Modelling HIV immune response and validation with clinical data

A system of ordinary differential equations is formulated to describe the pathogenesis of HIV infection, wherein certain features that have been shown to be important by recent experimental research are incorporated in the model. These include the role of CD4+memory cells that serve as a major reservoir of latently infected cells, a critical role for T-helper cells in the generation of CD8 memory cells capable of efficient recall response, and stimulation by antigens other than HIV. A stability analysis illustrates the capability of this model in admitting multiple locally asymptotically stable (locally a.s.) off-treatment equilibria. We show that this more biologically detailed model can exhibit the phenomenon of transient viremia experienced by some patients on therapy with viral load levels suppressed below the detection limit. We also show that the loss of CD4+T-cell help in the generation of CD8+memory cells leads to larger peak values for the viral load during transient viremia. Censored clinical data is used to obtain parameter estimates. We demonstrate that using a reduced set of 16 free parameters, obtained by fixing some parameters at their population averages, the model provides reasonable fits to the patient data and, moreover, that it exhibits good predictive capability. We further show that parameter values obtained for most clinical patients do not admit multiple locally a.s off-treatment equilibria. This suggests that treatment to move from a high viral load equilibrium state to an equilibrium state with a lower (or zero) viral load is not possible for these patients.     

Pre-exposure affects the olfactory response of Drosophila melanogaster to menthol

A modification of the trap assay (Woodard et al., 1989) was used to evaluate the response of Drosophila melanogaster (Meigen) to food media containing menthol. Dose-response curves for flies to mentholic foods were produced for flies that had been pre-exposed to menthol, during development and adult life, and flies that had not been exposed to menthol before the assay. Mentholic food media were less attractive to Drosophila than plain food medium. Rearing flies on a medium containing menthol reduced their aversion to some concentrations of menthol. The rearing effect was not simply due to lowered general activity levels resulting from developing in a medium containing menthol. There was a threshold concentration of menthol in the rearing medium below which we found no induced behavioural change.     

Reaction of small heat-shock proteins to different kinds of cellular stress in cultured rat hippocampal neurons

Upregulation of small heat-shock proteins (sHsps) in response to cellular stress is one mechanism to increase cell viability. We previously described that cultured rat hippocampal neurons express five of the 11 family members but only upregulate two of them (HspB1 and HspB5) at the protein level after heat stress. Since neurons have to cope with many other pathological conditions, we investigated in this study the expression of all five expressed sHsps on mRNA and protein level after sublethal sodium arsenite and oxidative and hyperosmotic stress. Under all three conditions, HspB1, HspB5, HspB6, and HspB8 but not HspB11 were consistently upregulated but showed differences in the time course of upregulation. The increase of sHsps always occurred earlier on mRNA level compared with protein levels. We conclude from our data that these four upregulated sHsps (HspB1, HspB5, HspB6, HspB8) act together in different proportions in the protection of neurons from various stress conditions.     

Adaptive developmental plasticity: what is it,how can we recognize it and when can it evolve?

Developmental plasticity describes situations where a specific input during an individual''s development produces a lasting alteration in phenotype. Some instances of developmental plasticity may be adaptive, meaning that the tendency to produce the phenotype conditional on having experienced the developmental input has been under positive selection. We discuss the necessary assumptions and predictions of hypotheses concerning adaptive developmental plasticity (ADP) and develop guidelines for how to test empirically whether a particular example is adaptive. Central to our analysis is the distinction between two kinds of ADP: informational, where the developmental input provides information about the future environment, and somatic state-based, where the developmental input enduringly alters some aspect of the individual''s somatic state. Both types are likely to exist in nature, but evolve under different conditions. In all cases of ADP, the expected fitness of individuals who experience the input and develop the phenotype should be higher than that of those who experience the input and do not develop the phenotype, while the expected fitness of those who do not experience the input and do not develop the phenotype should be higher than those who do not experience the input and do develop the phenotype. We describe ancillary predictions that are specific to just one of the two types of ADP and thus distinguish between them.     

