bluuebunny/crossref_metadata_2025 huggingface dataset:
Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4
Authors: Lyssiotis Costas A. , Foreman Ruth K. , Staerk Judith , Garcia Michael , Mathur Divya , Markoulaki Styliani , Hanna Jacob , Lairson Luke L. , Charette Bradley D. , Bouchez Laure C. , Bollong Michael , Kunick Conrad , Brinker Achim , Cho Charles Y. , Schultz Peter G. , Jaenisch Rudolf
Published: May 2009

Ectopic expression of defined transcription factors can reprogram somatic cells to induced pluripotent stem (iPS) cells, but the utility of iPS cells is hampered by the use of viral delivery systems. Small molecules offer an alternative to replace virally transduced transcription factors with chemical signaling cues responsible for reprogramming. In this report we describe a small-molecule screening platform applied to identify compounds that functionally replace the reprogramming factor Klf4. A series of small-molecule scaffolds were identified that activate Nanog expression in mouse fibroblasts transduced with a subset of reprogramming factors lacking Klf4. Application of one such molecule, kenpaullone, in lieu of Klf4 gave rise to iPS cells that are indistinguishable from murine embryonic stem cells. This experimental platform can be used to screen large chemical libraries in search of novel compounds to replace the reprogramming factors that induce pluripotency. Ultimately, such compounds may provide mechanistic insight into the reprogramming process.
Impossibility of successful classification when useful features are rare and weak
Authors: Jin Jiashun
Published: May 2009

We study a two-class classification problem with a large number of features, out of which many are useless and only a few are useful, but we do not know which ones they are. The number of features is large compared with the number of training observations. Calibrating the model with 4 key parameters—the number of features, the size of the training sample, the fraction, and strength of useful features—we identify a region in parameter space where no trained classifier can reliably separate the two classes on fresh data. The complement of this region—where successful classification is possible—is also briefly discussed.
Targeting cancer cells by using an antireceptor antibody-photosensitizer fusion protein
Authors: Serebrovskaya Ekaterina O. , Edelweiss Eveline F. , Stremovskiy Oleg A. , Lukyanov Konstantin A. , Chudakov Dmitry M. , Deyev Sergey M.
Published: May 2009

Antibody-photosensitizer chemical conjugates are used successfully to kill cancer cells in photodynamic therapy. However, chemical conjugation of photosensitizers presents several limitations, such as poor reproducibility, aggregation, and free photosensitizer impurities. Here, we report a fully genetically encoded immunophotosensitizer, consisting of a specific anti-p185
HER-2-ECD
antibody fragment 4D5scFv fused with the phototoxic fluorescent protein KillerRed. Both parts of the recombinant protein preserved their functional properties: high affinity to antigen and light activation of sensitizer. 4D5scFv-KillerRed showed fine targeting properties and efficiently killed p185
HER-2-ECD
-expressing cancer cells upon light irradiation. It also showed a remarkable additive effect with the commonly used antitumor agent cisplatin, further demonstrating the potential of the approach.
Relation Between Maternal Contingent Responsiveness and Infant Social Expectations
Authors: Mcquaid Nancy E. , Bibok Maximilian B. , Carpendale Jeremy I. M.
Published: May 2009

This study investigated the relation between maternal contingent responsiveness and 4‐ and 5‐month‐old infants' (N = 64) social expectation behavior in a still‐face procedure. Mothers were asked to interact with their infants for 2 min (interactive phase), remain still‐faced for 1 min (still‐face phase), and resume interaction for 2 min. Mother and infant behavior was assessed for the frequency of infant and mother smiles, mother smiles that were contingent to infant smiles and infant smiles were contingent to mother smiles during the interactive phase, and infant social bids to mother during the still‐face phase. Hierarchical regression showed that mother contingent smiles during the interactive phase accounted for unique variance in infant social bids during the still‐face phase beyond that accounted for by the frequency of mother and infant smiles during the interactive phase. These results support the view that young infants' social expectations and sense of self‐efficacy are formed within their interactions with their caregivers.
Scribble Interacts with β-Catenin to Localize Synaptic Vesicles to Synapses
Authors: Sun Yu , Aiga Mytyl , Yoshida Eileen , Humbert Patrick O. , Bamji Shernaz X.
Published: May 2009

