Monte Carlo Investigation of Diffusion of Receptors and Ligands that Bind Across Opposing Surfaces

Studies of receptor diffusion on a cell surface show a variety of behaviors, such as diffusive, sub-diffusive, or super-diffusive motion. However, most studies to date focus on receptor molecules diffusing on a single cell surface. We have previously studied receptor diffusion to probe the molecular mechanism of receptor clustering at the cell–cell junction between two opposing cell surfaces. Here, we characterize the diffusion of receptors and ligands that bind to each other across two opposing cell surfaces, as in cell–cell and cell–bilayer interactions. We use a Monte Carlo method, where receptors and ligands are simulated as independent agents that bind and diffuse probabilistically. We vary receptor–ligand binding affinity and plot the molecule-averaged mean square displacement (MSD) of ligand molecules as a function of time. Our results show that MSD plots are qualitatively different for flat and curved interfaces, as well as between the cases of presence and absence of directed transport of receptor–ligand complexes toward a specific location on the interface. Receptor–ligand binding across two opposing surfaces leads to transient sub-diffusive motion at early times provided the interface is flat. This effect is entirely absent if the interface is curved, however, in this instance we observe sub-diffusive motion. In addition, a decrease in the equilibrium value of the MSD occurs as affinity increases, something which is absent for a flat interface. In the presence of directed transport of receptor–ligand complexes, we observe super-diffusive motion at early times for a flat interface. Super-diffusive motion is absent for a curved interface, however, in this case we observe a transient decrease in MSD with time prior to equilibration for high-affinity values

A Role for Rebinding in Rapid and Reliable T Cell Responses to Antigen

Experimental work has shown that T cells of the immune system rapidly and specifically respond to antigenic molecules presented on the surface of antigen-presenting-cells and are able to discriminate between potential stimuli based on the kinetic parameters of the T cell receptor-antigen bond. These antigenic molecules are presented among thousands of chemically similar endogenous peptides, raising the question of how T cells can reliably make a decision to respond to certain antigens but not others within minutes of encountering an antigen presenting cell. In this theoretical study, we investigate the role of localized rebinding between a T cell receptor and an antigen. We show that by allowing the signaling state of individual receptors to persist during brief unbinding events, T cells are able to discriminate antigens based on both their unbinding and rebinding rates. We demonstrate that T cell receptor coreceptors, but not receptor clustering, are important in promoting localized rebinding, and show that requiring rebinding for productive signaling reduces signals from a high concentration of endogenous pMHC. In developing our main results, we use a relatively simple model based on kinetic proofreading. However, we additionally show that all our results are recapitulated when we use a detailed T cell receptor signaling model. We discuss our results in the context of existing models and recent experimental work and propose new experiments to test our findings

Brain injury-associated biomarkers of TGF-beta1, S100B, GFAP, NF-L, tTG, AbetaPP, and tau were concomitantly enhanced and the UPS was impaired during acute brain injury caused by Toxocara canis in mice

BACKGROUND: Because the outcomes and sequelae after different types of brain injury (BI) are variable and difficult to predict, investigations on whether enhanced expressions of BI-associated biomarkers (BIABs), including transforming growth factor beta1 (TGF-beta1), S100B, glial fibrillary acidic protein (GFAP), neurofilament light chain( NF-L), tissue transglutaminases (tTGs), beta-amyloid precursor proteins (AbetaPP), and tau are present as well as whether impairment of the ubiquitin-proteasome system (UPS) is present have been widely used to help delineate pathophysiological mechanisms in various BIs. Larvae of Toxocara canis can invade the brain and cause BI in humans and mice, leading to cerebral toxocariasis (CT). Because the parasitic burden is light in CT, it may be too cryptic to be detected in humans, making it difficult to clearly understand the pathogenesis of subtle BI in CT. Since the pathogenesis of murine toxocariasis is very similar to that in humans, it appears appropriate to use a murine model to investigate the pathogenesis of CT. METHODS: BIAB expressions and UPS function in the brains of mice inoculated with a single dose of 250 T. canis embryonated eggs was investigated from 3 days (dpi) to 8 weeks post- infection (wpi) by Western blotting and RT-PCR. RESULTS: Results revealed that at 4 and 8 wpi, T. canis larvae were found to have invaded areas around the choroid plexus but without eliciting leukocyte infiltration in brains of infected mice; nevertheless, astrogliosis, an indicator of BI, with 78.9~142.0-fold increases in GFAP expression was present. Meanwhile, markedly increased levels of other BIAB proteins including TGF-beta1, S100B, NF-L, tTG, AbetaPP, and tau, with increases ranging 2.0~12.0-fold were found, although their corresponding mRNA expressions were not found to be present at 8 wpi. Concomitantly, UPS impairment was evidenced by the overexpression of conjugated ubiquitin and ubiquitin in the brain. CONCLUSION: Further studies are needed to determine whether there is an increased risk of CT progression into neurodegenerative disease because neurodegeneration-associated AbetaPP and phosphorylated tau emerged in the brain. DOI: 10.1186/1471-2334-8-8

