Dynamics of Calcium Fluxes in Nonexcitable Cells: Mathematical Modeling

Mathematical models simulating the dynamics of calcium redistribution (elicited by experimental interference with the pathways of calcium fluxes) in cellular compartments have been developed, based on a minimal scheme of the pathways of calcium fluxes in nonexcitable cells suspended in calcium-free medium. The models are consistent with available experimental data. All parameters are quantitatively related to the intrinsic properties of calcium adenosine triphosphatases (ATPases) and cellular membranes; there is no interdependence between the parameters. The models can be used as the basis for quantitative analysis and interpretation of experimental data. The activities of plasma membrane and sarcoendoplasmic reticulum calcium ATPases (PMCA and SERCAs) are governed by different mechanisms. PMCA is likely to undergo transitions from inactive to active to “dormant” (not identical to the initial) and back to inactive states, the mean duration of the cycle lasting for minutes or longer. The sequence of the transitions is initiated, presumably, by an increase in cytosolic calcium concentration. The transition of PMCA from inactive to active (at least at low rates of increase in cytosolic calcium concentration) is likely to be slower than that from active to dormant. SERCA, presumably, transits from inactive to active state in response to increases in calcium leakage from calcium stores. Whereas PMCA extrudes excess calcium (a definite quantity of it) in a short pulse, SERCA retakes calcium back into the stores permanently at a high rate. The models presented here may be the best means for the moment to quantitatively relate the dynamics of calcium fluxes in nonexcitable cells with known or putative properties of the mechanisms underlying activation of calcium ATPases.     

Mathematical Modeling of the Intracellular Regulation of Immune Processes

Molecular Biology - The modern era of research in immunology is characterized by an unprecedented level of detail about structural characteristics of the immune system and the regulation of...     

Characterization of 3-Iodothyronamine In Vitro Dynamics by Mathematical Modeling

3-Iodothyronamine (T₁AM) is regarded as a hormone-like substance thanks to its endogenous nature, its interaction with specific receptors trace amine-associated receptor 1 and its biological effects. We characterized T₁AM transport and conversion in an in vitro culture of H9c2 murine cells, after a T₁AM bolus injection. Samples of cell medium culture and cell lysate were assayed by high-performance liquid chromatography coupled to tandem mass spectrometry. We performed comparative experiments by adding to T₁AM bolus amino oxidase inhibitors as iproniazid, pargyline (monoamine oxidase, MAO inhibitors), aminoguanidine, and semicarbazide (semicarbazide-sensitive amino oxidase, SSAO inhibitors). A mathematical model was developed, based on the assumption that T₁AM is transported with a mechanism that is typical of hormone transport (i.e., EGF or insulin). We noticed that surface receptors downregulation could play a major role in T₁AM dynamics. We also estimated that T₁AM catabolism is mainly affected by MAO inhibitors, which produce a dramatic decrease in the kinetic constants related to T₁AM degradation, while no significant changes were observed in experiments with SSAO inhibitors.     

Correction to: Development and Validation of Arc Nanobodies: New Tools for Probing Arc Dynamics and Function

Neurochemical Research -     

Mathematical Modeling of Population Dynamics Based on Recurrent Equations: Results and Prospects. Part II

Biology Bulletin - The second part of this article focuses on subjects devoted to mathematical modeling of the evolution of limited populations and migration affecting the dynamics of coupled...     

Development and Validation of Arc Nanobodies: New Tools for Probing Arc Dynamics and Function

Neurochemical Research - Activity-regulated cytoskeleton-associated (Arc) protein plays key roles in long-term synaptic plasticity, memory, and cognitive flexibility. However, an integral...     

Immune response and immune tolerance to the O-antigen of Shigella flexneri VI

The method for the determination of the number of cells synthetizing antibodies to S. flexneri VI O-antigen in the spleen of mice has been developed. Primary immune response to this antigen has been studied with the use of the new method. Immune response to the optimum immunogenic dose of O-antigen has a manifest variable character. The intensity of primary immune response has been shown to rise with the increase of the dose of O-antigen from 0.004 to 50 micrograms. The preliminary injection of 200 micrograms of O-antigen, followed by the injection of cyclophosphamide 2 days later, leads to the development of specific immunological tolerance to O-antigen in experimental animals.     

Modeling Microbial Community Networks: Methods and Tools

In the current research landscape, microbiota composition studies are of extreme interest, since it has been widely shown that resident microorganisms affect and shape the ecological niche they inhabit. This complex micro-world is characterized by different types of interactions. Understanding these relationships provides a useful tool for decoding the causes and effects of communities’ organizations. Next-Generation Sequencing technologies allow to reconstruct the internal composition of the whole microbial community present in a sample. Sequencing data can then be investigated through statistical and computational method coming from network theory to infer the network of interactions among microbial species.Since there are several network inference approaches in the literature, in this paper we tried to shed light on their main characteristics and challenges, providing a useful tool not only to those interested in using the methods, but also to those who want to develop new ones. In addition, we focused on the frameworks used to produce synthetic data, starting from the simulation of network structures up to their integration with abundance models, with the aim of clarifying the key points of the entire generative process.     

Responding to Vaccine Safety Signals during Pandemic Influenza: A Modeling Study

Background

Managing emerging vaccine safety signals during an influenza pandemic is challenging. Federal regulators must balance vaccine risks against benefits while maintaining public confidence in the public health system.

