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Cell division during early embryogenesis is linked to key morphogenic events such as embryo symmetry breaking and tissue patterning. It is thought that the physical surrounding of cells together with cell intrinsic cues act as a mechanical "mold," guiding cell division to ensure these events are robust. To quantify how cell division is affected by the mechanical and geometrical environment, we present a novel computational mechanical model of cytokinesis, the final phase of cell division. Simulations with the model reproduced experimentally observed furrow dynamics and describe the volume ratio of daughter cells in asymmetric cell divisions, based on the position and orientation of the mitotic spindle. For dividing cells in geometrically confined environments, we show how the orientation of confinement relative to the division axis modulates the volume ratio in asymmetric cell division. Further, we quantified how cortex viscosity and surface tension determine the shape of a dividing cell and govern bubble-instabilities in asymmetric cell division. Finally, we simulated the formation of the three body axes via sequential (a)symmetric divisions up until the six-cell stage of early C. elegans development, which proceeds within the confines of an eggshell. We demonstrate how model input parameters spindle position and orientation provide sufficient information to reliably predict the volume ratio of daughter cells during the cleavage phase of development. However, for egg geometries perturbed by compression, the model predicts that a change in confinement alone is insufficient to explain experimentally observed differences in cell volume. This points to an effect of the compression on the spindle positioning mechanism. Additionally, the model predicts that confinement stabilizes asymmetric cell divisions against bubble-instabilities. ispartof: BIOPHYSICAL JOURNAL vol:122 issue:10 pages:1858-1867 ispartof: location:United States status: published

MotivationThe shape of a cell reflects, among other things, actomyosin activity and adhesion properties. Cell shape is further tightly linked to cell differentiation and can reveal important cellular behaviors such as polarization. Hence, it is useful and informative to link cell shape to genetic and other perturbations. However, most currently used cell shape descriptors capture only simple geometric features such as volume and sphericity. We propose FlowShape, a new framework to study cell shapes in a complete and generic way.ResultsIn our framework a cell shape is first represented as a single function on a sphere. The curvature of the shape is measured and next mapped onto a sphere in a conformal manner. This special curvature map is then approximated by a series expansion: the spherical harmonics decomposition. This decomposition facilitates a wide range of shape analyses, including shape alignment, statistical cell shape comparison and inference of cell shape deformations over time. From this representation, we can reconstruct the cell shape using the Dirac equation. The new tool is applied to perform a complete, generic analysis of cell shapes, using the earlyCaenorhabditis elegansembryo as a model case. We distinguish and characterize the cells at the seven-cell stage. Next, a filter is designed to identify protrusions on the cell shape to highlight lamellipodia in cells. Furthermore, we use our framework to identify any shape changes following a gene knockdown of the Wnt pathway. Cells are first optimally aligned using the fast Fourier transform, followed by calculating an average shape. Shape differences between conditions are next quantified and compared to an empirical distribution. Finally, we put forward a highly performant implementation of the core algorithm, as well as routines to characterize, align and compare cell shapes, through the open-source software package FlowShape.AvailabilityThe data and code needed to recreate the results are freely available athttps://doi.org/10.5281/zenodo.7391185. The most recent version of the software is maintained athttps://bitbucket.org/pgmsembryogenesis/flowshape/.Author summaryWe present FlowShape, a framework for cell shape analysis, based on the concept ofspherical harmonicsdecomposition. This decomposition allows for any function defined on a sphere to be rewritten as a weighted sum of basis functions. Contrary to previous work, we use a single function to describe a shape, the mean curvature, which implies that the decomposition weights can be used as a complete shape description. The expression of a shape in this manner allows for very efficient calculations, as we illustrate with theC. elegansembryo as a model. The decomposition permits efficient comparison and alignment of shapes. We demonstrate this by clustering the cells in the early embryo and illustrating the different shapes by cluster. The decomposition further facilitates averaging of shapes and searching for particular features on the shape by defining filters that can then be efficiently applied. Finally, we illustrate how the framework can facilitate statistical comparisons between shapes.

