Estimation of response curves in closed-loop physiological control

Several recent reports have addressed the problem of estimating the response slope from repeated measurements of paired data when both stimulus and response variables are subject to biological variability. These earlier approaches suffer from several drawbacks: useful information about the relationships between the error components in a closed-loop system is not fully utilized; the response intercept cannot be directly estimated; and the normalization procedure required in some methods may fail under certain circumstances. This paper proposes a new, general method of simultaneously estimating the response slope and intercept from corrupted stimulus-response data when the errors in both variables are specifically related by the system structure. A direct extension of the least-squares approach, this method [directed least squares (DLS)] reduces to ordinary least-squares methods when either of the measured variables is error free and to the reduced-major-axis (RMA) method of Kermack and Haldane (Biometrics 37: 30-41, 1950) when the magnitudes of the normalized errors are equal. The DLS estimators are scale invariant, statistically unbiased and always assume the minimum variance. With simple modifications, the method is also applicable to paired data. If, however, the relation between error components is uncertain, then the RMA method is optimal, i.e., having the least possible asymptotic bias and variance. These results are illustrated by using various types of closed-loop respiratory response data.     

Conformation and restricted segmental flexibility of C1, the first component of human complement

Seventy selected images of chemically crosslinked C1 are analyzed to illustrate structural details of the C1qC1r2C1s2 complex. From inspection of these images, the C1r2C1s2 tetramer can be seen to be located in the region of the C1q arms, cleanly separated from the C1q heads and from at least 90%, if not all, of the C1q stem. From measurements made upon 65 images, the semicone angles formed between the spreading arms and the symmetry axis passing through the stem of C1 may be calculated. Unlike C1q, for which a wide variety of angles is found, the C1 complex appears to possess a restricted range of angular flexibility with an average value of about 50 degrees. The volume inside the cone formed by the spreading arms of C1q is too small to contain the entire C1r2C1s2 tetramer; at least some of the tetramer must lie outside the cone when it is bound to C1q to form C1. From our knowledge of the sizes and structures of its subunits, and from symmetry considerations, a model is proposed for the configuration of the C1 complex in which the middle portion of the C1r2C1s2 tetramer is centrally located among the arms close to the stem of the C1q and with the two protruding ends of the tetramer wrapped around the outside of the cone. Functional implications of this more rigid structure are discussed with relevance to C1q-induced aggregation of latex beads and C1-induced disaggregation.     

The phospholipid code: a key component of dying cell recognition,tumor progression and host–microbe interactions

A significant effort is made by the cell to maintain certain phospholipids at specific sites. It is well described that proteins involved in intracellular signaling can be targeted to the plasma membrane and organelles through phospholipid-binding domains. Thus, the accumulation of a specific combination of phospholipids, denoted here as the ‘phospholipid code'', is key in initiating cellular processes. Interestingly, a variety of extracellular proteins and pathogen-derived proteins can also recognize or modify phospholipids to facilitate the recognition of dying cells, tumorigenesis and host–microbe interactions. In this article, we discuss the importance of the phospholipid code in a range of physiological and pathological processes.     

In vitro effect of glucan on mouse hemopoietic committed progenitor cells

In vitro methylcellulose clonal cell culture assays of granulopoietic and erythropoietic colonies were used to study the primary effect of glucan on the hematopoietic stem cells. Addition of glucan to the cultures inhibits the formation of colony-forming units-erythrocytic (CFU-E), enhances the production of burst forming units-erythrocytic (BFU-E) and has no effect on colony-forming unit-culture (CFU-C). These results indicate that glucan has a direct effect on late and early erythroid precursor cells.