Polyparasite Helminth infections and their association to anaemia and undernutrition in Northern Rwanda

Abstract Background Intestinal schistosomiasis and soil-transmitted helminth (STH) infections constitute major public health problems in many parts of sub-Saharan Africa. In this study we examined the functional significance of such polyparasite infections in anemia and undernutrition in Rwandan individuals. Methods Three polyparasite infection profiles were defined, in addition to a reference profile that consisted of either no infections or low-intensity infection with only one of the focal parasite species. Logistic regression models were applied to data of 1,605 individuals from 6 schools in 2 districts of the Northern Province before chemotherapeutic treatment in order to correctly identify individuals who were at higher odds of being anaemic and/or undernourished. Findings Stunted relative to nonstunted, and males compared to females, were found to be at higher odds of being anaemic independently of polyparasite infection profile. The odds of being wasted were 2-fold greater for children with concurrent infection of at least 2 parasites at M+ intensity compared to those children with the reference profile. Males compared to females and anaemic compared to nonanaemic children were significantly more likely to be stunted. None of the three polyparasite infection profiles were found to have significant effects on stunting. Conclusion The present data suggest that the levels of polyparasitism, and infection intensities in the Rwandan individuals examined here may be lower as compared to other recent similar epidemiological studies in different regions across sub-Saharan Africa. Neither the odds of anaemia nor the odds of stunting were found to be significantly different in the three-polyparasite infection profiles. However, the odds of wasting were higher in those children with at least two parasites at M+ intensity compared to those children with the reference profile. Nevertheless, despite the low morbidity levels indicated in the population under study here, we recommend sustainable efforts for the deworming of affected populations to be continued in order to support the economic development of the country

Reduced subjective response to acute ethanol administration among young men with a broad bipolar phenotype

Elevated lifetime prevalence rates of alcohol use disorders (AUDs) are a feature of bipolar disorder (BD). Individuals at-risk for AUDs exhibit blunted subjective responses to alcohol (low levels of response), which may represent a biomarker for AUDs. Thus, individuals at-risk for BD may exhibit low responses to alcohol. Participants were 20 unmedicated adult males who reported high rates of hypomanic experiences (bipolar phenotype participants; BPPs), aged 18 to 21 years, and 20 healthy controls matched on age, gender, IQ, BMI, and weekly alcohol intake. Subjective and pharmacokinetic responses to acute alcohol (0.8 g/kg) vs placebo administration were collected in a randomized, double-blind, cross-over, placebo-controlled, within-subjects design. BPP participants reported significantly lower subjective intoxication effects ('feel high': F=14.2, p=0.001; 'feel effects': F=8.1, p=0.008) across time, but did not differ in their pharmacokinetic, stimulant, or sedative responses. Paradoxically, however, the BPP participants reported significantly higher expectations of the positive effects of alcohol than controls. Our results suggest that unmedicated young males with previous hypomanic experiences exhibit diminished subjective responses to alcohol. These blunted alcohol responses are not attributable to differences in weekly alcohol intake, pharmacokinetic effects (eg, absorption rates), or familial risk of AUDs. These observations suggest that the dampened intoxication may contribute to the increased rates of alcohol misuse in young people at-risk for BD, and suggest possible shared etiological factors in the development of AUDs and BD. © 2012 American College of Neuropsychopharmacology. All rights reserved