Rapid selective sweep of pre-existing polymorphisms and slow fixation of new mutations in experimental evolution of Desulfovibrio vulgaris

To investigate the genetic basis of microbial evolutionary adaptation to salt (NaCl) stress, populations of Desulfovibrio vulgaris Hildenborough (DvH), a sulfate-reducing bacterium important for the biogeochemical cycling of sulfur, carbon and nitrogen, and potentially the bioremediation of toxic heavy metals and radionuclides, were propagated under salt stress or non-stress conditions for 1200 generations. Whole-genome sequencing revealed 11 mutations in salt stress-evolved clone ES9-11 and 14 mutations in non-stress-evolved clone EC3-10. Whole-population sequencing data suggested the rapid selective sweep of the pre-existing polymorphisms under salt stress within the first 100 generations and the slow fixation of new mutations. Population genotyping data demonstrated that the rapid selective sweep of pre-existing polymorphisms was common in salt stress-evolved populations. In contrast, the selection of pre-existing polymorphisms was largely random in EC populations. Consistently, at 100 generations, stress-evolved population ES9 showed improved salt tolerance, namely increased growth rate (2.0-fold), higher biomass yield (1.8-fold) and shorter lag phase (0.7-fold) under higher salinity conditions. The beneficial nature of several mutations was confirmed by site-directed mutagenesis. All four tested mutations contributed to the shortened lag phases under higher salinity condition. In particular, compared with the salt tolerance improvement in ES9-11, a mutation in a histidine kinase protein gene lytS contributed 27% of the growth rate increase and 23% of the biomass yield increase while a mutation in hypothetical gene DVU2472 contributed 24% of the biomass yield increase. Our results suggested that a few beneficial mutations could lead to dramatic improvements in salt tolerance.     

What Biomonitoring Can and Cannot Tell Us about Causality in Human Health and Ecological Risk Assessments

Biomonitoring can provide exposure and effects information on various stressors (chemical or biological) that can be useful for human health and ecological risk assessments. It has been applied over the years where harmful changes in human health or the environment were observed and which may have warranted more detailed investigation. Sometimes biomonitoring programs may have been useful in determining the significance and/or cause of these harmful observations. These data can help to infer, but not confirm, causality as exemplified in classical studies conducted in humans and wildlife. However, in most cases we note that additional work was needed to provide the information necessary to support or refute causality. Today modern technology provides the ability to measure a wide variety of parameters in environmental media, plants, animals, and humans. Finding a chemical in an environmental medium or biological tissue may be helpful in understanding potential exposure (and perhaps to begin estimating hazard) to humans and ecological receptors, but mere presence does not necessarily help to establish effects or assign causality. In this article we evaluate the strengths and weaknesses, in a risk assessment context, of the use of biomonitoring data to support a determination of causality.     

Fibrillin-2 is dispensable for peripheral nerve development,myelination and regeneration

The extracellular matrix of peripheral nerve is formed from a diverse set of macromolecules, including glycoproteins, collagens and proteoglycans. Recent studies using knockout animal models have demonstrated that individual components of the extracellular matrix play a vital role in peripheral nerve development and regeneration. In this study we identified fibrillin-1 and fibrillin-2, large modular structural glycoproteins, as components of the extracellular matrix of peripheral nerve. Previously it was found that fibrillin-2 null mice display joint contractures, suggesting a possible defect of the peripheral nervous system in these animals. Close examination of the peripheral nerves of fibrillin-2 deficient animals described here revealed some structural abnormalities in the perineurium, while general structure of the nerve and molecular composition of nerve extracellular matrix remained unchanged. We also found that in spite of the obvious motor function impairment, fibrillin-2 null mice failed to display changes of nerve conduction properties or nerve regeneration capacity. Based on the data obtained we can conclude that peripheral neuropathy should be excluded as the cause of the impairment of locomotory function and joint contractures observed in fibrillin-2 deficient animals.     

Analysis of humoral immune responses in rhesus macaques vaccinated with attenuated SIVmac239Δnef and challenged with pathogenic SIVmac251

Background To determine the correlation between protection and humoral immune response against simian immunodeficiency virus (SIVmac251), 11 macaques were immunized with live‐attenuated SIVmac239Δnef either intravenously or via the tonsils and exposed to SIVmac251 after either 6 or 15 months along with unvaccinated controls. Results Independent of the route of vaccine application, viremia was significantly reduced in vaccinees compared with controls 2 weeks post‐challenge. Concomitantly, viremia correlated inversely with SIV‐specific IgG, complement‐mediated lysis and neutralizing antibodies and these parameters seemed to contribute to reduced viremia. During chronic infection, six monkeys controlled viremia in the circulation (two or fewer infectious units per 10⁶ PBMCs) and showed no signs of trapping in lymphatic tissues (Appendix S1). Conclusions As no significant differences were observed throughout the study, with respect to the humoral immune response and viremia control, between the two vaccinated cohorts, mucosal immunization strategies are recommended due to more simplified application.     

