A mathematical model for germinal centre kinetics and affinity maturation

We present a mathematical model which reproduces experimental data on the germinal centre (GC) kinetics of the primed primary immune response and on affinity maturation observed during the reaction. We show that antigen masking by antibodies which are produced by emerging plasma cells can drive affinity maturation and provide a feedback mechanism by which the reaction is stable against variations in the initial antigen amount over several orders of magnitude. This provides a possible answer to the long-standing question of the role of antigen reduction in driving affinity maturation. By comparing model predictions with experimental results, we propose that the selection probability of centrocytes and the recycling probability of selected centrocytes are not constant but vary during the GC reaction with respect to time. It is shown that the efficiency of affinity maturation is highest if clones with an affinity for the antigen well above the average affinity in the GC leave the GC for either the memory or plasma cell pool. It is further shown that termination of somatic hypermutation several days before the end of the germinal centre reaction is beneficial for affinity maturation. The impact on affinity maturation of simultaneous initiation of memory cell formation and somatic hypermutation vs. delayed initiation of memory cell formation is discussed.     

Edovum puttleri [Hym.: Eulophidae]: Biological activity and responses to normal and frozen eggs ofLeptinotarsa decemlineata [Col.: Chrysomelidae]

Biological control of eggplant pests in general, and (CPB)Leptinotarsa decemlineata (Say) in particular, is highly problematic.Edovum puttleri Grissell, an exotic egg parasitoid which has been found potentially effective, is being reared to this end. Frozen CPB eggs (?18°C) proved to be accepted and suitable for parasitization byE. puttleri. However, when given a choice between 20 frozen and 20 normal eggs every 2 days, the females exhibited a significant preference for the latter. Parasitization and host predation patterns related to female age are described by 2 opposing fourth-order polynomial functions. Parasitization increased up to day 10, followed by progressive decline. Average life span per female was 31.10±.58, with a recorded maximum of 56 days. High predatory behaviour of older females, which showed a decrease in parasitization, was observed in these experimental conditions.     

Hypoxia increases intensity of epidermal papillomatosis in roach Rutilus rutilus

Hypoxia, which occurs frequently in aquatic ecosystems and is mainly due to increasing eutrophication can cause severe environmental stress in fish. We investigated experimentally the hypothesis that hypoxia could be one of the environmental stress factors that can induce papillomatosis in fish. Male roach Rutilus rutilus exposed to periodic oxygen deficiency and accompanied temperature increases (OT group) showed the highest increase in the intensity of papillomatosis, as measured by the number of scales covered by papillomatosis tumors. The second highest increase in disease intensity was among male roach exposed to periodical temperature increases. The incidence of such tumors was lowest in the control group, which was exposed to neither hypoxia nor increased temperature. The mortality of fish during the 17 d experiment was highest and the condition factor was lowest in the OT group, indicating this group experienced a higher level of stress. The apparent interaction of hypoxia and temperature suggests that these environmental stressors are among the multifactorial elements leading to papillomatosis in roach. Furthermore, these results provide experimental evidence to indicate that hypoxia may contribute to tumor development in fish.     

Systems Model of T Cell Receptor Proximal Signaling Reveals Emergent Ultrasensitivity

Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy.     

Overview of Mathematical Approaches Used to Model Bacterial Chemotaxis II: Bacterial Populations

We review the application of mathematical modeling to understanding the behavior of populations of chemotactic bacteria. The application of continuum mathematical models, in particular generalized Keller–Segel models, is discussed along with attempts to incorporate the microscale (individual) behavior on the macroscale, modeling the interaction between different species of bacteria, the interaction of bacteria with their environment, and methods used to obtain experimentally verified parameter values. We allude briefly to the role of modeling pattern formation in understanding collective behavior within bacterial populations. Various aspects of each model are discussed and areas for possible future research are postulated.     

Overview of Mathematical Approaches Used to Model Bacterial Chemotaxis I: The Single Cell

Mathematical modeling of bacterial chemotaxis systems has been influential and insightful in helping to understand experimental observations. We provide here a comprehensive overview of the range of mathematical approaches used for modeling, within a single bacterium, chemotactic processes caused by changes to external gradients in its environment. Specific areas of the bacterial system which have been studied and modeled are discussed in detail, including the modeling of adaptation in response to attractant gradients, the intracellular phosphorylation cascade, membrane receptor clustering, and spatial modeling of intracellular protein signal transduction. The importance of producing robust models that address adaptation, gain, and sensitivity are also discussed. This review highlights that while mathematical modeling has aided in understanding bacterial chemotaxis on the individual cell scale and guiding experimental design, no single model succeeds in robustly describing all of the basic elements of the cell. We conclude by discussing the importance of this and the future of modeling in this area.     

