Non-circadian light inducible rhythm in Aspergillus nidulans

Aspergillus nidulans grown under standard laboratory conditions does not show circadian rhythmic growth. The presence of a circadian clock was demonstrated in A. nidulans at the level of gene expression (Greene et al. 2003), but a visually observable rhythm is lacking. We recently observed a remarkable rhythmic growth pattern in the formation of conidiospores and ascospores in a fludioxonil resistant mutant of A. nidulans (fldA1) grown in a dark incubator. This is reminiscent of a circadian rhythm. We found however that our observed rhythm is induced by light (leaking into the ‘dark’ incubator) and is not self-sustainable. In absolute darkness or constant light the rhythm is lost; therefore, we conclude that the rhythm is not a true intrinsic circadian rhythm

A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients

Background: Nivolumab is administered in a weight-based or fixed-flat dosing regimen. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported and may argue against the current dosing strategies. The primary objectives were to determine nivolumab pharmacokinetics (PK) and to assess the relationship between drug clearance and clinical outcome in NSCLC, melanoma, and renal cell cancer (RCC). Methods: In this prospective observational cohort study, individual estimates of nivolumab clearance and the impact of baseline covariates were determined using a population-PK model. Clearance was related to best overall response (RECISTv1.1), and stratified by tumor type. Results: Two-hundred-twenty-one patients with metastatic cancer receiving nivolumab-monotherapy were included of whom 1,715 plasma samples were analyzed. Three baseline parameters had a significant effect on drug clearance and were internally validated in the population-PK model: gender, BSA, and serum albumin. Women had 22% lower clearance compared to men, while the threshold of BSA and albumin that led to > 20% increase of clearance was > 2.2m2 and < 37.5 g/L, respectively. For NSCLC, drug clearance was 42% higher in patients with progressive disease (mean: 0.24; 95% CI: 0.22-0.27 L/day) compared to patients with partial/complete response (mean: 0.17; 95% CI: 0.15-0.19 L/day). A similar trend was observed in RCC, however, no clearance-response relationship was observed in melanoma. Conclusions: Based on the first real-world population-PK model of nivolumab, covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab clearance. A clearance-response relationship was observed in NSCLC, with a non-significant trend in RCC, but not in melanoma. Individual pharmacology of nivolumab in NSCLC appears important and should be prospectively studied

Mutation-rate plasticity and the germline of unicellular organisms

The mutation rate is a fundamental factor in evolutionary genetics. Recently, mutation rates were found to be strongly reduced at high density in a wide range of unicellular organisms, prokaryotic and eukaryotic. Independently, cell division was found to become more asymmetrical at increasing density in diverse organisms; some 'mother' cells continue dividing, while their 'offspring' cells do not divide further. Here, we investigate how this increased asymmetry in cell division at high density can be reconciled with reduced mutation-rate estimates. We calculated the expected number of mutant cells due to replication errors under various modes of segregation of template-DNA strands and copy-DNA strands, both under symmetrical (exponential) and asymmetrical (linear) growth. We show that the observed reduction in the mutation rate at high density can be explained if mother cells preferentially retain the template-DNA strands, since new mutations are then confined to non-dividing daughter cells, thus reducing the spread of mutant cells. Any other inheritance mode results in an increase in the number of mutant cells at higher density. The proposed hypothesis that patterns of DNA-strand segregation are density-dependent fundamentally challenges our current understanding of mutation-rate estimates and extends the distinction between germline and soma to unicellular organisms.</p

Azole-resistance development; how the Aspergillus fumigatus lifecycle defines the potential for adaptation

In order to successfully infect or colonize human hosts or survive changing environments, Aspergillus fumigatus needs to adapt through genetic changes or phenotypic plasticity. The genomic changes are based on the capacity of the fungus to produce genetic variation, followed by selection of the genotypes that are most fit to the new environment. Much scientific work has focused on the metabolic plasticity, biofilm formation or the particular genetic changes themselves leading to ad-aptation, such as antifungal resistance in the host. Recent scientific work has shown advances made in understanding the natural relevance of parasex and how both the asexual and sexual reproduction can lead to tandem repeat elongation in the target gene of the azoles: the cyp51A gene. In this review, we will explain how the fungus can generate genetic variation that can lead to adaptation. We will discuss recent advances that have been made in the understanding of the lifecycle of A. fumigatus to explain the differences observed in speed and type of mutations that are generated under different environments and how this can facilitate adaptation, such as azole-resistance selec-tion

Phylogeny of Paecilomyces, the causal agent of pistachio and some other trees dieback disease in Iran

