959 Nematode Genomes: a semantic wiki for coordinating sequencing projects

Genome sequencing has been democratized by second-generation technologies, and even small labs can sequence metazoan genomes now. In this article, we describe ‘959 Nematode Genomes’—a community-curated semantic wiki to coordinate the sequencing efforts of individual labs to collectively sequence 959 genomes spanning the phylum Nematoda. The main goal of the wiki is to track sequencing projects that have been proposed, are in progress, or have been completed. Wiki pages for species and strains are linked to pages for people and organizations, using machine- and human-readable metadata that users can query to see the status of their favourite worm. The site is based on the same platform that runs Wikipedia, with semantic extensions that allow the underlying taxonomy and data storage models to be maintained and updated with ease compared with a conventional database-driven web site. The wiki also provides a way to track and share preliminary data if those data are not polished enough to be submitted to the official sequence repositories. In just over a year, this wiki has already fostered new international collaborations and attracted newcomers to the enthusiastic community of nematode genomicists. www.nematodegenomes.org

A genomic perspective on variations in the molecular toolkit for development and on the evolution of parthenogenesis in Nematoda

The phylum Nematoda is characterised by a huge diversity of species that exploit almost all habitats on earth. Despite their prevalence in a wide range of different ecosystems, nematodes adhere to a strikingly strict Bauplan with only minor variations, even between two large groups that split more than 400 million years ago. The conservation of the final adult body form is quite special and not common in other animal taxa; this exceptional conservatism in the Bauplan, and the very similar patterns of early development observed in the model organisms C. elegans, P. pacificus and Ascaris together, have led scientist to suggest that these mechanisms of early development are archetypical for the phylum. However, analysis pioneered in the Schierenberg laboratory throughout the last 25 years challenged this view by describing considerable variations of early development in several species from different branches of the phylum. These observations together with data from divergent species in Panarthropoda gave rise to the question whether the molecular toolkit for nematode development could be subject to change as well. In the thesis presented here, this question is addressed from a genomic perspective, assembling and analysing large-scale data from species on different taxonomical levels. Based on these data comparisons have been made ranging from species at phylogenetically antipodal positions in the phylum separated by hundreds of millions of years of evolution to genera in one specific clade of the nema- tode tree, and finally the comparison of two closely related genera. In all these taxa Gene Regulatory Networks (GRNs) of early development are analysed and set into perspective with the common model of the nematode developmental toolkit drawn from C. elegans. I used these assays to test whether recently widely discussed theories on the role of GRNs for development deliver valid predictions for the evolution of early development in Nematoda. In fact, I find that the emerging picture supports such hypotheses of GRN evolution: in many pathways intermediate genetic switches appear to be exchanged by processes collectively called “Developmental System Drift (DSD), while upstream and downstream acting genes are more likely to be conserved. Despite this disparity across Nematoda, an analysis of genes retained across all Bilateria shows that this hugely diverse taxon, comprising Nematoda, could be characterized by aprocess of minimal divergence namely the phase in development when the adult body form is constructed. In Nematoda, parthenogenesis evolved in several genera, with a hotspot in clade IV of the phylum. The data sampled to assess the evolution of development in this thesis are used to elucidate the origin and molecular mechanisms underlying parthenogenesis in the genus Panagrolaimus. While the establishment of a re-shuffling mechanisms of GRNs through DSD does not yet allow us to unravel the distinct molecular mechanisms underpinning the establishment and maintenance of parthenogenesis, we have good evidence that parthenogenetic species in the genus Panagrolaimus are polyploid hybrids. This finding supports the hypothesis that hybridisation is a common route to parthenogenesis in Nematoda, as found in many other taxa as well. Parthenogenesis has also been linked to survival in novel and extreme environments, this would be facilitated in the Panagrolaimus species as they are capable of undergoing cryptobiosis (complete desiccation) in contrat to C.elegans and most other nematodes tested. Exploring the trait from a genomic perspective, we found genes known to be acting in this process in Panagrolaimus, but more importantly an intriguing link to Horizontal Gene Transfer (HGT) was found. Genes acquired through HGT appear to lend Panagrolaimus an adaptive advantage in extreme environments by acting in DNA repair mechanisms, which are important during rehydration. This illustrates the previously underestimated importance of HGT in Metazoa. The genomic and transcriptomic data sampled and assembled for this thesis can serve as a basis for future projects analysing the evolution of developmental systems with regards to GRNs and DSD, as well as detailed analyses of anhydrobiosis and the molecular background of parthenogenesis

The genome of Romanomermis culicivorax:revealing fundamental changes in the core developmental genetic toolkit in Nematoda