Methods

We developed a multi-criteria decision analysis model to explore regulatory decision-making in the context of emerging vaccine safety signals during a pandemic. We simulated vaccine safety surveillance system capabilities and used an age-structured compartmental model to develop potential pandemic scenarios. We used an expert-derived multi-attribute utility function to evaluate potential regulatory responses by combining four outcome measures into a single measure of interest: 1) expected vaccination benefit from averted influenza; 2) expected vaccination risk from vaccine-associated febrile seizures; 3) expected vaccination risk from vaccine-associated Guillain-Barre Syndrome; and 4) expected change in vaccine-seeking behavior in future influenza seasons.

Results

Over multiple scenarios, risk communication, with or without suspension of vaccination of high-risk persons, were the consistently preferred regulatory responses over no action or general suspension when safety signals were detected during a pandemic influenza. On average, the expert panel valued near-term vaccine-related outcomes relative to long-term projected outcomes by 3∶1. However, when decision-makers had minimal ability to influence near-term outcomes, the response was selected primarily by projected impacts on future vaccine-seeking behavior.

Conclusions

The selected regulatory response depends on how quickly a vaccine safety signal is identified relative to the peak of the pandemic and the initiation of vaccination. Our analysis suggested two areas for future investment: efforts to improve the size and timeliness of the surveillance system and behavioral research to understand changes in vaccine-seeking behavior.     

HIV-1 Envelope Resistance to Proteasomal Cleavage: Implications for Vaccine Induced Immune Responses

Background

Antigen processing involves many proteolytic enzymes such as proteasomes and cathepsins. The processed antigen is then presented on the cell surface bound to either MHC class I or class II molecules and induces/interacts with antigen-specific CD8+ and CD4+ T-cells, respectively. Preliminary immunological data from the RV144 phase III trial indicated that the immune responses were biased towards the Env antigen with a dominant CD4+ T-cell response.

Methods

In this study, we examined the susceptibility of HIV-1 Env-A244 gp120 protein, one of the protein boost subunits of the RV144 Phase III vaccine trial, to proteasomes and cathepsins and identified the generated peptide epitope repertoire by mass spectrometry. The peptide fragments were tested for cytokine production in CD4⁺ T-cell lines derived from RV144 volunteers.

Results

Env-A244 was resistant to proteasomes, thus diminishing the possibility of the generation of class I epitopes by the classical MHC class I pathway. However, Env-A244 was efficiently cleaved by cathepsins generating peptide arrays identified by mass spectrometry that contained both MHC class I and class II epitopes as reported in the Los Alamos database. Each of the cathepsins generated distinct degradation patterns containing regions of light and dense epitope clusters. The sequence DKKQKVHALF that is part of the V2 loop of gp120 produced by cathepsins induced a polyfunctional cytokine response including the generation of IFN-γ from CD4⁺ T-cell lines-derived from RV144 vaccinees. This sequence is significant since antibodies to the V1/V2-loop region correlated inversely with HIV-1 infection in the RV144 trial.

Conclusions

Based on our results, the susceptibility of Env-A244 to cathepsins and not to proteasomes suggests a possible mechanism for the generation of Env-specific CD4⁺T cell and antibody responses in the RV144 vaccinees.     

Genetic Control of Immune Responses to HIV-1 env DNA Vaccine

We investigated the genetic control of immunoglobulin production and the delayed-type hypersensitivity (DTH) response produced by an HIV-specific DNA vaccine using several strains of mice. Murine antigen-specific immunoglobulin production was determined by ELISA. The DTH response was assessed in terms of the footpad swelling reaction. All strains of mice, except for B10.RIII and B10.T(6R), exhibited strong immunoglobulin production and footpad swelling in response to the DNA vaccine. In vitro treatment of lymphoid cells with monoclonal antibodies showed that the footpad swelling response was mediated by CD4⁺8^? and Ia— T cells. However, CD8⁺ T cells did not suppress footpad swelling. There was no difference in the induction of HIV-specific immunoglobulin production or DTH response induced by the DNA vaccine among the strains, suggesting that HIV-specific DNA vaccine is useful for immunizing various populations against HIV-1.     

Immune Response in Goats to Different Payloads of FMDV Monovalent Vaccine: Protection Against Virulent Challenge and Development of Carrier Status

The relationship of Foot-and-Mouth Disease virus antigen payload and number of dose of vaccine conferring protection against virus challenge in goats was studied. Goats vaccinated with oil adjuvant Foot-and-Mouth Disease vaccines containing different antigen payloads with or without booster resisted virulent challenge at 21 days post-vaccination or 7 days after booster respectively. However, localized sub-clinical infection was observed in two vaccinated goats on 35 days post-challenge. RNA could be detected from 31.8% of vaccinated goats (10^2.69–10^4.99 viral RNA copies per cotton swab of nasal secretions) on day 35 post-challenge. Since no live virus could be isolated after 5 days post-challenge, the risk of these animals transmitting the disease was probably very low. The finding showed that oil adjuvant Foot-and-Mouth Disease vaccines containing antigen payload of 1.88 μg may prevent or reduce the local virus replication at the oropharynx and shedding of virus from nasal secretions and thereby reduce the amount of virus released into the environment subsequent to exposure to live virus. This study also showed that goats with poor sero conversion to vaccination can be infected without overt clinical signs and became carriers like sheep.     

Early-Life Antibiotic-Driven Dysbiosis Leads to Dysregulated Vaccine Immune Responses in Mice

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