An understanding of how synaptic vesicles are recruited to and maintained at presynaptic compartments is required to discern the molecular mechanisms underlying presynaptic assembly and plasticity. We have previously demonstrated that cadherin–β-catenin complexes cluster synaptic vesicles at presynaptic sites. Here we show that scribble interacts with the cadherin–β-catenin complex to coordinate vesicle localization. Scribble and β-catenin are colocalized at synapses and can be coimmunoprecipitated from neuronal lysates, indicating an interaction between scribble and β-catenin at the synapse. Using an RNA interference approach, we demonstrate that scribble is important for the clustering of synaptic vesicles at synapses. Indeed, in scribble knockdown cells, there is a diffuse distribution of synaptic vesicles along the axon, and a deficit in vesicle recycling. Despite this, synapse number and the distribution of the presynaptic active zone protein, bassoon, remain unchanged. These effects largely phenocopy those observed after ablation of β-catenin. In addition, we show that loss of β-catenin disrupts scribble localization in primary neurons but that the localization of β-catenin is not dependent on scribble. Our data supports a model by which scribble functions downstream of β-catenin to cluster synaptic vesicles at developing synapses.
Cortactin Promotes Migration and Platelet-derived Growth Factor-induced Actin Reorganization by Signaling to Rho-GTPases
Authors: Lai Frank P.L. , Szczodrak Malgorzata , Oelkers J. Margit , Ladwein Markus , Acconcia Filippo , Benesch Stefanie , Auinger Sonja , Faix Jan , Small J. Victor , Polo Simona , Stradal Theresia E.B. , Rottner Klemens
Published: May 2009

Dynamic actin rearrangements are initiated and maintained by actin filament nucleators, including the Arp2/3-complex. This protein assembly is activated in vitro by distinct nucleation-promoting factors such as Wiskott-Aldrich syndrome protein/Scar family proteins or cortactin, but the relative in vivo functions of each of them remain controversial. Here, we report the conditional genetic disruption of murine cortactin, implicated previously in dynamic actin reorganizations driving lamellipodium protrusion and endocytosis. Unexpectedly, cortactin-deficient cells showed little changes in overall cell morphology and growth. Ultrastructural analyses and live-cell imaging studies revealed unimpaired lamellipodial architecture, Rac-induced protrusion, and actin network turnover, although actin assembly rates in the lamellipodium were modestly increased. In contrast, platelet-derived growth factor-induced actin reorganization and Rac activation were impaired in cortactin null cells. In addition, cortactin deficiency caused reduction of Cdc42 activity and defects in random and directed cell migration. Reduced migration of cortactin null cells could be restored, at least in part, by active Rac and Cdc42 variants. Finally, cortactin removal did not affect the efficiency of receptor-mediated endocytosis. Together, we conclude that cortactin is fully dispensable for Arp2/3-complex activation during lamellipodia protrusion or clathrin pit endocytosis. Furthermore, we propose that cortactin promotes cell migration indirectly, through contributing to activation of selected Rho-GTPases.
A global meta-analysis of microarray expression data to predict unknown gene functions and estimate the literature-data divide
Authors: Wren Jonathan D.
Published: May 2009

Motivation: Approximately 9334 (37%) of Human genes have no publications documenting their function and, for those that are published, the number of publications per gene is highly skewed. Furthermore, for reasons not clear, the entry of new gene names into the literature has slowed in recent years. If we are to better understand human/mammalian biology and complete the catalog of human gene function, it is important to finish predicting putative functions for these genes based upon existing experimental evidence.

Results: A global meta-analysis (GMA) of all publicly available GEO two-channel human microarray datasets (3551 experiments total) was conducted to identify genes with recurrent, reproducible patterns of co-regulation across different conditions. Patterns of co-expression were divided into parallel (i.e. genes are up and down-regulated together) and anti-parallel. Several ranking methods to predict a gene's function based on its top 20 co-expressed gene pairs were compared. In the best method, 34% of predicted Gene Ontology (GO) categories matched exactly with the known GO categories for ∼5000 genes analyzed versus only 3% for random gene sets. Only 2.4% of co-expressed gene pairs were found as co-occurring gene pairs in MEDLINE.

Conclusions: Via a GO enrichment analysis, genes co-expressed in parallel with the query gene were frequently associated with the same GO categories, whereas anti-parallel genes were not. Combining parallel and anti-parallel genes for analysis resulted in fewer significant GO categories, suggesting they are best analyzed separately. Expression databases contain much unexpected genetic knowledge that has not yet been reported in the literature. A total of 1642 Human genes with unknown function were differentially expressed in at least 30 experiments.

