Biomedical subjects

Zeljko Bajzer

Publications and source records attributed to Zeljko Bajzer.

12 recordsLinked to original sources

PubMed2006

Branching morphology of the rat hepatic portal vein tree: a micro-CT study.

In contrast to the lung and the myocardium, the liver is a relatively homogeneous organ with fewer anatomic constraints on vascular branching. Hence, we hypothesize that the hepatic vasculature could more closely follow optimization of branching geometry than is the case in other organs. The geometrical and fractal properties of the rat hepatic portal vein tree were investigated, with the aid of three-dimensional micro-computed tomography data. Frequency distributions of vessel radii were obtained at three different voxel resolutions and fitted to a theoretical model of dichotomous branching. The model predicted an average junction exponent of 3.09. Hemodynamic model calculations showed that with generation, relative shear stress decreases. Branching angles were found to oscillate between those predicted by two optimality principles of minimum power loss and volume, and of minimum shear stress and surface. The liver shows a variation in branching morphology similar to that of other organs. Therefore, we conclude that anatomic constraints do not have a major perturbing impact.

Animals↗

PubMed2005

Mathematical modeling of cancer radiovirotherapy.

Cancer virotherapy represents a dynamical system that requires mathematical modeling for complete understanding of the outcomes. The combination of virotherapy with radiation (radiovirotherapy) has been recently shown to successfully eliminate tumors when virotherapy alone failed. However, it introduces a new level of complexity. We have developed a mathematical model, based on population dynamics, that captures the essential elements of radiovirotherapy. The existence of corresponding equilibrium points related to complete cure, partial cure, and therapy failure is proved and discussed. The parameters of the model were estimated by fitting to experimental data. By using simulations we analyzed the influence of parameters that describe the interaction between virus and tumor cell on the outcome of the therapy. Furthermore, we evaluated relevant therapeutic scenarios for radiovirotherapy, and offered elements for optimization.

Algorithms↗

PubMed2005

Modeling positive regulatory feedbacks in cell-cell interactions.

Our current understanding of molecular mechanisms of cellular regulation still does not support quantitative predictions of the overall growth kinetics of normal or malignant tissues. However, discernment of the role of growth-factor mediated cell-cell communication in tissue kinetics is possible by the use of simple mathematical models. Here we discuss the design and use of mathematical models in quantifying the contribution of autocrine and paracrine (i.e., humoral) interactions to the kinetics of tissue growth. We present models that include a humorally mediated regulatory feedback among cells built into phenomenological mathematical models of growth. Application of these models to data exemplifies the finite contributions of positive feedback in cell-cell interactions to the overall tissue growth. In addition, we propose a perturbation approach to allow separation of cell-cell interactions dependent on the perturbing agent (such as hormone antagonists in hormone-dependent tissues) from cell-cell interactions independent of it.

Animals↗

PubMed2004

Dynamic iodide trapping by tumor cells expressing the thyroidal sodium iodide symporter.

The thyroidal sodium iodide symporter (NIS) in combination with various radioactive isotopes has shown promise as a therapeutic gene in various tumor models. Therapy depends on adequate retention of the isotope in the tumor. We hypothesized that in the absence of iodide organification, isotope trapping is a dynamic process either due to slow efflux or re-uptake of the isotope by cells expressing NIS. Iodide efflux is slower in ARH-77 and K-562 cells expressing NIS compared to a thyroid cell line. Isotope retention half times varied linearly with the number of cells expressing NIS. With sufficient NIS expression, iodide efflux is a zero-order process. Efflux kinetics in the presence or absence of perchlorate also supports the hypothesis that iodide re-uptake occurs and contributes to the retention of the isotope in tumor cells. Iodide organification was insignificant. In vivo studies in tumors composed of mixed cell populations confirmed these observations.

Animals↗

PubMed2004

Changes in structure and stability of calbindin-D(28K) upon calcium binding.

