Phylodynamics of Infectious Disease Epidemics

We present a formalism for unifying the inference of population size from genetic sequences and mathematical models of infectious disease in populations. Virus phylogenies have been used in many recent studies to infer properties of epidemics. These approaches rely on coalescent models that may not be appropriate for infectious diseases. We account for phylogenetic patterns of viruses in susceptible–infected (SI), susceptible–infected–susceptible (SIS), and susceptible–infected–recovered (SIR) models of infectious disease, and our approach may be a viable alternative to demographic models used to reconstruct epidemic dynamics. The method allows epidemiological parameters, such as the reproductive number, to be estimated directly from viral sequence data. We also describe patterns of phylogenetic clustering that are often construed as arising from a short chain of transmissions. Our model reproduces the moments of the distribution of phylogenetic cluster sizes and may therefore serve as a null hypothesis for cluster sizes under simple epidemiological models. We examine a small cross-sectional sample of human immunodeficiency (HIV)-1 sequences collected in the United States and compare our results to standard estimates of effective population size. Estimated prevalence is consistent with estimates of effective population size and the known history of the HIV epidemic. While our model accurately estimates prevalence during exponential growth, we find that periods of decline are harder to identify.COALESCENT theory has found wide applications for inference of viral phylogenies (Nee et al. 1996; Rosenberg and Nordborg 2002; Drummond et al. 2005) and estimation of epidemic prevalence (Yusim et al. 2001; Robbins et al. 2003; Wilson et al. 2005), yet there have been few attempts to formally integrate coalescent theory with standard epidemiological models (Pybus et al. 2001; Goodreau 2006). While epidemiological models such as susceptible–infected–recovered (SIR) consider the dynamics of an entire population going forward in time, the coalescent theory operates on a small sample of an infected subpopulation and models the merging of lineages backward in time until a common ancestor has been reached. The original coalescent theory was based on a population of constant size with discrete generations (Kingman 1982a,b). Numerous extensions have been made for populations with overlapping generations in continuous time, exponential or logistic growth (Griffiths and Tavare 1994), and stochastically varying size (Kaj and Krone 2003). However, infectious disease epidemics are a special case of a variable size population, often characterized by early explosive growth followed by decline that leads to extinction or an endemic steady state.If superinfection is rare and if mutation is fast relative to epidemic growth, each lineage in a phylogenetic tree corresponds to a single infected individual with its own unique viral population. An infection event viewed in reverse time is equivalent to the coalescence of two lineages and every transmission of the virus between hosts can generate a new branch in the phylogeny of consensus viral isolates from infected individuals. Recently diverged sequences should represent transmissions in the recent past, and branches close to the root of a tree should represent transmissions from long ago. Consequently, branching patterns provide information about the frequency of transmissions over time (Wilson et al. 2005). The correspondence between transmission and phylogenetic branching is easiest to detect for viruses such as human immunodeficiency virus (HIV) and hepatitis C virus that have a high mutation rate relative to dispersal. Underlying SIR dynamics also apply to other pathogens, although in some cases it may be more difficult to reconstruct the transmission history.We examined the properties of viral phylogenies generated by the most common epidemiological models based on ordinary differential equations (ODEs). We are able to fit epidemiological models to a reconstructed phylogeny for sampled viral sequence data and make inferences regarding the size of the corresponding infected population. Our solution takes the form of an ODE analogous to those used to track epidemic prevalence and thereby provides a convenient link between commonly used epidemiological models and phylodynamics. Virtually all coalescent theory to date has been expressed in terms of integer-valued stochastic processes. Our motivation for using differential equations to describe the coalescent process is a desire to formalize a link with standard epidemiological models that are also expressed in terms of differential equations.We use our method to calculate the distribution of coalescent times for samples of viral sequences, fit SIR models to a viral phylogeny, and calculate median time to the most recent common ancestor (MRCA) of the sample. Our method also provides equations that describe the time evolution of the cluster size distribution (CSD)—the distribution of the number of descendants of a lineage over time. Clusters of related virus are often interpreted as epidemiologically linked. For example, clusters of acute HIV infections may represent short transmission chains between high-risk individuals (Yerly et al. 2001; Hue et al. 2005; Pao et al. 2005; Goodreau 2006; Brenner et al. 2007; Drumright and Frost 2008; Lewis et al. 2008). Because our model reproduces the moments of the cluster size distribution, it can be used to predict the level of clustering as a function of epidemiological conditions. The moments could be directly compared to empirical values or they could be used to reconstruct the entire CSD, whereupon standard statistical tests could be used for comparing distributions.Although our equations describe the macroscopic properties of the population distribution of cluster sizes, we generalize our method to the case of a small cross-sectional sample of sequences. This allows us to develop a likelihood-based approach to fitting SIR models to observed sequences.By considering variable degrees of incidence and the size of the infected population, our solution sheds light on the relationship between coalescent rates and epidemic dynamics. Coalescent rates are low near peak prevalence, but higher when there is a large ratio of incidence to prevalence. This can occur early on, when the epidemic is entering its expansion phase, as well as late if the epidemic has multiple periods of growth.     

