nuclear magnetic resonance (NMR) spectroscopy, that a nonapeptide selected by several monoclonal antibodies as the immunodominant site of a 36-amino-acid immunogen (residues 75-110 of influenza virus haemagglutinin) adopts a highly populated type-II reverse-turn conformation in water. This suggests that in this case the antibodies have selected a sequence possessing a conformational preference. Apart from helping us to understand immunological recognition, anti-peptide antibodies may provide reagents of sufficient precision for an immunological approach to the problem of protein folding.     

Correlation between a DNA restriction fragment length polymorphism and C4A6 protein

The fourth component of complement (C4) in man, is coded for by two separate but closely linked loci (C4A and C4B) within the major histocompatibility region (MHC), on the short arm of chromosome 6. Like class I and II loci of this region, the C4 genes are highly polymorphic with more than 30 alleles, including null alleles, assigned to the two loci. This extensive polymorphism, based mainly on electrophoretic mobility, provides a useful marker for studies of disease susceptibility. Several disorders, including systemic lupus erythematosus and type I diabetes, show associations with C4 phenotypes. We have used the technique of Southern with a C4 specific probe to examine the genomic DNA of individuals typed for C4 by protein electrophoresis. We have identified 10.7 and 3.8 kilobase (kb) BglII restriction fragments in each of 9 unrelated individuals with a C4A6 allele, and in none of 22 unrelated individuals in whom this allele was not expressed. This clear correlation of restriction fragment length polymorphism with C4 phenotype provides a precise basis for analysis of C4 polymorphism. It is likely to be of value in clinical investigations of autoimmune disease.     

An N-terminal peptide from p60src can direct myristylation and plasma membrane localization when fused to heterologous proteins

The src gene product, p60src, of Rous sarcoma virus (RSV) is a tyrosine-specific protein kinase which is associated with the plasma membrane of infected cells. Myristic acid is bound in an amide linkage to glycine 2 of p60src. Of the N-terminal 30 kilodaltons of p60src, only amino acids 1-14 are required for myristylation, and myristylation of p60src may be required for its membrane association, and for cell transformation. To test the hypothesis that the first 14 amino acids of p60src contain a recognition sequence for myristylation, we have fused the DNA sequence coding for these amino acids to either the fps gene of the F36 derivative of Fujinami sarcoma virus (FSV), or to the chimpanzee alpha-globin gene. We report here that although the fusion proteins were myristylated, the parental proteins were not, and unlike the non-myristylated F36 p91fps which was not bound to the plasma membrane, the myristylated fusion protein was bound, like p60src. We conclude that the first 14 amino acids of p60src contain a sequence which is sufficient for myristylation, and which may direct proteins to the plasma membrane.     

Robust forecast aggregation: Fourier L2E regression

The Good Judgment Team led by psychologists P. Tetlock and B. Mellers of the University of Pennsylvania was the most successful of five research projects sponsored through 2015 by the Intelligence Advanced Research Projects Activity to develop improved group forecast aggregation algorithms. Each team had at least 10 algorithms under continuous development and evaluation over the 4‐year project. The mean Brier score was used to rank the algorithms on approximately 130 questions concerning categorical geopolitical events each year. An algorithm would return aggregate probabilities for each question based on the probabilities provided per question by thousands of individuals, who had been recruited by the Good Judgment Team. This paper summarizes the theorized basis and implementation of one of the two most accurate algorithms at the conclusion of the Good Judgment Project. The algorithm incorporated a number of pre‐ and postprocessing steps, and relied upon a minimum distance robust regression method called L₂E. The algorithm was just edged out by a variation of logistic regression, which has been described elsewhere. Work since the official conclusion of the project has led to an even smaller gap.