Calbindin-D(28K) is a biologically important protein required for normal neural function and for the transport of calcium in epithelial cells of the intestine and kidney. We have used fluorescence and circular dichroism (CD) spectroscopy to characterize the effects of calcium binding on the structure and stability of calbindin. Ca(2+) titration monitored by fluorescence spectroscopy reveals the presence of two classes of calcium-binding sites with association constants approximately 10(7.5) and approximately 10(8.9)M(-1). CD spectra in the far-UV spectral range show minor changes upon Ca(2+) titration, implying that the secondary structure of calbindin-D(28K) is not greatly affected. On the basis of the CD spectra in the near-UV spectral range, we conclude that the tertiary structure is more sensitive to Ca(2+) addition. The most significant change occurs between pCa 7.0 and pCa 8.0. The variations in the protein thermostability are correlated with those in the near-UV CD spectra. The enthalpy changes upon heat denaturation of calbindin in the apo-state are characteristic of proteins containing several weakly interacting domains with similar thermodynamical properties. Thus, calcium binding by calbindin-D(28K) largely affects the local structure around the aromatic residues and the thermal stability of the protein; the changes in the secondary structure are insignificant.

Animals↗

PubMed2003

A model for the activation of plasma membrane calcium pump isoform 4b by calmodulin.

Overexpression of the plasma membrane calcium pump (PMCA) isoform 4b by means of the baculovirus system enabled us, for the first time, to study the kinetics of calmodulin binding to this pump. This was done by stopped-flow fluorescence measurements using 2-chloro-(amino-Lys(75))-[6-[4-(N,N-diethylamino)phenyl]-1,3,5-triazin-4-yl]calmodulin (TA-calmodulin). Upon mixing with PMCA, the fluorescence of TA-calmodulin changed along a biphasic curve: a rapid and small increase in fluorescence was followed by a slow and large decrease that lasted about 100 s. The experiment was done at several PMCA concentrations. Global fitting nonlinear regression analysis of these results led to a model in which PMCA is present in two forms: a closed conformation and an open conformation. Calmodulin reacts with both conformations but reacts faster and with higher affinity for the open conformation. Measurements of the ATPase activity of PMCA under similar conditions revealed that the open form has higher ATPase activity than the closed one. Contrasting with the reaction with the whole pump, TA-calmodulin reacted rapidly (in about 2 s) with a calmodulin-binding peptide made after the sequence of the calmodulin-binding domain of PMCA (C28). Results of TA-calmodulin binding to C28 are explained by a simpler model, in which only an open conformation exists.

Amino Acid Sequence↗

PubMed2003

Combining Gompertzian growth and cell population dynamics.

A two-compartment model of cancer cells population dynamics proposed by Gyllenberg and Webb includes transition rates between proliferating and quiescent cells as non-specified functions of the total population, N. We define the net inter-compartmental transition rate function: Phi(N). We assume that the total cell population follows the Gompertz growth model, as it is most often empirically found and derive Phi(N). The Gyllenberg-Webb transition functions are shown to be characteristically related through Phi(N). Effectively, this leads to a hybrid model for which we find the explicit analytical solutions for proliferating and quiescent cell populations, and the relations among model parameters. Several classes of solutions are examined. Our model predicts that the number of proliferating cells may increase along with the total number of cells, but the proliferating fraction appears to be a continuously decreasing function. The net transition rate of cells is shown to retain direction from the proliferating into the quiescent compartment. The death rate parameter for quiescent cell population is shown to be a factor in determining the proliferation level for a particular Gompertz growth curve.

Cell Division↗

PubMed2003

Novel map descriptors for characterization of toxic effects in proteomics maps.

We consider a novel numerical characterization of proteomics maps based on the construction of a graph obtained by connecting all protein spots in a proteomics map that are at distance equal to, or smaller than, a critical distance D(c). We refer to the so constructed graph as a cluster graph and we calculate four associated characteristic matrices, previously considered in the literature: (1) the Euclidean-distance matrix ED; (2) the neighborhood-distance matrix ND; (3) the path-distance matrix based on the shortest paths between connected spots PD; and (4) the quotient matrix Q, the elements of which are given as the quotient of the corresponding elements of ED and ND matrices. Numerical descriptors for proteomics maps include in particular the leading eigenvalue of the Q matrix and the family of associated "higher order" matrices defined as powers of Q. These map descriptors show considerable sensitivity to perturbations of proteomics maps by toxicants.

Animals↗

PubMed2002

Formation of the killer Ig-like receptor repertoire on CD4+CD28null T cells.

