High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology

Background

The hypothalamic-pituitary-adrenal (HPA) axis is a central regulator of stress response and its dysfunction has been associated with a broad range of complex illnesses including Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS). Though classical mathematical approaches have been used to model HPA function in isolation, its broad regulatory interactions with immune and central nervous function are such that the biological fidelity of simulations is undermined by the limited availability of reliable parameter estimates.

Method

Here we introduce and apply a generalized discrete formalism to recover multiple stable regulatory programs of the HPA axis using little more than connectivity between physiological components. This simple discrete model captures cyclic attractors such as the circadian rhythm by applying generic constraints to a minimal parameter set; this is distinct from Ordinary Differential Equation (ODE) models, which require broad and precise parameter sets. Parameter tuning is accomplished by decomposition of the overall regulatory network into isolated sub-networks that support cyclic attractors. Network behavior is simulated using a novel asynchronous updating scheme that enforces priority with memory within and between physiological compartments.

Results

Consistent with much more complex conventional models of the HPA axis, this parsimonious framework supports two cyclic attractors, governed by higher and lower levels of cortisol respectively. Importantly, results suggest that stress may remodel the stability landscape of this system, favoring migration from one stable circadian cycle to the other. Access to each regime is dependent on HPA axis tone, captured here by the tunable parameters of the multi-valued logic. Likewise, an idealized glucocorticoid receptor blocker alters the regulatory topology such that maintenance of persistently low cortisol levels is rendered unstable, favoring a return to normal circadian oscillation in both cortisol and glucocorticoid receptor expression.

Conclusion

These results emphasize the significance of regulatory connectivity alone and how regulatory plasticity may be explored using simple discrete logic and minimal data compared to conventional methods.

     

Phenotypic and molecular analyses of leaf rust resistance in some Iranian wheat genotypes

Host resistance is the most sustainable method of controlling leaf rust which can be achieved through exploring resistance genes by gene postulation and/or molecular markers. The experiment was conducted to postulate leaf rust resistance genes in 20 Iranian wheat cultivars using 10 Puccinia triticina pathotypes. Six sequence-tagged site and sequence-characterised amplified region markers were also used to detect the genes Lr9, Lr10, Lr19, Lr24, Lr26 and Lr37. The genes Lr3a, Lr3Ka, Lr10, Lr15, Lr19, Lr26, Lr28, Lr30 and Lr27 + Lr31 genes were postulated to be present either singly or in combination. The cultivars Toos and Dabira were found to have no effective seedling resistance gene(s); The former was shown to carry none of the genes, while the latter carried Lr10, Lr24 and Lr37 based on molecular markers. It was not possible to postulate resistance genes in Sirvan, Backcross Roshan, Zagross and Chamran cultivars. However, molecular association indicated the presence of Lr19, Lr10 and Lr24 in Sirvan, Backcross Roshan, and Chamran, respectively while none in Zagross.     

Evolutionarily conserved paired immunoglobulin-like receptor α (PILRα) domain mediates its interaction with diverse sialylated ligands

Paired immunoglobulin-like receptor (PILR) α is an inhibitory receptor that recognizes several ligands, including mouse CD99, PILR-associating neural protein, and Herpes simplex virus-1 glycoprotein B. The physiological function(s) of interactions between PILRα and its cellular ligands are not well understood, as are the molecular determinants of PILRα/ligand interactions. To address these uncertainties, we sought to identify additional PILRα ligands and further define the molecular basis for PILRα/ligand interactions. Here, we identify two novel PILRα binding partners, neuronal differentiation and proliferation factor-1 (NPDC1), and collectin-12 (COLEC12). We find that sialylated O-glycans on these novel PILRα ligands, and on known PILRα ligands, are compulsory for PILRα binding. Sialylation-dependent ligand recognition is also a property of SIGLEC1, a member of the sialic acid-binding Ig-like lectins. SIGLEC1 Ig domain shares ～22% sequence identity with PILRα, an identity that includes a conserved arginine localized to position 97 in mouse and human SIGLEC1, position 133 in mouse PILRα and position 126 in human PILRα. We observe that PILRα/ligand interactions require conserved PILRα Arg-133 (mouse) and Arg-126 (human), in correspondence with a previously reported requirement for SIGLEC1 Arg-197 in SIGLEC1/ligand interactions. Homology modeling identifies striking similarities between PILRα and SIGLEC1 ligand binding pockets as well as at least one set of distinctive interactions in the galactoxyl-binding site. Binding studies suggest that PILRα recognizes a complex ligand domain involving both sialic acid and protein motif(s). Thus, PILRα is evolved to engage multiple ligands with common molecular determinants to modulate myeloid cell functions in anatomical settings where PILRα ligands are expressed.     

Cell cycle dependent regulation of deoxycytidine kinase, deoxyguanosine kinase, and cytosolic 5'-nucleotidase I activity in MOLT-4 cells

Activation of nucleoside analogues is dependent on kinases and 5'-nucleotidases and the balance between the activity of these enzymes. The purpose of this study was to analyze deoxycytidine kinase, deoxyguanosine kinase, and 4 different 5'-nucleotidases during cell cycle progression in MOLT-4 cells. The activity of both kinases was cell cycle dependent and increased during proliferation while the activity of cytosolic 5'-nucleotidase I decreased. We could show that the kinase activity was higher than the total nucleotidase activity, which was unchanged or decreased during cell cycle progression. These data may be important in designing modern combination therapy with nucleoside analogues.     

Alloreactive CD4 T cell activation in vivo: an autonomous function of the indirect pathway of alloantigen presentation

Activation of alloreactive CD4 T cells occurs via the direct and indirect pathways of alloantigen presentation. A novel TCR/alloantigen transgenic system was designed that permitted in vivo visualization of CD4 T cell priming through these pathways. When both pathways of alloantigen presentation were intact, CD4 T cell activation in response to cardiac allografts was rapid and systemic by day 4 after transplantation, in contrast to that seen in response to skin allografts, which was delayed until 10-12 days after transplantation. Despite this systemic CD4 T cell activation in response to cardiac allografts, there was a paucity of activated graft-infiltrating CD4 T cells at 4 days posttransplantation. This finding suggests that the initial priming of alloimmune CD4 T cell responses occurs within draining lymphoid organs. Furthermore, alloantigens derived from cardiac allografts failed to promote thymic negative selection of developing thymocytes expressing the alloreactive TCR clonotype. In the absence of a functional direct pathway, the kinetics of activation, anatomic localization, and effector function of alloreactive CD4 T cells remained unchanged. Overall, the present study defines the anatomic and temporal characteristics of CD4 T cell alloimmune responses and demonstrates that CD4 T cell priming via the indirect pathway proceeds optimally in the absence of the direct pathway of alloantigen presentation.     

Understanding atherosclerosis through mouse genetics

During the past year studies with mouse models have significantly clarified our understanding of atherosclerosis. Noteworthy achievements include: the discovery of a number of novel genes and pathways; new evidence emphasizing the role of lymphocytes in atherogenesis; the development of mouse models exhibiting advanced lesions with evidence of thrombosis; and new results indicating an anti-atherogenic effect of testosterone.