Microbial translocation in simian immunodeficiency virus (SIV)‐infected rhesus monkeys (Macaca mulatta)

Background Chronic immune activation is a hallmark of HIV infection and has been postulated as major factor in the pathogenesis of AIDS. Recent evidence suggests that activation of immune cells is triggered by microbial translocation through the impaired gastrointestinal barrier. Methods To determine the association between microbial translocation and disease progression, we have retrospectively analyzed microbial products, viral load and markers of immune activation in a cohort of 37 simian immunodeficiency virus‐infected rhesus monkeys, divided in two groups with distinct disease courses. Results As seen in HIV‐infected patients, we found elevated levels of lipopolysaccharide (LPS) in infected animals. However, LPS levels or LPS control mechanisms like endotoxin core antibodies or LPS‐binding protein did not differ between groups with different disease progression. In contrast, neopterin, a metabolic product of activated macrophages, was higher in fast progressors than in slow progressors. Conclusion Our data indicate that translocation of microbial products is not the major driving force of immune activation in HIV infection.     

1,4-Naphthoquinones as inducers of oxidative damage and stress signaling in HaCaT human keratinocytes

Selected biological effects of 1,4-naphthoquinone, menadione (2-methyl-1,4-naphthoquinone) and structurally related quinones from natural sources - the 5-hydroxy-naphthoquinones juglone, plumbagin and the 2-hydroxy-naphthoquinones lawsone and lapachol - were studied in human keratinocytes (HaCaT). 1,4-naphthoquinone and menadione as well as juglone and plumbagin were highly cytotoxic, strongly induced reactive oxygen species (ROS) formation and depleted cellular glutathione. Moreover, they induced oxidative DNA base damage and accumulation of DNA strand breaks, as demonstrated in an alkaline DNA unwinding assay. Neither lawsone nor lapachol (up to 100 μM) were active in any of these assays. Cytotoxic and oxidative action was paralleled by stimulation of stress signaling: all tested quinones except lawsone and lapachol strongly induced phosphorylation of the epidermal growth factor receptor (EGFR) and the related ErbB2 receptor tyrosine kinase. EGFR activation by plumbagin, juglone and menadione was attenuated by a superoxide dismutase mimetic, indicating that ROS-related mechanisms contribute to EGFR activation by these naphthoquinones.     

Redundant role of DEAD box proteins p68 (Ddx5) and p72/p82 (Ddx17) in ribosome biogenesis and cell proliferation

The DEAD box proteins encoded by the genes ddx5 (p68) and ddx17 (isoforms p72 and p82) are more closely related to each other than to any other member of their family. We found that p68 negatively controls p72/p82 gene expression but not vice versa. Knocking down of either gene does not affect cell proliferation, in case of p68 suppression, however, only on condition that p72/p82 overexpression was granted. In contrast, co-silencing of both genes causes perturbation of nucleolar structure and cell death. In mutant studies, the apparently redundant role(s) of p68 and p72/p82 correspond to their ability to catalyze RNA rearrangement rather than RNA unwinding reactions. In search for possible physiological targets of this RNA rearrangement activity it is shown that the nucleolytic cleavage of 32S pre-rRNA is reduced after p68 subfamily knock-down, most probably due to a failure in the structural rearrangement process within the pre-60S ribosomal subunit preceding the processing of 32S pre-rRNA.     

Carotenoids and Flavonoids Contribute to Nutritional Protection against Skin Damage from Sunlight

The concept of photoprotection by dietary means is gaining momentum. Plant constituents such as carotenoids and flavonoids are involved in protection against excess light in plants and contribute to the prevention of UV damage in humans. As micronutrients, they are ingested with the diet and are distributed into light-exposed tissues, such as skin or the eye where they provide systemic photoprotection. β-Carotene and lycopene prevent UV-induced erythema formation. Likewise, dietary flavanols exhibit photoprotection. After about 10–12 weeks of dietary intervention, a decrease in the sensitivity toward UV-induced erythema was observed in volunteers. Dietary micronutrients may contribute to life-long protection against harmful UV radiation.     

Zahnanomalien in der Neuropädiatrie

Dental anomalies in children with neuropediatric disorders are easy to diagnose and can be essential in the diagnosis of different entities. They are present in well-known disorders as Incontinentia pigmenti, but also in rare diseases as in Kohlschütter-Tönz syndrome or the recently described ataxia, delayed dentition and hypomyelination. Anomalies of dental shape, enamel and in this case also teeth color, dental number and eruption are all encountered. Knowledge of these abnormalities is important for both clinical geneticist and child neurologist.