The evolution of resistance through costly acquired immunity

We examine the evolutionary dynamics of resistance to parasites through acquired immunity. Resistance can be achieved through the innate mechanisms of avoidance of infection and reduced pathogenicity once infected, through recovery from infection and through remaining immune to infection: acquired immunity. We assume that each of these mechanisms is costly to the host and find that the evolutionary dynamics of innate immunity in hosts that also have acquired immunity are quantitatively the same as in hosts that possess only innate immunity. However, compared with resistance through avoidance or recovery, there is less likely to be polymorphism in the length of acquired immunity within populations. Long-lived organisms that can recover at intermediate rates faced with fast-transmitting pathogens that cause intermediate pathogenicity (mortality of infected individuals) are most likely to evolve long-lived acquired immunity. Our work emphasizes that because whether or not acquired immunity is beneficial depends on the characteristics of the disease, organisms may be selected to only develop acquired immunity to some of the diseases that they encounter.     

The basic depression ratio of the host: the evolution of host resistance to microparasites

The basic reproduction ratio R0 occupies a central position in the theory of host pathogen interactions. However, this quantity stresses the role of the pathogen. This paper proposes an additional, more host-centred char acterization using the basic depression ratio D0. This quantity is the number of host individuals per infected by which the infected host population is depressed below its uninfected level. This paper shows that a baseline criterion for the evolution of host resistance to microparasites is that resistance evolves to minimize D0. This parallels the result for pathogen virulence where R0 is maximized. The tension between these two criteria is noted. The framework established allows a discussion of trade-offs between aspects of the pathogen-free host biology and the host pathogen interaction. For certain linear and convex trade-offs it is shown that the strain with the lowest transmission parameter beta wins (despite the fact that it has the lowest intrinsic birth rate a). For corresponding concave trade-offs, either the strain with minimum beta and a or the strain with maximum beta and a wins. Finally the connection with the techniques of adaptive dynamics is made. Evolutionary singular points are shown to occur at extrema of D0. The evolutionary attainment of the results is discussed.     

Characterization of RFLP probe sequences for gene discovery and SSR development in Sorghum bicolor (L.) Moench

In this study, we collected and analyzed DNA sequence data for 789 previously mapped RFLP probes from Sorghum bicolor (L.) Moench. DNA sequences, comprising 894 non-redundant contigs and end sequences, were searched against three GenBank databases, nucleotide (nt), protein (nr) and EST (dbEST), using BLAST algorithms. Matching ESTs were also searched against nt and nr. Translated DNA sequences were then searched against the conserved domain database (CDD) to determine if functional domains/motifs were congruent with the proteins identified in previous searches. More than half (500/894 or 56%) of the query sequences had significant matches in at least one of the GenBank searches. Overall, proteins identified for 148 sequences (17%) were consistent among all searches, of which 66 sequences (7%) contained congruent coding domains. The RFLP probe sequences were also evaluated for the presence of simple sequence repeats (SSRs) and 60 SSRs were developed and assayed in an array of sorghum germplasm comprising inbreds, landraces and wild relatives. Overall, these SSR loci had lower levels of polymorphism ( D = 0.46, averaged over 51 polymorphic loci) compared with sorghum SSRs that were isolated by library hybridization screens ( D = 0.69, averaged over 38 polymorphic loci). This result was probably due to the relatively small proportion of di-nucleotide repeat-containing markers (42% of the total SSR loci) obtained from the DNA sequence data. These di-nucleotide markers also contained shorter repeat motifs than those isolated from genomic libraries. Based on BLAST results, 24 SSRs (40%) were located within, or near, previously annotated or hypothetical genes. We determined the location of 19 of these SSRs relative to putative coding regions. In general, SSRs located in coding regions were less polymorphic ( D = 0.07, averaged over three loci) than those from gene flanking regions, UTRs and introns ( D = 0.49, averaged over 16 loci). The sequence information and SSR loci generated through this study will be valuable for application to sorghum genetics and improvement, including gene discovery, marker-assisted selection, diversity and pedigree analyses, comparative mapping and evolutionary genetic studies.     

Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy

In myotonic dystrophy (dystrophia myotonica, DM), expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (myotonia) in skeletal muscle. Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause myotonia. The expanded CUG repeats trigger aberrant splicing of pre-mRNA for ClC-1, the main chloride channel in muscle, resulting in loss of ClC-1 protein from the surface membrane. We also have identified a similar defect in ClC-1 splicing and expression in two types of human DM. We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.     