One of the most important fungal agents of pistachio dieback disease belongs to the ascomycete genus Paecilomyces that has been identified as P. variotii. In 2012–2014, 700 plant samples from pistachio trees and 27 other plant species with dieback symptoms were collected from 10 provinces of Iran. Of the 567 pistachio samples, 277 Paecilomyces strains were obtained and from the 133 samples of other plants (except pistachio and including Pistacia mutica, Punica granatum, Prunus amygdalus, Caesalpinia gilliesii, Nerium oleander, Tamarix aphylla, Tamarix hispida and Haloxylon sp.), 23 fungal isolates were recovered and five isolates were obtained from the air of infected pistachio orchards. Based on morphology, all 305 isolates were identified as P. variotii. Physiological studies revealed that 299 isolates belong to P. formosus. Three isolates were assigned to P. variotii, while three isolates could not be assigned to any of the known species. Of the 305 isolates, 62 were selected for phylogenetic analysis based on DNA variation (ITS, β-tubulin and calmodulin). This analysis showed that all of our isolates form a clade with P. formosus. P. formosus consists of the three former species P. formosa, P. lecythidis and P. maximus. This study shows that our isolates form a strongly supported clade with strains of P. lecythidis. So, the causal agent of dieback disease of pistachio and other examined trees is P. formosus which is closely related to the former species P. lecythidis and has some differences with the former species P. formosa and P. maximus. Based on phylogenetic studies P. formosus thus seems to be a species complex that could be divided into three separate species.</p

Mosaic structure of the fungal community in the Kislo-Sladkoe Lake that is detaching from the White Sea

The major part of the north polar region is intensely rising by postglacial crustal movement. This process gives rise to the separation of different basins from seas and oceans, which affects a combination of freshwater and marine organisms. Gradually losing contact with the seas, many near-shore lakes of the Arctic are mostly desalted and form bogs. Fungi as decomposers play an important role in all ecosystems. However, the diversity and role of fungi in Arctic aquatic ecosystems is largely unknown. It is also not clear how the taxonomic structure of the fungal community is affected by the process of gradual desalinization and waterlogging. We investigated the diversity of filamentous culturable fungi in different parts of the brackish Kislo-Sladkoe Lake (White Sea, Russia). Annually, 42 samples of the bottom and coastal soils have been collected at the lake from which fungi were recovered on standard and selective media. Based on morphological and molecular markers, a total of 127 taxa have been identified. The fungal community appeared to be influenced by its sea origin and comprised both marine (Paradendryphiella salina, Acremonium spp.) and terrestrial soil species of Penicillium, Talaromyces, Mucor, Umbelopsis, Cladosporium, Cadophora, Sistotrema, Helotiales, Pleosporales, sphagnum moss destructors (Oidiodendron spp.) and insect-associated species of Tolypocladium. The results indicate that the composition of the fungal community in the rising polar White Sea region reflects the dynamics of global changes in physical–chemical parameters and animal and plant associations because of separation from the sea.</p

Data from: Correlated evolution of senescence and ephemeral substrate use in the Sordariomycetes