A recombinant foot-and-mouth disease virus antigen inhibits DNA replication and triggers the SOS response in Escherichia coli

Abstract The 3D gene of foot-and-mouth disease virus encodes the viral RNA dependent RNA polymerase, also called virus infection associated (VIA) antigen, which is the most important serological marker of virus infection. This 3D gene from a serotype Cl virus has been cloned and overexpressed in Escherichia coli under the control of the strong lambda lytic promoters. The resulting 51 kDa recombinant protein has been shown to be immunoreactive with sera from infected animals. After induction of gene expression, an immediate and dramatic arrest of cell DNA synthesis occurs, similar to that produced by genotoxic doses of the drug mitomycin C. This effect does not occur during the production of either a truncated VIA antigen or other related and non-related viral proteins. The inhibition of DNA replication results in a subsequent induction of the host SOS DNA-repair response and in an increase of the mutation frequency in the surviving cells.     

Molecular basis of the Keap1–Nrf2 system

Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes, and Keap1 (Kelch-like ECH-associated protein 1), an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, regulates Nrf2 activity. Keap1 also acts as a sensor for oxidative and electrophilic stresses. Keap1 retains multiple sensor cysteine residues that detect various stress stimuli. Increasing attention has been paid to the roles that Nrf2 plays in the protection of our bodies against drug toxicity and stress-induced diseases. On the other hand, Nrf2 is found to promote both oncogenesis and cancer cell resistance against chemotherapeutic drugs. Thus, although Nrf2 acts to protect our body from deleterious stresses, cancer cells hijack the Nrf2 activity to support their malignant growth. Nrf2 has emerged as a new therapeutic target, and both inducers and inhibitors of Nrf2 are awaited. Studies challenging the molecular basis of the Keap1–Nrf2 system functions are now critically important to improve translational studies of the system. Indeed, recent studies identified cross talk between Nrf2 and other signaling pathways, which provides new insights into the mechanisms by which the Keap1–Nrf2 system serves as a potent regulator of our health and disease.     

Upregulation of miR-183 represses neuropathic pain through inhibiton of MAP3K4 in CCI rat models

Many studies have verified that microRNAs contribute a lot to neuropathic pain progression. Furthermore, nerve-related inflammatory cytokines play vital roles in neuropathic pain progression. miR-183 has been identified to have a common relationship with multiple pathological diseases. However, the potential effects of miR-183 in the process of neuropathic pain remain undetermined. Therefore, we performed the current study with the purpose of finding the functions of miR-183 in neuropathic pain progression using a chronic sciatic nerve injury (CCI) rat model. We demonstrated that miR-183 expression levels were evidently reduced in CCI rats in contrast with the control group. Overexpression of miR-183 produced significant relief of mechanical hyperalgesia, as well as thermal hyperalgesia in CCI rats. Furthermore, neuropathic pain-correlated inflammatory cytokine expression levels containing interleukin-6 (IL-6) and interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2) were obviously inhibited by upregulation of miR-183. Meanwhile, dual-luciferase reporter assays showed MAP3K4 was a direct downstream gene of miR-183. The expression levels of MAP3K4 were modulated by the increased miR-183 negatively, which lead to the downregulation of IL-6, IL-1β, and COX-2, and then reduced neuropathic pain progression, respectively. Overall, our study pointed out that miR-183 was a part of the negative regulator which could relieve neuropathic pain by targeting MAP3K4. Thus it may provide a new clinical treatment for neuropathic pain patients clinical therapy.     

Satiation and the functional response: a test of a new model

Abstract. 1. A model of the functional response to prey density is derived to include the reduction in time available for search, T_s , resulting from predator satiation.
2. For larger prey items predator satiation occurs at each prey capture and T_s is reduced by the attack time and digestive pause of a series of attack cycles. For small prey items predator foraging is continuous at low densities with T_s reduced solely by attack time. At higher densities predator satiation occurs after the capture of several small prey items and T_s is reduced by the attack time and digestive pause of a series of foraging cycles.
3. A comparison of the predicted asymptotic level of prey capture using experimentally estimated parameter values, with the maximum consumption of aphids by larval and adult coccinellids provides a test of the satiation model.
4. The limitation of prey capture by predator satiation is discussed with reference to handling time and the success of coccinellids in biological control.