Leben und Überleben im Boden

Myxobacteria - survivalists in soil Myxobacteria like Myxococccus xanthus are soil-living microorganisms featuring a complex lifestyle, including movement by coordinated swarming on surfaces, predatory feeding on other microorganisms, and the formation of multicellular fruiting bodies when unfavorable environmental conditions are encountered. Bioinformatic analysis of the large myxobacterial genomes has enabled fascinating insights into the molecular basis for the biosynthesis of complex secondary metabolite structures by myxobacteria, and has set the stage for the discovery of novel natural products. Moreover, well-characterized myxobacteria like M. xanthus increasingly play a role as “biochemical factories” for the biotechnological production of bioactive molecules using synthetic biology approaches.     

The oxidative and nitrosative stress defence network of Wolinella succinogenes: cytochrome c nitrite reductase mediates the stress response to nitrite, nitric oxide, hydroxylamine and hydrogen peroxide

Microorganisms employ diverse mechanisms to withstand physiological stress conditions exerted by reactive or toxic oxygen and nitrogen species such as hydrogen peroxide, organic hydroperoxides, superoxide anions, nitrite, hydroxylamine, nitric oxide or NO-generating compounds. This study identified components of the oxidative and nitrosative stress defence network of Wolinella succinogenes, an exceptional Epsilonproteobacterium that lacks both catalase and haemoglobins. Various gene deletion-insertion mutants were constructed, grown by either fumarate respiration or respiratory nitrate ammonification and subjected to disc diffusion, growth and viability assays under stress conditions. It was demonstrated that mainly two periplasmic multihaem c-type cytochromes, namely cytochrome c peroxidase and cytochrome c nitrite reductase (NrfA), mediated resistance to hydrogen peroxide. Two AhpC-type peroxiredoxin isoenzymes were shown to be involved in protection against different organic hydroperoxides. The phenotypes of two superoxide dismutase mutants lacking either SodB or SodB2 implied that both isoenzymes play important roles in oxygen and superoxide stress defence although they are predicted to reside in the cytoplasm and periplasm respectively. NrfA and a cytoplasmic flavodiiron protein (Fdp) were identified as key components of nitric oxide detoxification. In addition, NrfA (but not the hybrid cluster protein Hcp) was found to mediate resistance to hydroxylamine stress. The results indicate the presence of a robust oxidative and nitrosative stress defence network and identify NrfA as a multifunctional cytochrome c involved in both anaerobic respiration and stress protection.     

Electrode Positioning and Montage in Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a technique that has been intensively investigated in the past decade as this method offers a non-invasive and safe alternative to change cortical excitability². The effects of one session of tDCS can last for several minutes, and its effects depend on polarity of stimulation, such as that cathodal stimulation induces a decrease in cortical excitability, and anodal stimulation induces an increase in cortical excitability that may last beyond the duration of stimulation⁶. These effects have been explored in cognitive neuroscience and also clinically in a variety of neuropsychiatric disorders – especially when applied over several consecutive sessions⁴. One area that has been attracting attention of neuroscientists and clinicians is the use of tDCS for modulation of pain-related neural networks^3,5. Modulation of two main cortical areas in pain research has been explored: primary motor cortex and dorsolateral prefrontal cortex⁷. Due to the critical role of electrode montage, in this article, we show different alternatives for electrode placement for tDCS clinical trials on pain; discussing advantages and disadvantages of each method of stimulation.     