Motivation Uncovering the cellular and mechanical processes that drive embryo formation requires an accurate read out of cell geometries over time. However, automated extraction of 3D cell shapes from time-lapse microscopy remains challenging, especially when only membranes are labeled. Results We present an image analysis framework for automated tracking and three-dimensional cell segmentation in confocal time lapses. A sphere clustering approach allows for local thresholding and application of logical rules to facilitate tracking and unseeded segmentation of variable cell shapes. Next, the segmentation is refined by a discrete element method simulation where cell shapes are constrained by a biomechanical cell shape model. We apply the framework on Caenorhabditis elegans embryos in various stages of early development and analyze the geometry of the 7- and 8-cell stage embryo, looking at volume, contact area and shape over time. Availability and implementation The Python code for the algorithm and for measuring performance, along with all data needed to recreate the results is freely available at 10.5281/zenodo.5108416 and 10.5281/zenodo.4540092. The most recent version of the software is maintained at https://bitbucket.org/pgmsembryogenesis/sdt-pics. Supplementary information Supplementary data are available at Bioinformatics online.

Oviparous animals support reproduction via the incorporation of yolk as a nutrient source into the eggs. In Caenorhabditis elegans, however, yolk proteins seem dispensable for fecundity, despite constituting the vast majority of the embryonic protein pool and acting as carriers for nutrient-rich lipids. Here, we used yolk protein-deprived C. elegans mutants to gain insight into the traits that may yet be influenced by yolk rationing. We show that massive yolk provisioning confers a temporal advantage during embryogenesis, while also increasing early juvenile body size and promoting competitive fitness. Opposite to species that reduce egg production under yolk deprivation, our results indicate that C. elegans relies on yolk as a fail-safe to secure offspring survival, rather than to maintain offspring numbers. electronic-issn: 2575-1077 linking-issn: 2575-1077 article-doi: 10.26508/lsa.202201675 article-pii: LSA-2022-01675 electronic-publication: 20230414 history: 2023/04/15 06:00 [medline] location-id: e202201675 nlm-unique-id: 101728869 owner: NLM publication-status: epublish revised: 20230417 source: Life Sci Alliance. 2023 Apr 14;6(6):e202201675. doi: 10.26508/lsa.202201675. Print 2023 Jun. status: In-Process subset: IM title-abbreviation: Life Sci Alliance ispartof: LIFE SCIENCE ALLIANCE vol:6 issue:6 ispartof: location:United States status: accepted

Cell division during early embryogenesis has been linked to key morphogenic events such as embryo symmetry breaking and tissue patterning. It is thought that boundary conditions together with cell intrinsic cues act as a mechanical “mold”, guiding cell division to ensure these events are more robust. We present a novel computational mechanical model of cytokinesis, the final phase of cell division, to investigate how cell division is affected by mechanical and geometrical boundary conditions. The model reproduces experimentally observed furrow dynamics and predicts the volume ratio of daughter cells in asymmetric cell divisions based on the position and orientation of the mitotic spindle. We show that the orientation of confinement relative to the division axis modulates the volume ratio in asymmetric cell division and quantified the mechanical contribution of cortex mechanics, relative to the mechanical properties of the furrow ring. We apply this model to early C. elegans development, which proceeds within the confines of an eggshell, and simulate the formation of the three body axes via sequential (a)symmetric divisions up until the six cell stage. We demonstrate that spindle position and orientation alone can be used to predict the volume ratio of daughter cells during the cleavage phase of development. However, for compression perturbed egg geometries, the model predicts that the change in confinement alone is insufficient to explain experimentally observed differences in cell volume, inferring an unmodeled underlying spindle positioning mechanism. Finally, the model predicts that confinement stabilizes asymmetric cell divisions against bubble-instabilities, which can arise due to elevated mitotic cortical tension.Author summaryA crucial morphogenic step during early embryonic development is symmetry breaking in the embryo. For C. elegans the formation of the three body axes can be traced back to the six cell stage, where tissue-topology is the result of symmetric and asymmetric divisions. How cell mechanical boundary conditions and cell intrinsic cues influence this process of symmetry breaking is still an open question, as currently, a quantitative mechanical description of cytokinesis in complex architectures is lacking. We developed a simple mechanical model of cell division, incorporated in an existing mechanical cortex model, to simulate cytokinesis in geometrically confined environments. Our approach was able to both capture furrow ring dynamics and predict the volume ratio of daughter cells accurately. By simulating early C. elegans development with different geometrical boundary conditions, we were able to trace back the origin of volume discrepancies between the experimental setups to a quantifiable shift in spindle positioning during cytokinesis. Finally, we showed how embryo confinement partially stabilizes bubble-instabilities that arise during asymmetric cell division during the early cleavage phase.

