BRITISH MEDICAL JOURNAL 8 MARCH 1975 553 fetal breathing movements; but further control studies will have to be done to exclude the possibility of the degree of inhalation varying with the type of cigarette.Cigarette smoking in pregnancy is suspected of being detrimental to the fetus. Statistical surveys have shown that the babies are smaller at birth (Butler et al., 1972) and suggested an increase in prematurity and perinatal mortality. It is not easy to relate our observations on the acute effects of smoking two cigarettes to the long-term epidemiological reports. Nevertheless, physiological factors such as hypoxia and hypoglycaemia, which might be expected to have a detrimental effect on the fetus, also reduce the normal incidence of fetal breathing movements in animals and man (Boddy and Dawes, 1975; Boddy et al., 1975). Whether the similar effect of cigarette smoking is to be interpreted in the same way is as yet a matter for conjecture. The size of the transient change observed (see fig.) was less than the normal diurnal variation in the incidence of fetal breathing.We make this report because clinical physiologists and obstetricians in several countries are beginning to use fetal breathing movements as an index of health. These observations are best made some hours after the last cigarette has been smoked to exclude the acute effects of this variable.This work was carried out with the aid of a grant from the Medical Research Council. We thank Professors G. S. Dawes and Alec Turnbull for their help, the consulting staff of the department of obstetrics for access to their patients, the nursing staff, and the subjects. who volunteered for the study.

There is a dearth of approaches to experimentally direct cell migration by continuously varying signal input to a single cell, evoking all possible migratory responses and quantitatively monitoring the cellular and molecular response dynamics. Here we used a visual blue opsin to recruit the endogenous G-protein network that mediates immune cell migration. Specific optical inputs to this optical trigger of signaling helped steer migration in all possible directions with precision. Spectrally selective imaging was used to monitor cellwide phosphatidylinositol (3,4,5)-triphosphate (PIP3), cytoskeletal, and cellular dynamics. A switch-like PIP3 increase at the cell front and a decrease at the back were identified, underlying the decisive migratory response. Migration was initiated at the rapidly increasing switch stage of PIP3 dynamics. This result explains how a migratory cell filters background fluctuations in the intensity of an extracellular signal but responds by initiating directionally sensitive migration to a persistent signal gradient across the cell. A twocompartment computational model incorporating a localized activator that is antagonistic to a diffusible inhibitor was able to simulate the switch-like PIP3 response. It was also able simulate the slow dissipation of PIP3 on signal termination. The ability to independently apply similar signaling inputs to single cells detected two cell populations with distinct thresholds for migration initiation. Overall the optical approach here can be applied to understand G-proteincoupled receptor network control of other cell behaviors.optogenetics | ultrasensitivity A variety of cells sense gradients of chemoattractants and respond by migrating toward increasing concentrations. Migration is central to immune cell function, morphogenesis, cancer cell metastasis, and the life cycle of the social amoeba, Dictyostelium discoideum (1). Cell migration is made up of a characteristic sequence of identifiable cellular events that are governed by G-protein-coupled receptor (GPCR)-driven signaling networks. Although considerable information exists about molecules involved in migration, the challenge is in translating a static map of these molecules into a spatially and temporally dynamic network that orchestrates migratory behavior. Effective methods to probe the basis of network control of migration need to be able to faithfully evoke migratory behavior experimentally and quantitatively monitor response dynamics at the cellular and molecular level. Microfluidic devices and electrical fields have been used to regulate migration and provide insights into the process (2-6). However, there are limitations at present in the ability to direct a series of signaling inputs to a single cell in spatially and temporally complex patterns. Such inputs are essential to continually choreograph the events that constitute the migratory response: initiation, translocation, directional changes, and adaptation. A light-sensitive domain of a plant protein has been inserted into Rac1, a downstrea...

G-protein βγ subunits translocate reversibly from the plasma membrane to internal membranes on receptor activation. Translocation rates differ depending on the γ subunit type. There is limited understanding of the role of the differential rates of Gβγ translocation in modulating signaling dynamics in a cell. Bifurcation analysis of the calcium oscillatory network structure predicts that the translocation rate of a signaling protein can regulate the damping of system oscillation. Here, we examined whether the Gβγ translocation rate regulates calcium oscillations induced by G-protein-coupled receptor activation. Oscillations in HeLa cells expressing γ subunit types with different translocation rates were imaged and quantitated. The results show that differential Gβγ translocation rates can underlie the diversity in damping characteristics of calcium oscillations among cells. Mathematical modeling shows that a translocation embedded motif regulates damping of G-protein-mediated calcium oscillations consistent with experimental data. The current study indicates that such a motif may act as a tuning mechanism to design oscillations with varying damping patterns by using intracellular translocation of a signaling component.

Integral control design ensures that a key variable in a system is tightly maintained within acceptable levels. This approach has been widely used in engineering systems to ensure offset free operation in the presence of perturbations. Several biological systems employ such an integral control design to regulate cellular processes. An integral control design motif requires a negative feedback and an integrating process in the network loop. This review describes several biological systems, ranging from bacteria to higher organisms in which the presence of integral control principle has been hypothesized. The review highlights that in addition to the negative feedback, occurrence of zero-order kinetics in the process is a key element to realize the integral control strategy. Although the integral control motif is common to these systems, the mechanisms involved in achieving it are highly specific and can be incorporated at the level of signaling, metabolism, or at the phenotypic levels.

Multilevel regulations by metabolic, signaling and transcription pathways form a complex network that works to provide robust metabolic regulation in the liver. This analysis indicates that dietary perturbations in these networks can lead to insulin resistance.