Biomedical subjects
Publications and source records attributed to L Lim.
The binding of rat uterine cytosol oestrogen receptor in vitro to oligo(dT)-cellulose is mediated by an activating factor in the cytosol [Thrower, Hall, Lim & Davison (1976) Biochem. J. 160, 271-280]. A potent inhibitor of this binding is present in hypothalamic cytosol. This inhibitor may have a role in vivo in regulating receptor translocation in the hypothalamus.
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Fifteen patients in the early stages of the adult respiratory distress syndrome with severe hypoxemia who were capable of maintaining adequate spontaneous ventilation were treated with continuous positive airway pressure (CPAP). The optimal level of CPAP was adjusted for each patient to achieve the highest oxygenation with the least adverse hemodynamic effects. The optimal intravascular volume, judged by pulmonary arterial occlusion pressure, was maintained by infusion of lactated Ringer's solution. Application of an optimal CPAP ranging between 10 and 25 cm H2O significantly reduced the intrapulmonary shunt, increased the forced vital capacity, and decreased the respiration rate. The improvement in pulmonary status was achieved with no significant changes in cardiac output or the arterial-mixed venous oxygen content difference. Early application of an adjusted level of positive end-expiratory pressure using CPAP in patients with adequate levels of fluid is an effective and safe method of treating selected groups of patients in the early stages of the adult respiratory distress syndrome.
The regional metabolism of high-molecular-weight RNA in the developing female rat brain was investigated after the intracranial injection of [32P]P1. The synthesis of polyadenylated RNA relative to high-molecular-weight RNA was determined after oligo(dT)-cellulose chromatography of total cellular high-molecular-weight RNA labelled after 4h. In both hypothalamus and cortex this synthesis was significantly higher during the first 10 days post partum than at subsequent ages. In both regions apparently more mRNA is synthesized in the young. The ratio of the specific radioactivity of cytoplasmic high-molecular-weight RNA relative to that of the nucleus, measured after a 48 h period of labelling, was considered to be an index of the nucleocytoplasmic transport of newly synthesized RNA [Berthold & Lim (1976) Biochem. J. 154, 529--539]. In the cortex, nucleo-cytoplasmic RNA transport in rats aged up to 20 days was significantly higher than in older rats, with the maximal value being attained between 16 and 19 days post partum. In contrast, in the hypothalamus, nucleo-cytoplasmic transport of RNA was low during the neonatal period and comparable with that of the mature animal. However, there were two periods of increased transport at later stages of development, the first between 15 and 19 days post partum and the second between 25 and 29 days post partum. These prepubertal changes in the nucleo-cytoplasmic transport of RNA in the female hypothalamus during weeks 3 and 4 post partum are coincident with other reported changes occurring during sexual differentiation. Differences in the timing of the maturational changes of the two brain regions thus appear to be reflected in developmental changes in RNA transport.
We investigated the binding characteristics, content and intracellular distribution of nuclear and cytosolic oestrogen receptors in the uteri of rats bearing a unilateral intrauterine device, fitted 14--18 days earlier, at four phases of a 5-day oestrous cycle. The patterns of changes in wet weight and content of cytosolic and nuclear receptor that normally occur during the oestrous cycle were not altered by the presence of the device. At all stages of the cycle the intra-uterine-device-containing horn had a greater wet weight and a correspondingly higher content of cytosolic receptor than its contralateral control horn, the cellular concentration of cytosolic receptor being apparently maintained. However, the intra-uterine-device-containing horn had significantly lower cellular concentrations (i.e. per mg of DNA) of nuclear receptor, particularly at late dioestrus and pro-oestrus. Thus the treated horn showed a decreased translocation of receptor in response to increases in circulating oestrogens. Both horns contained equivalent amounts of an activating factor implicated in translocation and measured in vitro by binding of cytosol receptor to oligo(dT)-cellulose. The presence of an intra-uterine device neither altered the dissociation constants (Kd) of the nuclear and cytosolic oestrogen-receptor complexes nor the stability of the nuclear receptor complex in vitro. The decreased translocation cannot thus be directly attributed to changes in the physical properties of the receptor. This decrease may be responsible for the anti-fertility effect of the intra-uterine device (which affects only the treated horn of the bicornuate rat uterus), since implantation of the blastocyst requires correct concentrations of nuclear oestrogen receptor.
Simultaneous measurements were made of the specific oestrogen receptor in the nuclear and cytosol fractions prepared from the uterus and hypothalamus of 50--81-day-old female rats undergoing a 4-day oestrous cycle. In the uterus, the content of nuclear receptor fluctuated in concert with known cyclic changes in the secretion of oestrogen, being maximal at pro-oestrus. Over the period of 50--81 days, the nuclear content at all phases increased with age, again corresponding to known age-related increases in ovarian secretion of oestrogen. This age-related increase in nuclear content, averaged from the values of the different phases in each age group, was related to equivalent increases in uterine wet weight, an increase of 1 pmol of receptor being accompanied by an increase of 80--90 mg. The concentration of cytosol receptor was maintained constant, with respect to wet weight, throughout the cycle and with age, irrespective of changes in nuclear content. In the uterus of normal mature females, translocation of receptor into the nucleus did not lead to depletion of cytosol receptor, suggesting a process of continuous replenishment/synthesis. In the hypothalamus, the nuclear content of oestrogen receptor was also maximal at pro-oestrus. In contrast with the uterus, the content of hypothalamic cytosol receptor was minimal at this phase and reflects depletion of the cytosol receptor, possibly as a result of translocation. The extent of translocation was low compared with that in the uterus and did not alter with age during the age-period studied. This low nuclear binding of the receptor in vivo is discussed in relation to the presence of a cytosol factor, present in limiting amounts, which in vitro mediates the binding of cytosol receptor to oligo(dT)-cellulose. The difference in the physiological response of the uterus and of the hypothalamus to oestrogens may be related to the extent of nuclear binding of receptor.
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The [3H]oestradiol-receptor complex was selectively isolated from rat uterus cytosol by column chromatography on oligo(dT)-cellulose. Optimal conditions are described for the binding of the complex to oligo(dT)-cellulose, which is shown to be similar to its binding to DNA-cellulose. The cytosol complex has an apparent mol. wt. of 50,000-60,000 in high salt concentrations, as determined by Sephadex G-100 chromatography. This corresponds to the 4S cytoplasmic oestradiol receptor. In binding to oligo(dT)-cellulose the receptor is transformed into a form with an apparent mol.wt. of 100,000-120,000, corresponding to the 5S nuclear receptor complex. This transformation mimics the conversion in vivo of the cytoplasmic oestradiol receptor into the nuclear form. The binding of the complex to oligo(dT)-cellulose as a 5S nuclear form is unequivocally demonstrated to require the mediation of an activating present in the cytosol. The requirement for an activating factor is discussed in relation to reports that nuclear binding of the oestradiol-receptor complex is not dictated solely by the availability of the cytoplasmic oestradiol receptor.