Upregulation of the Tim-3/Galectin-9 Pathway of T Cell Exhaustion in Chronic Hepatitis B Virus Infection

The S-type lectin galectin-9 binds to the negative regulatory molecule Tim-3 on T cells and induces their apoptotic deletion or functional inactivation. We investigated whether galectin-9/Tim-3 interactions contribute to the deletion and exhaustion of the antiviral T cell response in chronic hepatitis B virus infection (CHB). We found Tim-3 to be expressed on a higher percentage of CD4 and CD8 T cells from patients with CHB than healthy controls (p<0.0001) and to be enriched on activated T cells and those infiltrating the HBV-infected liver. Direct ex vivo examination of virus-specific CD8 T cells binding HLA-A2/peptide multimers revealed that Tim-3 was more highly upregulated on HBV-specific CD8 T cells than CMV-specific CD8 T cells or the global CD8 T cell population in patients with CHB (p<0.001) or than on HBV-specific CD8 after resolution of infection. T cells expressing Tim-3 had an impaired ability to produce IFN-γ and TNF-α upon recognition of HBV-peptides and were susceptible to galectin-9-triggered cell death in vitro. Galectin-9 was detectable at increased concentrations in the sera of patients with active CHB-related liver inflammation (p = 0.02) and was strongly expressed by Kupffer cells within the liver sinusoidal network. Tim-3 blockade resulted in enhanced expansion of HBV-specific CD8 T cells able to produce cytokines and mediate cytotoxicity in vitro. Blocking PD-1 in combination with Tim-3 enhanced the number of patients from whom functional antiviral responses could be recovered and/or the strength of responses, indicating that these co-inhibitory molecules play a non-redundant role in driving T cell exhaustion in CHB. Patients taking antivirals able to potently suppress HBV viraemia continued to express Tim-3 on their T cells and respond to Tim-3 blockade. In summary, both Tim-3 and galectin-9 are increased in CHB and may contribute to the inhibition and deletion of T cells as they infiltrate the HBV-infected liver.     

Explicit formulation of different receptor-G-protein interactions and effector regulation

MOTIVATION: G-protein-coupled receptors (GPCRs) can create different intracellular signals depending on which G-proteins they couple to and which intracellular signal-integrators, such as adenylyl cyclases, are expressed in the cell. One and the same GPCR can activate multiple G-protein species, generating signals, which either inhibit or amplify each other. Because of this complexity, extraction of mechanistic information from concentration-response curves is not straightforward. RESULTS: To tackle this problem, I describe in this paper explicit equations for GPCR-interaction with two G-protein species by different possible mechanisms, and also an equation for the regulation of an effector enzyme by the activated G-proteins or their effectors. Arithmetic solutions to these equations are presented, which resulted in the equations being applicable in a spreadsheet program environment. These equations are useful in simulations to analyze results, to design experiments and to test hypotheses. Some examples of this are presented in this study.     

Sex pheromone components of the leafroller moth Pandemis cerasana

Female-tip washings of the leafroller moth, Pandemis cerasana, were found to contain (E)-11-tetradecenyl acetate, (Z)-11-tetradecenyl acetate, (E)-11-tetradecenol, (Z)-11-tetradecenol and tetradecyl acetate, based on chemical analysis and electroantennogram tests. The relative amounts of these compounds in the gland were ca. 64:21:10:3:2 in the order named. Only (E)-11 and (Z)-11-tetradecenyl acetate were required for attraction of males to trap dispensed in the ratio 3:1, respectively.     

Climatic Factors Influencing the Anthrax Outbreak of 2016 in Siberia,Russia

In 2016, an outbreak of anthrax killing thousands of reindeer and affecting dozens of humans occurred on the Yamal peninsula, Northwest Siberia, after 70 years of epidemiological situation without outbreaks. The trigger of the outbreak has been ascribed to the activation of spores due to permafrost thaw that was accelerated during the summer heat wave. The focus of our study is on the dynamics of local environmental factors in connection with the observed anthrax revival. We show that permafrost was thawing rapidly for already 6 years before the outbreak. During 2011–2016, relatively warm years were followed by cold years with a thick snow cover, preventing freezing of the soil. Furthermore, the spread of anthrax was likely intensified by an extremely dry summer of 2016. Concurrent with the long-term decreasing trend in the regional annual precipitation, the rainfall in July 2016 was less than 10% of its 30-year mean value. We conclude that epidemiological situation of anthrax in the previously contaminated Arctic regions requires monitoring of climatic factors such as warming and precipitation extremes.