Killer Ig-like receptors (KIRs) are expressed on CD4(+)CD28(null) T cells, a highly oligoclonal subset of T cells that is expanded in patients with rheumatoid arthritis. It is unclear at what stage of development these T cells acquire KIR expression. To determine whether KIR expression is a consequence of clonal expansion and replicative senescence, multiple CD4(+)CD28(null) T cell clones expressing the in vivo dominant TCR beta-chain sequences were identified in three patients and analyzed for their KIR gene expression pattern. Based on sharing of TCR sequences, the clones were grouped into five clone families. The repertoire of KIRs was diverse, even within each clone family; however, the gene expression was not random. Three particular receptors, KIR2DS2, KIR2DL2, and KIR3DL2, had significant differences in gene expression frequencies between the clone families. These data suggest that KIRs are successively acquired after TCR rearrangement, with each clone family developing a dominant expression pattern. The patterns did not segregate with the individual from whom the clones were derived, indicating that peripheral selection in the host environment was not a major shaping force. Several models were examined using a computer algorithm that was designed to simulate the expression of KIRs at various times during T cell proliferation. The computer simulations favored a model in which KIR gene expression is inducible for a limited time during the initial stages of clonal expansion.

Arthritis, Rheumatoid↗

PubMed2002

The metal-binding properties of DREAM: evidence for calcium-mediated changes in DREAM structure.

DREAM, an EF-hand protein, associates with and modulates the activity of presenilins and Kv4 potassium channels in neural and cardiac tissues and represses prodynorphin and c-fos gene expression by binding to DNA response elements in these genes. Information concerning the metal-binding properties of DREAM and the consequences of metal binding on protein structure are important in understanding how this protein functions in cells. We now show that DREAM binds 1 mol of calcium/mol of protein with relatively high affinity and another 3 mol of calcium with lower affinity. DREAM binds 1 mol of magnesium/mol of protein. DREAM, pre-loaded with 1 mol of calcium, binds 1 mol of magnesium, thus demonstrating that the magnesium-binding site is distinct from the high affinity calcium-binding site. Analysis of metal binding to mutant DREAM protein constructs localizes the high affinity calcium-binding site and the magnesium-binding site to EF-hands 3 or 4. Binding of calcium but not magnesium changes the conformation, stability, and alpha-helical content of DREAM. Calcium, but not magnesium, reduces the affinity of apo-DREAM for specific DNA response elements in the prodynorphin and c-fos genes. We conclude that DREAM binds calcium and magnesium and that calcium, but not magnesium, modulates DREAM structure and function.

Amino Acid Sequence↗

PubMed2002

Quantification of myocardial microcirculatory function with X-ray CT.

A mathematical model of the intramyocardial coronary microcirculation is used to explore the validity of a fast CT imaging method for characterizing the myocardial microcirculatory functional status. The fast CT method depends on the demonstrated CT-based estimation of myocardial perfusion (F) and the intramyocardial blood volume (B(v)). The observed curvilinear myocardial blood volume-to-flow relationship, empirically fitted to B(v) = a.F + b.F(0.5), is a signature of the underlying early pathophysiologic processes thought to be involved in systemic disease processes, such as atherosclerosis, hypertension, and diabetes mellitus. The sensitivity and specificity of the CT-based estimate of this characteristic relationship is explored by altering the characteristics of the vascular diameter-to-flow relationship and the variation in the fraction of capillaries perfused at different coronary flows. The simulation results also indicate that if the vascular diameters change so that the vascular resistance corresponds to the change in flow, then the empirically observed myocardial B(v)-to-F relationship holds well.

Animals↗

PubMed2002

Renal handling of X-ray contrast media imaging and exploration with electron beam CT.

Physiologic changes in renal hemodynamics and function reflect its role as a regulatory organ in maintaining homeostasis, whereas other alterations may mirror development of renal injury and often precede overt signs of morphologic changes. Furthermore, intrarenal alterations may be discreet and manifest only in the renal cortical, medullary, or papillary zones. The high spatial and temporal resolution of electron-beam computed tomography enables external detection and quantification of cortical, medullary, and papillary tissue density changes following an intravenous bolus injection of X-ray contrast media. These changes reflect flow of contrast media in these renal zones through the successive renal vascular, glomerular, and tubular compartments that can be individually plotted as time-density curves (TDC). Mathematical modeling then allows calculation of unique parameters of renal function from these TDC. This ability to quantify renal regional attributes may not only shed light on the physiologic mechanisms that the kidney controls, but also assist in detecting subtle impairment in its function.

Contrast Media↗