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Biomedical subjects

A Golubev

Publications and source records attributed to A Golubev.

6 recordsLinked to original sources
PubMed2004

Does Makeham make sense?

Numerical modeling was used to explore the behavior of ideal cohorts obeying the Gompertz-Makeham (GM) law of mortality (-dn/dt 1/n(t) = C + lambda egammat) supplemented with the Strehler-Mildvan (SM) correlation (ln lambda = A - Bgamma) and to show how changes in the age-independent parameter C will produce an apparent SM correlation if C is ignored in mortality data treatment as in the case of the so-called longitudinal gompertzian analysis of historical changes in human mortality patterns. The essential difference between the Makeham term C and Gompertz term lambda e(gammat) has been suggested to be not that the latter is age-dependent whereas the former is not, but that C comprises the contributions of inherently irresistible stresses to mortality, whereas lambda e(gammat) comprises the contributions of resistible stresses and shows how changes in the resistance to them are translated into changes in mortality. This assumption was used to show by modeling how the transition of stresses from irresistible to resistible may result in decreased late survivorship as the cost of increased early survivorship, in line with the antagonistic pleiotropy theory of aging. On the whole, the modeling suggests that the GM equation is not only a mathematical tool for treatment of mortality data but that it also has a fundamental biological significance, and its Makeham term C should not be ignored in any analysis of mortality data.

Cohort Studies↗
PubMed2003

An in silico investigation into the causes of telomere length heterogeneity and its implications for the Hayflick limit.

UNLABELLED: In telomerase-negative cell populations the mean telomere length (TL) decreases with increasing population doubling number (PD). A critically small TL is believed to stop cell proliferation at a cell-, age- and species-specific PD thus defining the Hayflick limit. However, positively skewed TL distributions are broad compared to differences between initial and final mean TL and strongly overlap at middle and late PD, which is inconsistent with a limiting role of TL. We used computer-assisted modelling to define what set of premises may account for the above. Our model incorporates the following concepts. DNA end replication problem: telomeres loose 1 shortening unit (SU) upon each cell division. Free radical-caused TL decrease: telomeres experience random events resulting in the loss of a random SU number within a remaining TL. Stochasticity of gene expression and cell differentiation: cells experience random events inducing mitoses or committing cells to proliferation arrest, the latter option requiring a specified number of mitoses to be passed. Cells whose TL reaches 1SU cannot divide. The proliferation kinetics of such virtual cells conforms to the transition probability model of cell cycle. When no committing events occur and at realistic SU estimates of the initial TL, maximal PD values far exceed the Hayflick limit observed in normal cells and are consistent with the crisis stage entered by transformed cells that have surpassed the Hayflick limit. At intermediate PD, symmetrical TL distributions are yielded. Upon introduction of committing events making the ratio of the rates of proliferating and committing events (P/C) range from 1.10 to 1.25, TL distributions at intermediate PD become positively skewed, and virtual cell clones show bimodal size distributions. At P/C as high as 1.25 the majority of virtual cells at maximal PD contain telomeres with TL>1SU. A 10% increase in P/C within the 1.10-1.25 range produces a two-fold increase in the maximal PD, which can reach values of up to 25 observed in rodent and some human cells. Increasing the number of committed mitoses from 0 to 10 can increases PD to about 50 observed in human fibroblasts. Introduction of the random TL breakage makes the shapes of TL distributions quite dissimilar from those observed in real cells. CONCLUSIONS: Telomere length decrease is a correlate of cell proliferation that cannot alone account for the Hayflick limit, which primarily depends on parameters of cell population kinetics. Free radical damage influences the Hayflick limit not through TL but rather by affecting the ratio of the rates of events that commit cells to mitoses or to proliferation arrest.

Animals↗
PubMed1992

Crystal structure of glucoamylase from Aspergillus awamori var. X100 to 2.2-A resolution.

The crystal structure of a catalytically active fragment of glucoamylase-I from Aspergillus awamori var. X100 has been determined to a resolution of 2.2 A. Twelve of its 13 alpha-helices are arranged into an "alpha/alpha-barrel." An inner core of six mutually parallel alpha-helices are connected to each other through a peripheral set of six alpha-helices. The peripheral helices are parallel to each other, but approximately antiparallel to the inner core of alpha-helices. The putative active site lies in the packing void of the inner set of helices. The last 30 residues of the enzyme comprise a separate domain containing 10 sites of O-glycosylation. Each instance of O-glycosylation involves a serine or threonine side chain linked to the alpha-anomer of a single mannosyl residue. The O-glycosylated domain is in an extended conformation, wrapping around the "waist" of the alpha/alpha-barrel. Two additional sites of N-glycosylation contribute well ordered glycosyl chains that lie in proximity to the belt of O-glycosylation. The model developed for glucoamylase is a rare and valuable structural example of a glycoprotein and an exo-acting amylolytic enzyme.

Amino Acid Sequence↗
PubMed1991

The interface between the Leishmania-infected macrophage and the host's immune system.

The protozoan parasite Leishmania exploits the lysosomal compartment of the macrophages of its vertebrate host. Given that the macrophage is capable of killing the parasite if supplied with the correct stimulus from the host's immune system, the successful continuation of the infection is in the balance. This paper examines certain aspects of the Leishmania/macrophage interplay, with particular emphasis on the nature of defined protective antigens, and of the interface between the infected macrophage and the host's immune system.

Animals↗
PubMed1989

The use of targetted liposomes to isolate cells bearing immunoglobulin receptors.

A new method of mouse B cell isolation has been developed. It is based on the differences in buoyant density of free lymphocytes and cells bound within liposome-cellular complexes (LCC). LCC arise during the interaction of B cells bearing surface immunoglobulins (Ig) with liposomes loaded with affinity purified rabbit antibodies to mouse IgM/IgG. Advantage was taken of the fact that LCC can be selectively removed from other cell populations by differential flotation in Ficoll gradients. Because of their lower density the LCC did not sediment under conditions where free lymphocytes and complexes of the liposomes with dead or damaged lymphocytes did sediment. The method was highly specific and the recovery of B cells was about 50%. B cells isolated with the use of targetted liposomes retained viability and functional activity. Theoretically, liposomes loaded with antibodies to any cell surface marker could be used for the isolation of cells bearing such markers.

Animals↗