Biomedical subjects

K Yusim

Publications and source records attributed to K Yusim.

5 recordsLinked to original sources

PubMed2001

Using human immunodeficiency virus type 1 sequences to infer historical features of the acquired immune deficiency syndrome epidemic and human immunodeficiency virus evolution.

In earlier work, human immunodeficiency virus type 1 (HIV-1) sequences were analysed to estimate the timing of the ancestral sequence of the main group of HIV-1, the virus that is responsible for the acquired immune deficiency syndrome pandemic, yielding a best estimate of 1931 (95% confidence interval of 1915-1941). That work will be briefly reviewed, outlining how phylogenetic tools were extended to incorporate improved evolutionary models, how the molecular clock model was adapted to incorporate variable periods of latency, and how the approach was validated by correctly estimating the timing of two historically documented dates. The advantages, limitations, and assumptions of the approach will be summarized, with particular consideration of the implications of branch length uncertainty and recombination. We have recently undertaken new phylogenetic analysis of an extremely diverse set of human immunodeficiency virus envelope sequences from the Democratic Republic of the Congo (the DRC, formerly Zaire). This analysis both corroborates and extends the conclusions of our original study. Coalescent methods were used to infer the demographic history of the HIV-1 epidemic in the DRC, and the results suggest an increase in the exponential growth rate of the infected population through time.

Acquired Immunodeficiency Syndrome↗

PubMed2001

A model for proto-tRNA loading.

A kinetic model for loading of proto-tRNA is presented. The kinetic parameters were first estimated from the results of Francklyn & Schimmel (1989;Nature337, 478--481), who studied the aminoacylation of both tRNA and its minihelix. Then these parameters were reduced several-fold, as is more appropriate for the prebiotic world. The simulations revealed a very slow time course of the loading reaction. We also consider a possibility for the proto-tRNA loading without a catalyst and discuss the feasibility of such processes. Analytical approximations are presented for the kinetics of proto-tRNA loading with and without enzyme. An estimate is given for the time required for the development of template- and sequence-directed systems.

Animals↗

PubMed2001

One-vesicle hypothesis for neurotransmitter release: a possible molecular mechanism.

Neurotransmitter-containing vesicles are clustered in release sites. Although a given site can contain tens of vesicles, there is evidence that under a wide range of conditions, following an action potential, rarely is more than one vesicle released from each site. Such findings led to the one vesicle hypothesis, for which this paper suggests a molecular mechanism. The release of a vesicle from a site provides a transient high concentration of transmitter in that site. It is proposed here that the local high transmitter concentration interrupts further vesicle releases from the same release site. The suggested mechanism for this 'release interruption' is based on a theory of release control by the authors wherein inhibitory transmitter autoreceptors play a central role. (That transmitter binding to these autoreceptors can inhibit release on a fast time scale has recently been shown experimentally.) A detailed kinetic scheme is presented for the proposed mechanism. Stochastic simulations of this scheme demonstrate how the mechanism accounts for the one vesicle hypothesis. In agreement with recent experiments, the simulations also show that changes in conditions that affect the release process can cause frequent release of more than one vesicle per site.

Acetylcholine↗

PubMed2001

Evolutionary and immunological implications of contemporary HIV-1 variation.

Evolutionary modelling studies indicate less than a century has passed since the most recent common ancestor of the HIV-1 pandemic strains and, in that time frame, an extraordinarily diverse viral population has developed. HIV-1 employs a multitude of schemes to generate variants: accumulation of base substitutions, insertions and deletions, addition and loss of glycosylation sites in the envelope protein, and recombination. A comparison between HIV and influenza virus illustrates the extraordinary scale of HIV variation, and underscores the importance of exploring innovative HIV vaccine strategies. Deeper understanding of the implications of variation for both antibody and T-cell responses may help in the effort to rationally design vaccines that stimulate broad cross-reactivity. The impact of HIV-1 variation on host immune response is reviewed in this context.

AIDS Vaccines↗

PubMed2000

Theory for the feedback inhibition of fast release of neurotransmitter.

Autoinhibition of neurotransmitter release occurs via binding of transmitter to appropriate receptors. Experiments have provided evidence suggesting that the control of neurotransmitter release in fast systems is mediated by these inhibitory autoreceptors. Earlier, the authors formulated and analysed a mathematical model for a theory of release control in which these autoreceptors played a key role. The key experimental findings on which the release-control theory is based are: (i) the inhibitory autoreceptor has high affinity for transmitter under rest potential and shifts to low affinity upon depolarization; (ii) the bound (with transmitter) autoreceptor associates with exocytotic machinery Ex and thereby blocks it, preventing release of neurotransmitter. Release commences when depolarization shifts the autoreceptor to a low-affinity state and thereby frees Ex from its association with the autoreceptors. Here we extend the model that describes control of release so that it also accounts for release autoinhibition. We propose that inhibition is achieved because addition of transmitter, above its rest level, causes transition of the complex of autoreceptor and Ex to a state of stronger association. Relief of Ex from this state requires higher depolarization than from the weakly associated complex. In contrast to the weakly associated complex that only requires binding of transmitter to the autoreceptor to be formed, the transition to the strongly associated complex is induced by a second messenger, which is produced as a result of the receptor binding to transmitter. The theory explains the following experimental results (among others): for inhibition via transmitter or its agonists, the magnitude of inhibition decreases with depolarization; a plot of inhibition as a function of the concentration of muscarine (an acetylcholine agonist) yields an S-shaped curve that shifts to the right for higher depolarizations; the time course of release does not change when transmitter is added; the time course of release also does not change when transmitter antagonists are added, although quantal content increases; however, addition of acetylcholine esterase (an enzyme that hydrolyses acetylcholine) prolongs release.

Acetylcholine↗