Genomic selection for fruit quality traits in apple (Malus×domestica Borkh.)

The genome sequence of apple (Malus×domestica Borkh.) was published more than a year ago, which helped develop an 8K SNP chip to assist in implementing genomic selection (GS). In apple breeding programmes, GS can be used to obtain genomic breeding values (GEBV) for choosing next-generation parents or selections for further testing as potential commercial cultivars at a very early stage. Thus GS has the potential to accelerate breeding efficiency significantly because of decreased generation interval or increased selection intensity. We evaluated the accuracy of GS in a population of 1120 seedlings generated from a factorial mating design of four females and two male parents. All seedlings were genotyped using an Illumina Infinium chip comprising 8,000 single nucleotide polymorphisms (SNPs), and were phenotyped for various fruit quality traits. Random-regression best liner unbiased prediction (RR-BLUP) and the Bayesian LASSO method were used to obtain GEBV, and compared using a cross-validation approach for their accuracy to predict unobserved BLUP-BV. Accuracies were very similar for both methods, varying from 0.70 to 0.90 for various fruit quality traits. The selection response per unit time using GS compared with the traditional BLUP-based selection were very high (>100%) especially for low-heritability traits. Genome-wide average estimated linkage disequilibrium (LD) between adjacent SNPs was 0.32, with a relatively slow decay of LD in the long range (r(2)?=?0.33 and 0.19 at 100 kb and 1,000 kb respectively), contributing to the higher accuracy of GS. Distribution of estimated SNP effects revealed involvement of large effect genes with likely pleiotropic effects. These results demonstrated that genomic selection is a credible alternative to conventional selection for fruit quality traits.     

Metabolic and gene expression analysis of apple (Malus x domestica) carotenogenesis

Carotenoid accumulation confers distinct colouration to plant tissues, with effects on plant response to light and as well as health benefits for consumers of plant products. The carotenoid pathway is controlled by flux of metabolites, rate-limiting enzyme steps, feed-back inhibition, and the strength of sink organelles, the plastids, in the cell. In apple (Malus × domestica Borkh), fruit carotenoid concentrations are low in comparison with those in other fruit species. The apple fruit flesh, in particular, begins development with high amounts of chlorophylls and carotenoids, but in all commercial cultivars a large proportion of this is lost by fruit maturity. To understand the control of carotenoid concentrations in apple fruit, metabolic and gene expression analysis of the carotenoid pathway were measured in genotypes with varying flesh and skin colour. Considerable variation in both carotenoid concentrations and compound profile was observed between tissues and genotypes, with carotenes and xanthophylls being found only in fruit accumulating high carotenoid concentrations. The study identified potential rate-limiting steps in carotenogenesis, which suggested that the expression of ZISO, CRTISO, and LCY-ε, in particular, were significant in predicting final carotenoid accumulation in mature apple fruit.     

Exclusion of ferritins and iron-responsive element (IRE)-binding proteins as candidates for the hemochromatosis gene

We have looked for genes for ferritin and its translational control protein that could account for anomalies in the expression of ferritin (FT) and the transferrin receptor in the duodenum of individuals with hemochromatosis (HC). We show that there are probably only two FTH-like sequences near the HC locus on the short arm of chromosome 6 and no FTL-like sequences. We report the cloning of the previously uncharacterized FTH sequence from 6p (FTHL15) and show that it is probably a processed pseudogene. This gene has been mapped with a panel of radiation hybrid cells to near 6p12. Additionally, we show that there are no sequences on chromosome 6p for a protein that coordinately regulates expression of ferritin and the transferrin receptor.     

Space-related research in mycology concurrent with the first decade of manned space exploration

Fungi and Actinomycetes, aside from other microorganisms, have been placed aboard balloons, earth satellites, or high altitude sounding rockets for evaluation of environmental conditions of spaceflight missions. The incursion of harmful effects, including chromosomal breaks or elevated mutation frequencies were identified.