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Biomedical subjects

R F Brooks

Publications and source records attributed to R F Brooks.

31 records · Page 2Linked to original sources
PubMed1981

Random transitions and cell cycle control.

Differences between the cycle times of sister cells are exponentially distributed, which means that these differences can be explained entirely by the existence of a single critical step in the cell cycle which occurs at random. Cycle times as a whole are not exponentially distributed, indicating an additional source of variation in the cell cycle. It follows that this additional variation must affect sister cells identically; ie, sister cell cycle times are correlated. This correlation and the overall distribution of cycle times can be predicted quantitatively by a model that was developed initially in order to explain certain problematic features of the response of quiescent cells to mitogenic stimulation - in particular, the significance of the lag that almost invariably occurs between stimulation and the onset of DNA synthesis. This model proposes that each cell cycle depends not on one but two random transitions, one of which (at reasonably high growth rates) occurs in the mother cell, its effects being inherited equally by the two daughter cells. The fundamental timing element in the cell cycle is proposed to be a lengthy process, called L, which accounts for most of the lag on mitogenic stimulation and also for the minimum cycle time in growing cultures. One of the random transitions is concerned with the initiation of L, whereas the other becomes possible on completion of L. The latter transition has two consequences: the first is the initiation of a sequence of events which includes S, G2 and M; the second is the restoration of the state from which L may be initiated once more. As a result, L may begin (at random) at any stage of the conventional cycle, ie, S, G2, M, or G1. There are marked similarities between the hypothetical process L and the biogenesis of mitotic centres - the structures responsible for organising the spindle poles.

Animals↗
PubMed1980

Mammalian cell cycles need two random transitions.

Although a single transition in the cell cycle is both sufficient and necessary to account for the distribution of differences in the intermitotic times of sister cells, two random transitions seem necessary to account for the responses of quiescent cells to stimulation by growth factors. We propose that serum-depleted quiescent cells "rest" in an indeterminate state (Q) which they leave at random upon stimulation and initiate a lengthy process (L). Upon completion of L the cells enter another indeterminate state (A) which they also leave at random and shortly thereafter initiate S phase and subsequently divide. On leaving A they also re-enter Q, and, again at random, initiate L. This sequence, Q leads to L leads to A, is maintained in steady state proliferation, and because of the random exit from Q and A, overlaps to varying degrees with the conventional cell cycle (M-G1-S-G2-M). The hypothesis provides a qualitative account of various problematic features of the lag between stimulation and entry into S phase. It also provides a good quantitative account of the distribution of sibling differences, the correlation coefficient of sibling intermitotic times and the distribution of intermitotic times and the distribution of intermitotic times in steady state growing cultures. There are striking similarities between the hypothetical cycle and the centriole cycle.

Animals↗
PubMed1979

The cytoplasmic origin of variability in the timing of S phase in mammalian cells.

The time at which S phase begins in mammalian cells is highly variable with respect to cell age. Evidence is presented that this variability does not arise because the initiation of DNA synthesis depends on the stochastic interaction of an initiator substance with a rare initiation site. Instead, the signal responsible for starting S phase must appear at random in the cytoplasm and may be transient.

Animals↗
PubMed1978

3' deoxycytidine, like hydroxyurea, inhibits DNA synthesis without preventing the initiation of the cell cycle.

3' Deoxycytidine, the cytidine analogue of cordycepin and selective inhibitor of pre-ribosomal RNA in HeLa cells, has been found to be a reversible inhibitor of DNA replication in RNA accumulation. Like other inhibitors of DNA replication such as hydroxyurea, it does not prevent serum-stimulated quiescent 3T3 cells from undergoing the random transition which is rate-limiting for entry into S phase.

Cell Cycle↗
PubMed1977

Dislodgeable residues of ethion in Florida citrus and relationships to weather variables.

Five different treatments of ethion on Valencia orange trees were compared for decay rates and for ethion monoxon and ethion dioxon production under different environmental conditions. The oxon metabolite levels observed were low and always below the residue level of ethion itself. There were no significant differences in the decay rates of ethion between treatments. A model of ethion decay utilizing environmental variables as a time base is presented. This model explains 94% of the variation observed in ethion decay during very wet and very dry periods in Florida. The application of these results and general experimental approach to worker safety reentry standards is discussed.

Chromatography, Gas↗
PubMed1977

Continuous protein synthesis is required to maintain the probability of entry into S phase.

"Normal fibroblast" lines such as 3T3 cells arrest in the G0/G1 compartment of the cell cycle when starved of serum. Following readdition of serum and after a lag of 14 hr, the cells enter S phase with first-order kinetics. Cell cycle progress after stimulation is thus consistent with the existence of a single, rate-limiting random event (or transition) in G1 as proposed by Smith and Martin (1973). The addition of low concentrations of cycloheximide (33-100 ng/ml) at any time after the end of the lag phase brings about a rapid reduction (within 1-2 hr) of the rate constant for entry into S phase by an amount that is proportional to the inhibition of leucine incorporation. This suggests that the transition probability depends upon the continuous synthesis of a protein with a short half-life, or on some other unstable substance whose concentration is geared to the rate of translation. More importantly at present, the results indicate that the rate-limiting transition occurs within 2 hr of the start of DNA synthesis. When the same low concentrations of cycloheximide are added at the time of serum stimulation, they also lead to a marked elongation of the lag phase which again is related to the inhibitor concentration. This result is surprising since the lag is independent of serum concentration which itself influences the rate of protein synthesis.

Blood↗
PubMed1975

The kinetics of serum-induced initiation of DNA synthesis in BHK 21/C13 cells, and the influence of exogenous adenosine.

After the re-addition of serum in the presence of adenosine (25 muM), the entry of quiescent, serum starved BHK 21 cells into DNA synthesis follows first order kinetics after a well defined lag period of eight hours, and with a rate constant dependent on serum concentration. Initiation of DNA synthesis under these conditions can therefore be considered to be a random event occurring with a "Transition Probability" determined by the serum concentration. In the presence of adenosine, the change of Transition Probability following the addition of serum occurs abruptly. In the absence of exogenous adenosine, however, the change of Transition Probability after serum addition appears to be both gradual and bi-phasic. The initial changes in the absence of adenosine, though smaller in magnitude, display a similar dependence on serum concentration to the changes occurring in the presence of the nucleoside. In contrast, the secondary gradual increase of Transition Probability in the absence of added purines exhibits a higher serum requirement. It is suggested that the regulation of Transition Probability by serum involves some purine-dependent process, and that in the absence of an exogenous supply this becomes limited by endogenous synthesis which in turn may be dependent on serum concentration.

Adenosine↗