During asymmetrical division of the endomesodermal precursor cell EMS, a cortical flow arises, and the daughter cells, endodermal precursor E and mesodermal precursor MS, have an enduring difference in the levels of F-actin and non-muscular myosin. Ablation of the cell cortex suggests that these observed differences lead to differences in cortical tension. The higher F-actin and myosin levels in the MS daughter coincide with cell shape changes and relatively lower tension, indicating a soft, actively moving cell, whereas the lower signal in the E daughter cell is associated with higher tension and a more rigid, spherical shape. The cortical flow is under control of the Wnt signaling pathway. Perturbing the pathway removes the asymmetry arising during EMS division and induces subtle defects in the cellular movements at the eight-cell stage. The perturbed cellular movement appears to be associated with an asymmetric distribution of E-cadherin across the EMS cytokinesis groove. ABpl forms a lamellipodium which preferentially adheres to MS by the E-cadherin HMR-1. The HMR-1 asymmetry across the groove is complete just at the moment cytokinesis completes. Perturbing Wnt signaling equalizes the HMR-1 distribution across the lamellipodium. We conclude that Wnt signaling induces a cortical flow during EMS division, which results in a transition in the cortical contractile network for the daughter cells, as well as an asymmetric distribution of E-cadherin. ispartof: Frontiers In Cell And Developmental Biology vol:9 ispartof: location:Switzerland status: published

During asymmetrical division of the endomesodermal precursor cell EMS, a cortical flow arises, and the daughter cells, endodermal precursor E and mesodermal precursor MS, have an enduring difference in the levels of F-actin and non-muscular myosin. Ablation of the cell cortex suggests that these observed differences lead to differences in cortical tension. The higher F-actin and myosin levels in the MS daughter coincide with cell shape changes and relatively lower tension, indicating a soft, actively moving cell, whereas the lower signal in the E daughter cell is associated with higher tension and a more rigid, spherical shape. The cortical flow is under control of the Wnt signaling pathway. Perturbing the pathway removes the asymmetry arising during EMS division and induces subtle defects in the cellular movements at the eight-cell stage. The perturbed cellular movement appears to be associated with an asymmetric distribution of E-cadherin across the EMS cytokinesis groove. ABpl forms a lamellipodium which preferentially adheres to MS by the E-cadherin HMR-1. The HMR-1 asymmetry across the groove is complete just at the moment cytokinesis completes. Perturbing Wnt signaling equalizes the HMR-1 distribution across the lamellipodium. We conclude that Wnt signaling induces a cortical flow during EMS division, which results in a transition in the cortical contractile network for the daughter cells, as well as an asymmetric distribution of E-cadherin.

Asymmetric divisions that yield daughter cells of different sizes are frequent during early embryogenesis, but the importance of such a physical difference for successful development remains poorly understood. Here, we investigated this question using the first division ofCaenorhabditis elegansembryos, which yields a large AB cell and a small P1cell. We equalized AB and P1sizes using acute genetic inactivation or optogenetic manipulation of the spindle positioning protein LIN-5. We uncovered that only some embryos tolerated equalization, and that there was a size asymmetry threshold for viability. Cell lineage analysis of equalized embryos revealed an array of defects, including faster cell cycle progression in P1descendants, as well as defects in cell positioning, division orientation, and cell fate. Moreover, equalized embryos were more susceptible to external compression. Overall, we conclude that unequal first cleavage is essential for invariably successful embryonic development ofC. elegans.

Asymmetric divisions that yield daughter cells of different sizes are frequent during early embryogenesis, but the importance of such a physical difference for successful development remains poorly understood. Here, we investigated this question using the first division ofC. elegansembryos, which yields a large AB cell and a small P1cell. We equalized AB and P1sizes using acute genetic inactivation or optogenetic manipulation of the spindle positioning protein LIN-5. We uncovered that only some embryos tolerated equalization, and that there was a size asymmetry threshold for viability. Cell lineage analysis of equalized embryos revealed an array of defects, including faster cell cycle progression in P1descendants, as well as defects in cell positioning, division orientation and cell fate. Moreover, equalized embryos were more susceptible to external compression. Overall, we conclude that unequal first cleavage is essential for invariably successful embryonic development ofC. elegans.