Availability: Data matrix available upon request.

Contact:  jdwren@gmail.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
Highly accelerated feature detection in proteomics data sets using modern graphics processing units
Authors: Hussong Rene , Gregorius Barbara , Tholey Andreas , Hildebrandt Andreas
Published: May 2009

Motivation: Mass spectrometry (MS) is one of the most important techniques for high-throughput analysis in proteomics research. Due to the large number of different proteins and their post-translationally modified variants, the amount of data generated by a single wet-lab MS experiment can easily exceed several gigabytes. Hence, the time necessary to analyze and interpret the measured data is often significantly larger than the time spent on sample preparation and the wet-lab experiment itself. Since the automated analysis of this data is hampered by noise and baseline artifacts, more sophisticated computational techniques are required to handle the recorded mass spectra. Obviously, there is a clear tradeoff between performance and quality of the analysis, which is currently one of the most challenging problems in computational proteomics.

Results: Using modern graphics processing units (GPUs), we implemented a feature finding algorithm based on a hand-tailored adaptive wavelet transform that drastically reduces the computation time. A further speedup can be achieved exploiting the multi-core architecture of current computing devices, which leads to up to an approximately 200-fold speedup in our computational experiments. In addition, we will demonstrate that several approximations necessary on the CPU to keep run times bearable, become obsolete on the GPU, yielding not only faster, but also improved results.

Availability: An open source implementation of the CUDA-based algorithm is available via the software framework OpenMS (http://www.openms.de).

Contact:  rene@bioinf.uni-sb.de; anhi@bioinf.uni-sb.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Structure discovery in PPI networks using pattern-based network decomposition
Authors: Bachman Philip , Liu Ying
Published: May 2009

Motivation: The large, complex networks of interactions between proteins provide a lens through which one can examine the structure and function of biological systems. Previous analyses of these continually growing networks have primarily followed either of two approaches: large-scale statistical analysis of holistic network properties, or small-scale analysis of local topological features. Meanwhile, investigation of meso-scale network structure (above that of individual functional modules, while maintaining the significance of individual proteins) has been hindered by the computational complexity of structural search in networks. Examining protein–protein interaction (PPI) networks at the meso-scale may provide insights into the presence and form of relationships between individual protein complexes and functional modules.

Results: In this article, we present an efficient algorithm for performing sub-graph isomorphism queries on a network and show its computational advantage over previous methods. We also present a novel application of this form of topological search which permits analysis of a network's structure at a scale between that of individual functional modules and that of network-wide properties. This analysis provides support for the presence of hierarchical modularity in the PPI network of Saccharomyces cerevisiae.

Contact:  ying.liu@utdallas.edu
Hierarchical hidden Markov model with application to joint analysis of ChIP-chip and ChIP-seq data
Authors: Choi Hyungwon , Nesvizhskii Alexey I. , Ghosh Debashis , Qin Zhaohui S.
Published: May 2009

Motivation: Chromatin immunoprecipitation (ChIP) experiments followed by array hybridization, or ChIP-chip, is a powerful approach for identifying transcription factor binding sites (TFBS) and has been widely used. Recently, massively parallel sequencing coupled with ChIP experiments (ChIP-seq) has been increasingly used as an alternative to ChIP-chip, offering cost-effective genome-wide coverage and resolution up to a single base pair. For many well-studied TFs, both ChIP-seq and ChIP-chip experiments have been applied and their data are publicly available. Previous analyses have revealed substantial technology-specific binding signals despite strong correlation between the two sets of results. Therefore, it is of interest to see whether the two data sources can be combined to enhance the detection of TFBS.

Results: In this work, hierarchical hidden Markov model (HHMM) is proposed for combining data from ChIP-seq and ChIP-chip. In HHMM, inference results from individual HMMs in ChIP-seq and ChIP-chip experiments are summarized by a higher level HMM. Simulation studies show the advantage of HHMM when data from both technologies co-exist. Analysis of two well-studied TFs, NRSF and CCCTC-binding factor (CTCF), also suggests that HHMM yields improved TFBS identification in comparison to analyses using individual data sources or a simple merger of the two.

Availability: Source code for the software ChIPmeta is freely available for download at http://www.umich.edu/∼hwchoi/HHMMsoftware.zip, implemented in C and supported on linux.