Background: The genetics of development in the nematode Caenorhabditis elegans has been described in exquisite detail. The phylum Nematoda has two classes: Chromadorea (which includes C. elegans) and the Enoplea. While the development of many chromadorean species resembles closely that of C. elegans, enoplean nematodes show markedly different patterns of early cell division and cell fate assignment. Embryogenesis of the enoplean Romanomermis culicivorax has been studied in detail, but the genetic circuitry underpinning development in this species has not been explored. Results: We generated a draft genome for R. culicivorax and compared its gene content with that of C. elegans, a second enoplean, the vertebrate parasite Trichinella spiralis, and a representative arthropod, Tribolium castaneum. This comparison revealed that R. culicivorax has retained components of the conserved ecdysozoan developmental gene toolkit lost in C. elegans. T. spiralis has independently lost even more of this toolkit than has C. elegans. However, the C. elegans toolkit is not simply depauperate, as many novel genes essential for embryogenesis in C. elegans are not found in, or have only extremely divergent homologues in R. culicivorax and T. spiralis. Our data imply fundamental differences in the genetic programmes not only for early cell specification but also others such as vulva formation and sex determination. Conclusions: Despite the apparent morphological conservatism, major differences in the molecular logic of development have evolved within the phylum Nematoda. R. culicivorax serves as a tractable system to contrast C. elegans and understand how divergent genomic and thus regulatory backgrounds nevertheless generate a conserved phenotype. The R. culicivorax draft genome will promote use of this species as a research model

Lymphocytosis after treatment with dasatinib in chronic myeloid leukemia : Effects on response and toxicity

BACKGROUNDThe proliferation of clonal cytotoxic T-cells or natural killer cells has been observed after dasatinib treatment in small studies of patients with chronic myeloid leukemia (CML). METHODSThe incidence of lymphocytosis and its association with response, survival, and side effects were assessed in patients from 3 large clinical trials. Overall, 1402 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP), CML-CP refractory/intolerant to imatinib, or with CML in accelerated or myeloid-blast phase were analyzed. RESULTSLymphocytosis developed in 32% to 35% of patients and persisted for >12 months. This was not observed in the patients who received treatment with imatinib. Dasatinib-treated patients in all stages of CML who developed lymphocytosis were more likely to achieve a complete cytogenetic response, and patients who had CML-CP with lymphocytosis were more likely to achieve major and deep molecular responses. Progression-free and overall survival rates were significantly longer in patients with CML-CP who were refractory to or intolerant of imatinib and had lymphocytosis. Pleural effusions developed more commonly in patients with lymphocytosis. CONCLUSIONSOverall, lymphocytosis occurred and persisted in many dasatinib-treated patients in all phases of CML. Its presence was associated with higher response rates, significantly longer response durations, and increased overall survival, suggesting an immunomodulatory effect. Prospective studies are warranted to characterize the functional activity of these cells and to assess whether an immunologic effect against CML is detectable. Cancer 2016;122:1398-1407. (c) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Lymphocytosis develops frequently after treatment of chronic myeloid leukemia with dasatinib and is associated with higher response rates, significantly longer response durations, and increased overall survival. Prospective studies are warranted to assess whether dasatinib produces an immunomodulatory effect against chronic myeloid leukemia.Peer reviewe

Exploring different types of inhibition during bilingual language production

Multilinguals have to control their languages constantly to produce accurate verbal output. They have to inhibit possible lexical competitors not only from the target language, but also from non-target languages. Bilinguals' training in inhibiting incongruent or irrelevant information has been used to endorse the so-called bilingual advantage in executive functions, assuming a transfer effect from language inhibition to domain-general inhibitory skills. Recent studies have suggested that language control may rely on language-specific inhibitory control mechanisms. In the present study, unbalanced highly proficient bilinguals completed a rapid naming multi-inhibitory task in two languages. The task assessed three types of inhibitory processes: inhibition of the non-target language, inhibition of lexical competitors, and inhibition of erroneous auditory feedback. The results showed an interaction between lexical competition and erroneous auditory feedback, but no interactions with the inhibition of the non-target language. The results suggested that different subcomponents of language inhibition are involved during bilingual language production

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Fitness Landscape of the Fission Yeast Genome.

The relationship between DNA sequence, biochemical function, and molecular evolution is relatively well-described for protein-coding regions of genomes, but far less clear in noncoding regions, particularly, in eukaryote genomes. In part, this is because we lack a complete description of the essential noncoding elements in a eukaryote genome. To contribute to this challenge, we used saturating transposon mutagenesis to interrogate the Schizosaccharomyces pombe genome. We generated 31 million transposon insertions, a theoretical coverage of 2.4 insertions per genomic site. We applied a five-state hidden Markov model (HMM) to distinguish insertion-depleted regions from insertion biases. Both raw insertion-density and HMM-defined fitness estimates showed significant quantitative relationships to gene knockout fitness, genetic diversity, divergence, and expected functional regions based on transcription and gene annotations. Through several analyses, we conclude that transposon insertions produced fitness effects in 66-90% of the genome, including substantial portions of the noncoding regions. Based on the HMM, we estimate that 10% of the insertion depleted sites in the genome showed no signal of conservation between species and were weakly transcribed, demonstrating limitations of comparative genomics and transcriptomics to detect functional units. In this species, 3'- and 5'-untranslated regions were the most prominent insertion-depleted regions that were not represented in measures of constraint from comparative genomics. We conclude that the combination of transposon mutagenesis, evolutionary, and biochemical data can provide new insights into the relationship between genome function and molecular evolution