Evolutionary theory predicts that senescence – a decline in reproduction and survival with increasing age - can evolve as a trade-off between the investment in reproduction on one side and in somatic maintenance and repair on the other side. The ecology of a species is crucial here, since it provides the external causes of death that determine the statistical limit to a species’ lifespan. Filamentous fungi are generally believed to be non-senescent, and there are indeed spectacular examples of very old fungal individuals in nature. Yet, for some fungi the growth conditions are ephemeral and therefore senescence is expected to have evolved, like in the coprophilic Podospora anserina, the only well-studied filamentous fungus with intrinsic senescence. Here we hypothesize that rapid senescence is more common in fungi than generally believed and that the phylogenetic distribution of senescence correlates with its ecology. We examined a set of Sordariomycetes for their lifespan and constructed phylogenies based on several nuclear sequences. Part of the strains were from the CBS culture collection, originally isolated from various substrates, some of which ephemeral. In addition we isolated new strains from short-lived substrates. Senescence was observed throughout the phylogeny. Correlation tests support the hypothesis that in the Sordariomycetes senescence is a trait that has arisen as an evolved adaptation to ephemeral substrates, and that it has evolved repeatedly and independently along the phylogeny.,Alignment ITS sequencesFasta (txt) file with all the aligned ITS sequences of all strains from our culture collection and isolated from dung, used in the analysis to detect correlated evolution between substrate and (rapid) senescence.Alignment non-redundant ITS sequencesFasta (txt) file with the aligned non-redundant ITS sequences, used in the analysis to detect correlated evolution between substrate and (rapid) senescence.Character matrix-non-redundant scenarioBinomic character matrix of the strains used in the non-redundant scenario; Character states: Ephemeral substrate: 1=ephemeral substrate, 0= non-ephemeral substrate; Senescence:1=(rapid) senescence, 0= not senescent within 8 weeks of growth (pdf-file).Character matric-non-redundant scenario.pdfCharacter matrix-best scenarioBinomic character matrix of the strains used in the 'best case' scenario; Character states: Ephemeral substrate: 1=ephemeral substrate, 0= non-ephemeral substrate; Senescence:1=(rapid) senescence, 0= not senescent within 8 weeks of growth (pdf-file).Character matrix-final scenarioBinomic character matrix of the strains used in the final scenario; Character states: Ephemeral substrate: 1=ephemeral substrate, 0= non-ephemeral substrate; Senescence:1=(rapid) senescence, 0= not senescent within 8 weeks of growth (pdf-file).Character matrix-worst case scenarioBinomic character matrix of the strains used in the 'worst case' scenario; Character states: Ephemeral substrate: 1=ephemeral substrate, 0= non-ephemeral substrate; Senescence:1=(rapid) senescence, 0= not senescent within 8 weeks of growth (pdf-file).Tree-all Most Parsimonious ITS trees allAll most Parsimonious trees based on the ITS sequences of all strains. In newick format (Mega5; 1000 bootstraps).Tree-all Most Parsimonious trees non-redundantAll most Parsimonious trees based on the ITS sequences of non-redundant strains. In newick format (Mega5; 1000 bootstraps).Tree-Maximum Likelihood ITS non-redundantMaximum Likelihood tree based on the ITS sequences of the non-redundant strains. In newick format (Mega5; 1000 bootstraps).Tree-Maximum Likelihood ITS tree allMaximum Likelihood tree based on the ITS sequences of all strains. In newick format (Mega5; 1000 bootstraps).Tree-Minimum Evolution ITS Tree allMinimum Evolution tree based on the ITS sequences of all strains. In newick format (Mega5; 1000 bootstraps).Tree-Minimum Evolution non-redundantMinimum Evolution tree based on the ITS sequences of the non-redundant strains. In newick format (Mega5; 1000 bootstraps).

Flower Bulb Waste Material is a Natural Niche for the Sexual Cycle in Aspergillus fumigatus

With population genetic evidence of recombination ongoing in the natural Aspergillus fumigatus population and a sexual cycle demonstrated in the laboratory the question remained what the natural niche for A. fumigatus sex is. Composting plant-waste material is a known substrate of A. fumigatus to thrive and withstand temperatures even up to 70°C. Previous studies have shown indirect evidence for sexual reproduction in these heaps but never directly demonstrated the sexual structures due to technical limitations. Here, we show that flower bulb waste material from stockpiles undergoing composting can provide the conditions for sexual reproduction. Direct detection of ascospore structures was shown in agricultural flower bulb waste material by using a grid-based detection assay. Furthermore, we demonstrate that ascospores can germinate after exposure to 70°C for up to several days in contrast to asexual conidia that are unable to survive a two-hour heat shock. This indicates a sufficient time frame for ascospores to survive and escape composting stockpiles. Finally, sexual crosses with cleistothecium and viable ascospore formation could successfully be performed on flower bulb waste material. Recombination of A. fumigatus can now be explained by active sexual reproduction in nature as we show in this study that flower bulb waste material provides an environmental niche for sex

Why some fungi senesce and others do not: An evolutionary perspective on fungal senescence

<p>Fungi are generally considered to be modular organisms with no clear distinction of a germ line: With the expansion of the mycelium, chances for reproduction are expected to increase, and each unit under favourable circumstances may produce offspring. Fungi with such modular body plans are expected to be long-lived, as most fungi indeed seem to be. However, fungi exist that do senesce, and their growth often seems to be limited by space or time. For these fungi, we can consider the term 'pseudo-unitary', as life history details and ecological conditions constrain the size of the soma and the opportunities for reproduction. We may predict the life history traits and ecological conditions that favour such evolution of fungal senescence. Known proximate mechanisms of fungal senescence can be viewed in the light of this evolutionary context.</p

Why some fungi senesce and others do not: An evolutionary perspective on fungal senescence

Fungi are generally considered to be modular organisms with no clear distinction of a germ line: With the expansion of the mycelium, chances for reproduction are expected to increase, and each unit under favourable circumstances may produce offspring. Fungi with such modular body plans are expected to be long-lived, as most fungi indeed seem to be. However, fungi exist that do senesce, and their growth often seems to be limited by space or time. For these fungi, we can consider the term 'pseudo-unitary', as life history details and ecological conditions constrain the size of the soma and the opportunities for reproduction. We may predict the life history traits and ecological conditions that favour such evolution of fungal senescence. Known proximate mechanisms of fungal senescence can be viewed in the light of this evolutionary context