Contact:  ghoshd@psu.edu; qin@umich.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Data structures and compression algorithms for genomic sequence data
Authors: Brandon Marty C. , Wallace Douglas C. , Baldi Pierre
Published: May 2009

Motivation: The continuing exponential accumulation of full genome data, including full diploid human genomes, creates new challenges not only for understanding genomic structure, function and evolution, but also for the storage, navigation and privacy of genomic data. Here, we develop data structures and algorithms for the efficient storage of genomic and other sequence data that may also facilitate querying and protecting the data.

Results: The general idea is to encode only the differences between a genome sequence and a reference sequence, using absolute or relative coordinates for the location of the differences. These locations and the corresponding differential variants can be encoded into binary strings using various entropy coding methods, from fixed codes such as Golomb and Elias codes, to variables codes, such as Huffman codes. We demonstrate the approach and various tradeoffs using highly variables human mitochondrial genome sequences as a testbed. With only a partial level of optimization, 3615 genome sequences occupying 56 MB in GenBank are compressed down to only 167 KB, achieving a 345-fold compression rate, using the revised Cambridge Reference Sequence as the reference sequence. Using the consensus sequence as the reference sequence, the data can be stored using only 133 KB, corresponding to a 433-fold level of compression, roughly a 23% improvement. Extensions to nuclear genomes and high-throughput sequencing data are discussed.

Availability: Data are publicly available from GenBank, the HapMap web site, and the MITOMAP database. Supplementary materials with additional results, statistics, and software implementations are available from http://mammag.web.uci.edu/bin/view/Mitowiki/ProjectDNACompression.

Contact:  pfbaldi@ics.uci.edu
Gradient lasso for Cox proportional hazards model
Authors: Sohn Insuk , Kim Jinseog , Jung Sin-Ho , Park Changyi
Published: May 2009

Motivation: There has been an increasing interest in expressing a survival phenotype (e.g. time to cancer recurrence or death) or its distribution in terms of a subset of the expression data of a subset of genes. Due to high dimensionality of gene expression data, however, there is a serious problem of collinearity in fitting a prediction model, e.g. Cox's proportional hazards model. To avoid the collinearity problem, several methods based on penalized Cox proportional hazards models have been proposed. However, those methods suffer from severe computational problems, such as slow or even failed convergence, because of high-dimensional matrix inversions required for model fitting. We propose to implement the penalized Cox regression with a lasso penalty via the gradient lasso algorithm that yields faster convergence to the global optimum than do other algorithms. Moreover the gradient lasso algorithm is guaranteed to converge to the optimum under mild regularity conditions. Hence, our gradient lasso algorithm can be a useful tool in developing a prediction model based on high-dimensional covariates including gene expression data.

Results: Results from simulation studies showed that the prediction model by gradient lasso recovers the prognostic genes. Also results from diffuse large B-cell lymphoma datasets and Norway/Stanford breast cancer dataset indicate that our method is very competitive compared with popular existing methods by Park and Hastie and Goeman in its computational time, prediction and selectivity.

Availability: R package glcoxph is available at http://datamining.dongguk.ac.kr/R/glcoxph.

Contact:  park463@uos.ac.kr
Relating periodicity of nucleosome organization and gene regulation
Authors: Wan Jun , Lin Jimmy , Zack Donald J. , Qian Jiang
Published: May 2009

Motivation: The relationship between nucleosome positioning and gene regulation is fundamental yet complex. Previous studies on genomic nucleosome positions have revealed a correlation between nucleosome occupancy on promoters and gene expression levels. Many of these studies focused on individual nucleosomes, especially those proximal to transcription start sites. To study the collective effect of multiple nucleosomes on the gene expression, we developed a mathematical approach based on autocorrelation to relate genomic nucleosome organization to gene regulation.

Results: We found that nucleosome organization in gene promoters can be well described by autocorrelation transformation. Some promoters show obvious periods in their nucleosome organization, while others have no clear periodicity. The genes with periodic nucleosome organization in promoters tend to be lower expressed than the genes without periodic nucleosome organization. These suggest that regular organization of nucleosomes plays a critical role in gene regulation. To quantitatively associate nucleosome organization and gene expression, we predicted gene expression solely based on nucleosome status and found that nucleosome status accounts for ∼25% of the observed gene expression variability. Furthermore, we explored the underlying forces that maintain the periodicity in nucleosome organization, namely intrinsic (i.e. DNA sequence) and extrinsic forces (i.e. chromatin remodeling factors). We found that the extrinsic factors play a critical role in maintaining the periodic nucleosome organization.