Learning and memory are regulated by neuromodulatory pathways, but the contribution and temporal requirement of most neuromodulators in a learning circuit are unknown. Here we identify the evolutionarily conserved neuromedin U (NMU) neuropeptide family as a regulator of C. elegans gustatory aversive learning. The NMU homolog CAPA-1 and its receptor NMUR-1 are required for the retrieval of learned salt avoidance. Gustatory aversive learning requires the release of CAPA-1 neuropeptides from sensory ASG neurons that respond to salt stimuli in an experience-dependent manner. Optogenetic silencing of CAPA-1 neurons blocks the expression, but not the acquisition, of learned salt avoidance. CAPA-1 signals through NMUR-1 in AFD sensory neurons to modulate two navigational strategies for salt chemotaxis. Aversive conditioning thus recruits NMU signaling to modulate locomotor programs for expressing learned avoidance behavior. Because NMU signaling is conserved across bilaterian animals, our findings incite further research into its function in other learning circuits., Learning and memory are regulated by neuropeptides. Here, the authors show that the neuropeptide CAPA-1 and its receptor NMUR-1 are required to retrieve learned salt avoidance in C. elegans. CAPA-1/NMUR-1 activation in AFD sensory neurons modulates locomotor programs to express learned avoidance.

Mutations in theclk-1gene impair mitochondrial ubiquinone biosynthesis and extend the lifespan ofC. elegans.We demonstrate here that this life extension is linked to the repression of cytoplasmic protein translation.Clk-1mutations inhibit polyribosome formation similarly todaf-2mutations that dampen insulin signaling. Comparisons of total versus polysomal RNAs inclk-1mutants reveal a reduction in the translational efficiencies of mRNAs coding for elements of the translation machinery and an increase in those coding for the oxidative phosphorylation and autophagy pathways. Knocking down the transcription initiation factor TAF-4, a protein that becomes sequestered in the cytoplasm during early embryogenesis to induce transcriptional silencing, ameliorates theclk-1inhibition of polyribosome formation. These results underscore a prominent role for the repression of cytoplasmic protein translation in eukaryotic lifespan extension, and suggest that mutations impairing mitochondrial function are able to exploit this repression similarly to reductions of insulin signaling. Moreover, this report reveals an unexpected role for TAF-4 as a repressor of polyribosome formation when ubiquinone biosynthesis is compromised.

Chromatin regulators are widely expressed proteins with diverse roles in gene expression, nuclear organization, cell cycle regulation, pluripotency, physiology and development, and are frequently mutated in human diseases such as cancer. Their inhibition often results in pleiotropic effects that are difficult to study using conventional approaches. We have developed a semi-automated nuclear tracking algorithm to quantify the divisions, movements and positions of all nuclei during the early development of Caenorhabditis elegans and have used it to systematically study the effects of inhibiting chromatin regulators. The resulting high dimensional datasets revealed that inhibition of multiple regulators, including F55A3.3 (encoding FACT subunit SUPT16H), lin-53 (RBBP4/7), rba-1 (RBBP4/7), set-16 (MLL2/3), hda-1 (HDAC1/2), swsn-7 (ARID2), and let-526 (ARID1A/1B) affected cell cycle progression and caused chromosome segregation defects. In contrast, inhibition of cir-1 (CIR1) accelerated cell division timing in specific cells of the AB lineage. The inhibition of RNA polymerase II also accelerated these division timings, suggesting that normal gene expression is required to delay cell cycle progression in multiple lineages in the early embryo. Quantitative analyses of the dataset suggested the existence of at least two functionally distinct SWI/SNF chromatin remodeling complex activities in the early embryo, and identified a redundant requirement for the egl-27 and lin-40 MTA orthologs in the development of endoderm and mesoderm lineages. Moreover, our dataset also revealed a characteristic rearrangement of chromatin to the nuclear periphery upon the inhibition of multiple general regulators of gene expression. Our systematic, comprehensive and quantitative datasets illustrate the power of single cell-resolution quantitative tracking and high dimensional phenotyping to investigate gene function. Furthermore, the results provide an overview of the functions of essential chromatin regulators during the early development of an animal. publisher: Elsevier articletitle: Comprehensive single cell-resolution analysis of the role of chromatin regulators in early C. elegans embryogenesis journaltitle: Developmental Biology articlelink: http://dx.doi.org/10.1016/j.ydbio.2014.10.014 content_type: article copyright: Copyright © 2014 Elsevier Inc. All rights reserved. ispartof: Developmental Biology vol:398 issue:2 pages:153-162 ispartof: location:United States status: published

