Finite mixtures of mean-parameterized Conway-Maxwell-Poisson models.

For modeling count data, the Conway-Maxwell-Poisson (CMP) distribution is a popular generalization of the Poisson distribution due to its ability to characterize data over- or under-dispersion. While the classic parameterization of the CMP has been well-studied, its main drawback is that it is does not directly model the mean of the counts. This is mitigated by using a mean-parameterized version of the CMP distribution. In this work, we are concerned with the setting where count data may be comprised of subpopulations, each possibly having varying degrees of data dispersion. Thus, we propose a finite mixture of mean-parameterized CMP distributions. An EM algorithm is constructed to perform maximum likelihood estimation of the model, while bootstrapping is employed to obtain estimated standard errors. A simulation study is used to demonstrate the flexibility of the proposed mixture model relative to mixtures of Poissons and mixtures of negative binomials. An analysis of dog mortality data is presented. Supplementary Information: The online version contains supplementary material available at 10.1007/s00362-023-01452-x.

Integrin subtype-dependent CD18 cleavage under shear and its influence on leukocyte-platelet binding.

Previous studies showed that exposure of neutrophils to shear stress induces cysteine protease-mediated shedding of surface CD18 integrins involved in leukocyte-platelet interactions. Based on this, we hypothesized that, under noninflamed conditions, shear-induced CD18 cleavage is a control mechanism to minimize spontaneous leukocyte-platelet binding. For this purpose, we characterized the influence of shear on CD18 surface expression and platelet binding by the different leukocyte subsets. Shear stress elicited magnitude- (between 0 and 5 dyn/cm(2)) and time-dependent reductions in CD18 surface expression. This response was integrin- and cell type-specific, with neutrophils and monocytes exhibiting Mac-1 proteolysis but lymphocytes displaying LFA-1 shedding. Correspondingly, platelet binding, through CD18-fibrinogen interactions, was also influenced by shear exposure in a leukocyte-dependent manner. After treatment with cysteine protease inhibitor E64, neutrophils, but neither monocytes nor lymphocytes, exhibited significantly (P<0.05) enhanced platelet binding and CD18 surface expression under shear. Furthermore, shear exposure significantly (P<0.05) inhibited binding of naïve but not E64-treated neutrophils to fibrinogen. Combined, we provide first evidence that the CD18-cleavage responses of neutrophils to shear interfere with fibrinogen binding and platelet adhesion. These findings have implications as it relates to the efficiency of leukocyte passage through the microcirculation.

Two-dimensional kinetics of beta 2-integrin and ICAM-1 bindings between neutrophils and melanoma cells in a shear flow.

Cell adhesion, mediated by specific receptor-ligand interactions, plays an important role in biological processes such as tumor metastasis and inflammatory cascade. For example, interactions between beta 2-integrin (lymphocyte function-associated antigen-1 and/or Mac-1) on polymorphonuclear neutrophils (PMNs) and ICAM-1 on melanoma cells initiate the bindings of melanoma cells to PMNs within the tumor microenvironment in blood flow, which in turn activate PMN-melanoma cell aggregation in a near-wall region of the vascular endothelium, therefore enhancing subsequent extravasation of melanoma cells in the microcirculations. Kinetics of integrin-ligand bindings in a shear flow is the determinant of such a process, which has not been well understood. In the present study, interactions of PMNs with WM9 melanoma cells were investigated to quantify the kinetics of beta 2-integrin and ICAM-1 bindings using a cone-plate viscometer that generates a linear shear flow combined with a two-color flow cytometry technique. Aggregation fractions exhibited a transition phase where it first increased before 60 s and then decreased with shear durations. Melanoma-PMN aggregation was also found to be inversely correlated with the shear rate. A previously developed probabilistic model was modified to predict the time dependence of aggregation fractions at different shear rates and medium viscosities. Kinetic parameters of beta 2-integrin and ICAM-1 bindings were obtained by individual or global fittings, which were comparable to respectively published values. These findings provide new quantitative understanding of the biophysical basis of leukocyte-tumor cell interactions mediated by specific receptor-ligand interactions under shear flow conditions.