Contact:  jiang.qian@jhmi.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Integrative analysis of transcriptomic and proteomic data of Desulfovibrio vulgaris: a non-linear model to predict abundance of undetected proteins
Authors: Torres-García Wandaliz , Zhang Weiwen , Runger George C. , Johnson Roger H. , Meldrum Deirdre R.
Published: May 2009

Motivation: Gene expression profiling technologies can generally produce mRNA abundance data for all genes in a genome. A dearth of proteomic data persists because identification range and sensitivity of proteomic measurements lag behind those of transcriptomic measurements. Using partial proteomic data, it is likely that integrative transcriptomic and proteomic analysis may introduce significant bias. Developing methodologies to accurately estimate missing proteomic data will allow better integration of transcriptomic and proteomic datasets and provide deeper insight into metabolic mechanisms underlying complex biological systems.

Results: In this study, we present a non-linear data-driven model to predict abundance for undetected proteins using two independent datasets of cognate transcriptomic and proteomic data collected from Desulfovibrio vulgaris. We use stochastic gradient boosted trees (GBT) to uncover possible non-linear relationships between transcriptomic and proteomic data, and to predict protein abundance for the proteins not experimentally detected based on relevant predictors such as mRNA abundance, cellular role, molecular weight, sequence length, protein length, guanine-cytosine (GC) content and triple codon counts. Initially, we constructed a GBT model using all possible variables to assess their relative importance and characterize the behavior of the predictive model. A strong plateau effect in the regions of high mRNA values and sparse data occurred in this model. Hence, we removed genes in those areas based on thresholds estimated from the partial dependency plots where this behavior was captured. At this stage, only the strongest predictors of protein abundance were retained to reduce the complexity of the GBT model. After removing genes in the plateau region, mRNA abundance, main cellular functional categories and few triple codon counts emerged as the top-ranked predictors of protein abundance. We then created a new tuned GBT model using the five most significant predictors. The construction of our non-linear model consists of a set of serial regression trees models with implicit strength in variable selection. The model provides variable relative importance measures using as a criterion mean square error. The results showed that coefficients of determination for our nonlinear models ranged from 0.393 to 0.582 in both datasets, providing better results than linear regression used in the past. We evaluated the validity of this non-linear model using biological information of operons, regulons and pathways, and the results demonstrated that the coefficients of variation of estimated protein abundance values within operons, regulons or pathways are indeed smaller than those for random groups of proteins.

Contact:  weiwen.zhang@asu.edu; george.runger@asu.edu

Supplementary Information:  Supplementary data are available at Bioinformatics online.
A two-stage biomass model for Irish Sea herring allowing for additional variance in the recruitment index caused by mixing of stocks
Authors: Roel Beatriz A. , De Oliveira José A. A. , Beggs Steven
Published: May 2009

Roel, B. A., De Oliveira, J. A. A., and Beggs, S. 2009. A two-stage biomass model for Irish Sea herring allowing for additional variance in the recruitment index caused by mixing of stocks. – ICES Journal of Marine Science, 66: 1808–1813. An assessment of Irish Sea (ICES Division VIIa, North) herring using a two-stage biomass model was undertaken given lack of internal consistency in the survey age-disaggregated index. The model constrains recruitment variability and reduces the number of catchability parameters to address concerns of overparameterization. An extra parameter was incorporated to estimate the component of the variance resulting from the mixing of Celtic Sea and Irish Sea juvenile herring in the survey area. This additional variance, although imprecise, represented a large part of the total variance associated with the recruit survey data. More information on the variability of Irish Sea herring recruitment is required to estimate additional variance in the context of the two-stage biomass model presented. Limitations in the age-composition data and potential interannual variation in the selection pattern of the fishery favour an assessment method, such as the two-stage biomass method, which is based on a simplified age structure and does not require separability assumptions.
Parental Worries and Beliefs About Abdominal Pain
Authors: van Tilburg Miranda AL , Chitkara Denesh K , Palsson Olafur S , Levy Rona L , Whitehead William E
Published: May 2009

Background:

Solicitous parental responses to stomachaches may perpetuate chronic abdominal pain in children. Discussing these issues in clinical practice is difficult because parents feel misunderstood and blamed for their child's pain. Focusing on parental worries and beliefs that motivate solicitous responses may be better accepted.