A central challenge in genetics is to predict phenotypic variation from individual genome sequences. Here we construct and evaluate phenotypic predictions for 19 strains of Saccharomyces cerevisiae. We use conservation-based methods to predict the impact of protein-coding variation within genes on protein function. We then rank strains using a prediction score that measures the total sum of function-altering changes in different sets of genes reported to influence over 100 phenotypes in genome-wide loss-of-function screens. We evaluate our predictions by comparing them with the observed growth rate and efficiency of 15 strains tested across 20 conditions in quantitative experiments. The median predictive performance, as measured by ROC AUC, was 0.76, and predictions were more accurate when the genes reported to influence a trait were highly connected in a functional gene network.

Mutations in theclk-1gene impair mitochondrial ubiquinone biosynthesis and extend the lifespan inCaenorhabditis elegans. We demonstrate here that this life extension is linked to the repression of cytoplasmic mRNA translation, independent of the alleged nuclear form of CLK-1.Clk-1mutations inhibit polyribosome formation similarly todaf-2mutations that dampen insulin signaling. Comparisons of total versus polysomal RNAs inclk-1(qm30)mutants reveal a reduction in the translational efficiencies of mRNAs coding for elements of the translation machinery and an increase in those coding for the oxidative phosphorylation and autophagy pathways. Knocking down the transcription initiation factor TATA-binding protein-associated factor 4, a protein that becomes sequestered in the cytoplasm during early embryogenesis to induce transcriptional silencing, ameliorates theclk-1inhibition of polyribosome formation. These results underscore a prominent role for the repression of cytoplasmic protein synthesis in eukaryotic lifespan extension and suggest that mutations impairing mitochondrial function are able to exploit this repression similarly to reductions of insulin signaling. Moreover, this report reveals an unexpected role for TATA-binding protein-associated factor 4 as a repressor of polyribosome formation when ubiquinone biosynthesis is compromised.

Background: Text-mining has been used to link biomedical concepts, such as genes or biological processes, to each other for annotation purposes or the generation of new hypotheses. To relate two concepts to each other several authors have used the vector space model, as vectors can be compared efficiently and transparently. Using this model, a concept is characterized by a list of associated concepts, together with weights that indicate the strength of the association. The associated concepts in the vectors and their weights are derived from a set of documents linked to the concept of interest. An important issue with this approach is the determination of the weights of the associated concepts. Various schemes have been proposed to determine these weights, but no comparative studies of the different approaches are available. Here we compare several weighting approaches in a large scale classification experiment. Methods: Three different techniques were evaluated: (1) weighting based on averaging, an empirical approach; (2) the log likelihood ratio, a test-based measure; (3) the uncertainty coefficient, an information-theory based measure. The weighting schemes were applied in a system that annotates genes with Gene Ontology codes. As the gold standard for our study we used the annotations provided by the Gene Ontology Annotation project. Classification performance was evaluated by means of the receiver operating characteristics (ROC) curve using the area under the curve (AUC) as the measure of performance. Results and discussion: All methods performed well with median AUC scores greater than 0.84, and scored considerably higher than a binary approach without any weighting. Especially for the more specific Gene Ontology codes excellent performance was observed. The differences between the methods were small when considering the whole experiment. However, the number of documents that were linked to a concept proved to be an important variable. When larger amounts of texts were available for the generation of the concepts' vectors, the performance of the methods diverged considerably, with the uncertainty coefficient then outperforming the two other methods. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Motivation: The advent of high-throughput experiments in molecular biology creates a need for methods to efficiently extract and use information for large numbers of genes. Recently, the associative concept space (ACS) has been developed for the representation of information extracted from biomedical literature. The ACS is a Euclidean space in which thesaurus concepts are positioned and the distances between concepts indicates their relatedness. The ACS uses co-occurrence of concepts as a source of information. In this paper we evaluate how well the system can retrieve functionally related genes and we compare its performance with a simple gene co-occurrence method. Results: To assess the performance of the ACS we composed a test set of five groups of functionally related genes. With the ACS good scores were obtained for four of the five groups. When compared to the gene co-occurrence method, the ACS is capable of revealing more functional biological relations and can achieve results with less literature available per gene. Hierarchical clustering was performed on the ACS output, as a potential aid to users, and was found to provide useful clusters. Our results suggest that the algorithm can be of value for researchers studying large numbers of genes. Availability: The ACS program is available upon request from the authors. Contact: r.jelier@erasmusmc.nl

