Reconstructing the history of helminth prevalence in the UK

Intestinal helminth parasites (worms) have afflicted humans throughout history and their eggs are readily detected in archaeological deposits including at locations where intestinal parasites are no longer considered endemic (e.g. the UK). Parasites provide valuable archaeological insights into historical health, sanitation, hygiene, dietary and culinary practices, as well as other factors. Differences in the prevalence of helminths over time may help us understand factors that affected the rate of infection of these parasites in past populations. While communal deposits often contain relatively high numbers of parasite eggs, these cannot be used to calculate prevalence rates, which are a key epidemiological measure of infection. The prevalence of intestinal helminths was investigated through time in England, based on analysis of 464 human burials from 17 sites, dating from the Prehistoric to Industrial periods. Eggs from two faecal-oral transmitted nematodes (Ascaris sp. and Trichuris sp.) and the food-derived cestodes (Taenia spp. and Diphyllobothrium latum syn Dibothriocephalus latus) were identified, although only Ascaris was detected at a high frequency. The changing prevalence of nematode infections can be attributed to changes in effective sanitation or other factors that affect these faecal-oral transmitted parasites and the presence of cestode infections reflect dietary and culinary preferences. These results indicate that the impact of helminth infections on past populations varied over time, and that some locations witnessed a dramatic reduction in parasite prevalence during the industrial era (18^th-19^th century), whereas other locations continued to experience high prevalence levels. The factors underlying these reductions and the variation in prevalence provide a key historical context for modern anthelmintic programs.     

Viral protein instability enhances host-range evolvability

Viruses are highly evolvable, but what traits endow this property? The high mutation rates of viruses certainly play a role, but factors that act above the genetic code, like protein thermostability, are also expected to contribute. We studied how the thermostability of a model virus, bacteriophage λ, affects its ability to evolve to use a new receptor, a key evolutionary transition that can cause host-range evolution. Using directed evolution and synthetic biology techniques we generated a library of host-recognition protein variants with altered stabilities and then tested their capacity to evolve to use a new receptor. Variants fell within three stability classes: stable, unstable, and catastrophically unstable. The most evolvable were the two unstable variants, whereas seven of eight stable variants were significantly less evolvable, and the two catastrophically unstable variants could not grow. The slowly evolving stable variants were delayed because they required an additional destabilizing mutation. These results are particularly noteworthy because they contradict a widely supported contention that thermostabilizing mutations enhance evolvability of proteins by increasing mutational robustness. Our work suggests that the relationship between thermostability and evolvability is more complex than previously thought, provides evidence for a new molecular model of host-range expansion evolution, and identifies instability as a potential predictor of viral host-range evolution.     

Focus: The Science of Stress: The Impact of Maternal Antioxidants on Prenatal Stress Effects on Offspring Neurobiology and Behavior

Prenatal stress is a neuropsychiatric risk factor, and effects may be mediated by prenatal oxidative stress. Cell types in the brain sensitive to oxidative stress—cortical microglia and cortical and hippocampal interneurons—may be altered by oxidative stress generated during prenatal stress and may be neurobiological substrates for altered behavior. Our objective was to determine the critical nature of oxidative stress in prenatal stress effects by manipulating prenatal antioxidants. CD1 mouse dams underwent restraint embryonic day 12 to 18 three times daily or no stress and received intraperitoneal injections before each stress period of vehicle, N-acetylcysteine (200 mg/kg daily), or astaxanthin (30 mg/kg before first daily stress, 10 mg/kg before second/third stresses). Adult male and female offspring behavior, microglia, and interneurons were assessed. Results supported the hypothesis that prenatal stress-induced oxidative stress affects microglia; microglia ramification increased after prenatal stress, and both antioxidants prevented these effects. In addition, N-acetylcysteine or astaxanthin was effective in preventing distinct male and female interneuron changes; decreased female medial frontal cortical parvalbumin interneurons was prevented by either antioxidant; increased male medial frontal cortical parvalbumin interneurons was prevented by N-acetylcysteine and decreased male hippocampal GAD67GFP+ cells prevented by astaxanthin. Prenatal stress-induced increased anxiety-like behavior and decreased sociability were not prevented by prenatal antioxidants. Sensorimotor gating deficits in males was partially prevented by prenatal astaxanthin. This study demonstrates the importance of oxidative stress for persistent impacts on offspring cortical microglia and interneurons, but did not link these changes with anxiety-like, social, and sensorimotor gating behaviors.     

Null RPGRIP1 alleles in patients with Leber congenital amaurosis

We isolated and characterized the entire coding sequence of a human gene encoding a protein that interacts with RPGR, a protein that is absent or mutant in many cases of X-linked retinitis pigmentosa. The newly identified gene, called "RPGRIP1" for RPGR-interacting protein (MIM 605446), is located within 14q11, and it encodes a protein predicted to contain 1,259 amino acids. Previously published work showed that both proteins, RPGR and RPGRIP1, are present in the ciliary structure that connects the inner and outer segments of rod and cone photoreceptors. We surveyed 57 unrelated patients who had Leber congenital amaurosis for mutations in RPGRIP1 and found recessive mutations involving both RPGRIP1 alleles in 3 (6%) patients. The mutations all create premature termination codons and are likely to be null alleles. Patients with RPGRIP1 mutations have a degeneration of both rod and cone photoreceptors, and, early in life, they experience a severe loss of central acuity, which leads to nystagmus.     

Sphingosine-1-phosphate plays a role in the suppression of lateral pseudopod formation during Dictyostelium discoideum cell migration and chemotaxis

Sphingosine-1-phosphate (S-1-P) is a bioactive lipid that plays a role in diverse biological processes. It functions both as an extracellular ligand through a family of high-affinity G-protein-coupled receptors, and intracellularly as a second messenger. A growing body of evidence has implicated S-1-P in controlling cell movement and chemotaxis in cultured mammalian cells. Mutant D. discoideum cells, in which the gene encoding the S-1-P lyase had been specifically disrupted by homologous recombination, previously were shown to be defective in pseudopod formation, suggesting that a resulting defect might exist in motility and/or chemotaxis. To test this prediction, we analyzed the behavior of mutant cells in buffer, and in both spatial and temporal gradients of the chemoattractant cAMP, using computer-assisted 2-D and 3-D motion analysis systems. Under all conditions, S-1-P lyase null mutants were unable to suppress lateral pseudopod formation like wild-type control cells. This resulted in a reduction in velocity in buffer and spatial gradients of cAMP. Mutant cells exhibited positive chemotaxis in spatial gradients of cAMP, but did so with lowered efficiency, again because of their inability to suppress lateral pseudopod formation. Mutant cells responded normally to simulated temporal waves of cAMP but mimicked the temporal dynamics of natural chemotactic waves. The effect must be intracellular since no homologs of the S-1-P receptors have been identified in the Dictyostelium genome. The defects in the S-1-P lyase null mutants were similar to those seen in mutants lacking the genes for myosin IA, myosin IB, and clathrin, indicating that S-1-P signaling may play a role in modulating the activity or organization of these cytoskeletal elements in the regulation of lateral pseudopod formation.