Synthesis and Characterization of N,N-Dichlorinated Amino Acids: Taurine,Homotaurine, GABA and L-Leucine

Epilepsy, trauma and other circumstances leading to hyperexcitable conditions in the CNS tend neurochemically to be associated with excessive stimulated release of glutamic acid and/or a failure of GABA modulated inhibition. Somewhat to a lesser extent, taurine and its homologue homotaurine, have also been shown to antagonize the excitatory actions of glutamic acid. Here we report the successful synthesis and isolation in pure form of N,N-dichlorinated GABA, taurine, homotaurine and leucine. These compounds are much more lipophilic than their parent compounds and may therefore more readily penetrate the blood-brain barrier systems into the neural tissue, where they can be easily dechlorinated. Very preliminary biological testing shows that this may indeed occur. The synthesis and purification methodology will likely also be applicable to a number of other amino acids as well as certain peptides or selected proteins.     

Synergy of L-arginine and growth hormone (GH)-releasing peptide-2 on GH release: influence of gender

We test the hypotheses that 1) growth hormone (GH)-releasing peptide-2 (G) synergizes with L-arginine (A), a compound putatively achieving selective somatostatin withdrawal and 2) gender modulates this synergy on GH secretion. To these ends, 18 young healthy volunteers (9 men and 9 early follicular phase women) each received separate morning intravenous infusions of saline (S) or A (30 g over 30 min) or G (1 microg/kg) or both, in randomly assigned order. Blood was sampled at 10-min intervals for later chemiluminescence assay of serum GH concentrations. Analysis of covariance revealed that the preinjection (basal) serum GH concentrations significantly determined secretagogue responsiveness and that sex (P = 0.02) and stimulus type (P < 0.001) determined the slope of this relationship. Nested ANOVA applied to log-transformed measures of GH release showed that gender determines 1) basal rates of GH secretion, 2) the magnitude of the GH secretory response to A, 3) the rapidity of attaining the GH maximum, and 4) the magnitude or fold (but not absolute) elevation in GH secretion above preinjection basal, as driven by the combination of A and G. In contrast, the emergence of the G and A synergy is sex independent. We conclude that gender modulates key facets of basal and A/G-stimulated GH secretion in young adults.     

An Arsenic Exposure Model: Probabilistic Validation Using Empirical Data

This paper describes development of a multi-pathway arsenic exposure model. The model uses information on arsenic concentrations in food, water, soil, and dust, combined with estimates of intake and medium-specific absorption. Urinary arsenic is predicted assuming that 60% of absorbed arsenic is excreted in urine under steady state conditions. Fecal arsenic is predicted assuming all unabsorbed arsenic is excreted in feces. We applied this model at a former copper smelter site. Site specific distributions were available for the following parameters: soil and dust arsenic concentration (geometric mean approximately 100 to 200?ppm and 50 to 100?ppm, respectively); the combined childhood soil and dust ingestion rate (geometric mean of 20?mg/d); soil and dust arsenic relative bioavailability (geometric mean 0.20 and 0.28, respectively); exposure duration; water arsenic concentration; air arsenic concentration; and total arsenic in food. Monte Carlo simulation was used to predict daily arsenic uptake and excretion in urine and feces for children. Predicted urine arsenic levels were less than measured levels (73% to 88% of measured values, depending on region of site). On the other hand, predicted fecal arsenic levels exceeded measured levels by a factor of 1.7 to 4.6. We were able to improve the correspondence between predicted and measured arsenic excretion rates by decreasing the assumed value of the combined soil and dust ingestion rate, and increasing the assumed bioavailability of arsenic in soil and dust.     

A web server to locate periodicities in a sequence

Summary : FT is a tool written in C++, which implements the Fourier analysis method to locate periodicities in aminoacid or DNA sequences. It is provided for free public use on a WWW server with a Java interface. Availability : The server address is http://o2.db. uoa.gr/FT Contact : shamodr@atlas.uoa.gr      

Impaired TNF-α control of IP3R-mediated Ca2+ release in Alzheimer's disease mouse neurons

The misguided control of inflammatory signaling has been previously implicated in the pathogenesis of several neurological disorders, including Alzheimer's disease (AD). Induction of tumor necrosis factor-alpha (TNF-α), a central mediator of neuroinflammation, occurs commensurate with the onset of early disease in 3xTg-AD mice, which develop both amyloid plaque and neurofibrillary tangle pathologies in an age- and region-dependent pattern. Herein, we describe regulation inherent to 3xTg-AD neurons, which results in the loss of TNF-α mediated enhancement of inositol 1,4,5 trisphosphate (IP₃R)-mediated Ca²⁺ release. This modulation also leads to significant down-regulation of IP₃R signaling following protracted cytokine exposure. Through the experimental isolation of each AD-related transgene, it was determined that expression of the PS1^M146V transgene product is responsible for the loss of the TNF-α effect on IP₃R-mediated Ca²⁺ release. Furthermore, it was determined that the suppression of TNF-α receptor expression occurred in the presence of the presenilin transgene. Our findings attribute this familial AD mutation to suppressing a Ca²⁺-regulated signal cascade potentially intended to “inform” neurons of proximal neuroinflammatory events and trigger compensatory responses for protection of neural transmission.