Motivation: Full-text documents potentially hold more information than their abstracts, but require more resources for processing. We investigated the added value of full text over abstracts in terms of information content and occurrences of gene symbol—gene name combinations that can resolve gene-symbol ambiguity. Results: We analyzed a set of 3902 biomedical full-text articles. Different keyword measures indicate that information density is highest in abstracts, but that the information coverage in full texts is much greater than in abstracts. Analysis of five different standard sections of articles shows that the highest information coverage is located in the results section. Still, 30–40% of the information mentioned in each section is unique to that section. Only 30% of the gene symbols in the abstract are accompanied by their corresponding names, and a further 8% of the gene names are found in the full text. In the full text, only 18% of the gene symbols are accompanied by their gene names.

A GENiE (EU COST action, www.worm-genie.eu) workshop was held at the Babraham Institute in Cambridge, UK on April 19 and 20, 2017, to discuss global challenges around Caenorhabditis elegans metabol...

The nematode Caenorhabditis elegans (C. elegans) is a widely used model organism in biological investigations. Due to its well-known and invariant cell lineage tree, it can be used to study the effects of mutations and various disease processes. Effective and efficient analysis of the wealth of time-lapse fluorescence microscopy image data acquired in such studies requires automation of the cell segmentation and tracking tasks involved. This is hampered by many factors, including autofluorescence effects, low and uneven contrast throughout the images, high noise levels, large numbers of possibly simultaneous cell divisions, and touching or clustering cells. In this paper, we present a new algorithm for segmentation and tracking of cells in C. elegans embryogenesis image data. It is based on the model evolution framework for image segmentation and uses a novel multi-object tracking scheme based on energy minimization via graph cuts. Preliminary experiments on publicly available test data demonstrate the potential of the algorithm compared to existing approaches.

Anni 2.0 provides an ontology-based interface to MEDLINE., Anni 2.0 is an online tool () to aid the biomedical researcher with a broad range of information needs. Anni provides an ontology-based interface to MEDLINE and retrieves documents and associations for several classes of biomedical concepts, including genes, drugs and diseases, with established text-mining technology. In this article we illustrate Anni's usability by applying the tool to two use cases: interpretation of a set of differentially expressed genes, and literature-based knowledge discovery.

Tolerance to high levels of ethanol is an ecologically and industrially relevant phenotype of microbes, but the molecular mechanisms underlying this complex trait remain largely unknown. Here, we use long-term experimental evolution of isogenic yeast populations of different initial ploidy to study adaptation to increasing levels of ethanol. Whole-genome sequencing of more than 30 evolved populations and over 100 adapted clones isolated throughout this two-year evolution experiment revealed how a complex interplay of de novo single nucleotide mutations, copy number variation, ploidy changes, mutator phenotypes, and clonal interference led to a significant increase in ethanol tolerance. Although the specific mutations differ between different evolved lineages, application of a novel computational pipeline, PheNetic, revealed that many mutations target functional modules involved in stress response, cell cycle regulation, DNA repair and respiration. Measuring the fitness effects of selected mutations introduced in non-evolved ethanol-sensitive cells revealed several adaptive mutations that had previously not been implicated in ethanol tolerance, including mutations in PRT1, VPS70 and MEX67. Interestingly, variation in VPS70 was recently identified as a QTL for ethanol tolerance in an industrial bio-ethanol strain. Taken together, our results show how, in contrast to adaptation to some other stresses, adaptation to a continuous complex and severe stress involves interplay of different evolutionary mechanisms. In addition, our study reveals functional modules involved in ethanol resistance and identifies several mutations that could help to improve the ethanol tolerance of industrial yeasts., Author Summary Organisms can evolve resistance to specific stress factors, which allows them to thrive in environments where non-adapted organisms fail to grow. However, the molecular mechanisms that underlie adaptation to complex stress factors that interfere with basic cellular processes are poorly understood. In this study, we reveal how yeast populations adapt to high ethanol concentrations, an ecologically and industrially relevant stress that is still poorly understood. We exposed six independent populations of genetically identical yeast cells to gradually increasing ethanol levels, and we monitored the changes in their DNA sequence over a two-year period. Together with novel computational analyses, we could identify the mutational dynamics and molecular mechanisms underlying increased ethanol resistance. Our results show how adaptation to high ethanol is complex and can be reached through different mutational pathways. Together, our study offers a detailed picture of how populations adapt to a complex continuous stress and identifies several mutations that increase ethanol resistance, which opens new routes to obtain superior biofuel yeast strains.

DNA microarray technology produces large amounts of data. For data mining of these datasets, background information on genes can be helpful. Unfortunately most information is stored in free text. Here, we present an approach to use this information for DNA microarray data mining.

High throughput microarray analyses result in many differentially expressed genes that are potentially responsible for the biological process of interest. In order to identify biological similarities between genes, publications from MEDLINE were identified in which pairs of gene names and combinations of gene name with specific keywords were co-mentioned. MEDLINE search strings for 15,621 known genes and 3,731 keywords were generated and validated. PubMed IDs were retrieved from MEDLINE and relative probability of co-occurrences of all gene-gene and gene-keyword pairs determined. To assess gene clustering according to literature co-publication, 150 genes consisting of 8 sets with known connections (same pathway, same protein complex, or same cellular localization, etc.) were run through the program. Receiver operator characteristics (ROC) analyses showed that most gene sets were clustered much better than expected by random chance. To test grouping of genes from real microarray data, 221 differentially expressed genes from a microarray experiment were analyzed with CoPub Mapper, which resulted in several relevant clusters of genes with biological process and disease keywords. In addition, all genes versus keywords were hierarchical clustered to reveal a complete grouping of published genes based on co-occurrence. The CoPub Mapper program allows for quick and versatile querying of co-published genes and keywords and can be successfully used to cluster predefined groups of genes and microarray data.

With the information on the World Wide Web and in specialized databases exploding, researchers and physicians are in dire need to browse efficiently though the large corpus of information resources in their field of interest. The focus is not any longer to find everything related to your interest, but it shifts to zooming in, based on context and expanding again in neighboring knowledge domains. This paper describes an attempt to develop a completely new, interactive way of browsing distributed corpora of information without the need for multiple different queries in different information resources. Classical search engines generally treat search requests in isolation. The results for a given query are identical, and do not automatically take on board the context in which the user made the request. The system described here explores implicit contexts as obtained from the document that the user is reading. The new approach merges the searching and browsing into one combined "read-and-search" mode and alleviates the shift users are normally forced to between searching and reading.

Search engines generally treat search requests in isolation. The results for a given query are identical, independent of the user, or the context in which the user made the request. An approach is demonstrated that explores implicit contexts as obtained from a document the user is reading. The approach inserts into an original (web) document functionality to directly activate context driven queries that yield related articles obtained from various information sources.

Genes are discovered almost on a daily basis and new names have to be found. Although there are guidelines for gene nomenclature, the naming process is highly creative. Human genes are often named with a gene symbol and a longer, more descriptive term; the short form is very often an abbreviation of the long form. Abbreviations in biomedical language are highly ambiguous, i.e., one gene symbol often refers to more than one gene. Using an existing abbreviation expansion algorithm, we explore MEDLINE for the use of human gene symbols derived from LocusLink. It turns out that just over 40% of these symbols occur in MEDLINE, however, many of these occurrences are not related to genes. Along the process of making an inventory, a disambiguation test collection is constructed automatically.