Objectives:

Our aim was to determine parental fears, worries, and beliefs about their child's chronic abdominal pain that influence parental responses to child's pain.

Materials and Methods:

In 2 studies, a large online sample and a smaller community sample consisting of parents with children who have abdominal pain, we developed and evaluated a self‐report questionnaire to assess parental Worries and Beliefs about Abdominal Pain (WAP).

Results:

Principal component analysis identified 4 subscales: “pain is real,” “desire for care,” “worry about coping,” and “exacerbating factors.” The WAP is easily understood and possesses adequate initial reliability (Cronbach α = 0.7–0.9). It shows good initial validity (ie, families who consulted a physician for their child's pain scored higher on the WAP than families who did not consult a physician and the WAP correlates with parental reactions to the child's pain).

Conclusions:

Discussing parents' fears and worries about their children's chronic abdominal pain may facilitate discussions of social learning of gastrointestinal illness behavior.
Trends in Nonalcoholic Fatty Liver Disease–related Hospitalizations in US Children, Adolescents, and Young Adults
Authors: Koebnick Corinna , Getahun Darios , Reynolds Kristi , Coleman Karen J , Porter Amy H , Lawrence Jean M , Punyanitya Mark , Quinn Virginia P , Jacobsen Steven J
Published: May 2009

Objective:

To investigate temporal trends of nonalcoholic fatty liver disease (NAFLD) and obesity among hospitalized US children, adolescents, and young adults over the past 2 decades and to examine potential sex disparities in NAFLD hospitalizations.

Methods:

Hospitalization discharges with NAFLD or obesity were identified among children and young adults (6–25 years, weighted n = 91,687,413) from the 1986 to 2006 National Hospital Discharge Survey data. Age‐ and sex‐specific rates and trends in hospitalizations with NAFLD and obesity were estimated. Rates were standardized to age distribution of the 2000 US Census population. Sex disparities were examined for the most recent period 2004 to 2006 (weighted n = 12,969,532).

Results:

Between 1986 to 1988 and 2004 to 2006, hospitalizations with NAFLD diagnosis increased from 0.9 to 4.3/100,000 population (P < 0.001). During the same time, hospitalizations with a diagnosis of obesity increased from 35.5 to 114.7/100,000 population (P < 0.001). During 2004 to 2006, hospitalization rates with a diagnosis of NAFLD were higher among females than among males (5.9 vs 2.7/100,000 population, P < 0.001), as were hospitalizations with a diagnosis of obesity (140.8 vs 61.5/100,000 population, P < 0.001). Obesity and diabetes were reported in 43.3% and 31.9%, respectively, of discharges with NAFLD.

Conclusion:

The prevalence of NAFLD among young hospitalized patients increased in the past 2 decades, paralleling obesity‐related hospitalizations. This could be a consequence of the obesity epidemic or of increased screening for liver disease.
Evolving Concepts of the Pathogenesis of Irritable Bowel Syndrome: To Treat the Brain or the Gut?
Authors: Camilleri Michael
Published: May 2009

Recent in‐depth studies of irritable bowel syndrome (IBS) that assessed multiple physiological endpoints in large patient cohorts confirm evidence of abnormal motility, sensation, and psychosocial disturbances. However, the proportion with hypersensitivity has dropped from the time of the original claim that it is a “biological marker” of IBS. Discomfort thresholds in male and female IBS patients normalize over time, whereas IBS symptoms persist, and increased colonic sensitivity in IBS is strongly influenced by a psychological tendency to report pain and urge rather than increased neurosensory sensitivity. The objectives of this article are to review the classical pathophysiology of IBS, the putative roles of infection, inflammation, and bacterial flora; consider mimics of IBS; assess the evidence that IBS is a serotonergic disease; evaluate recent advances in membrane biology and neuroscience related to IBS; consider genetic association with IBS and its endophenotype; and discuss whether to treat the gut or the brain.
New Frontiers in the Treatment of Hirschsprung Disease
Authors: Thapar Nikhil
Published: May 2009

Background:

Hirschsprung disease (HSCR) is the most common identifiable developmental disorder of the enteric nervous system (ENS), characterized by a failure of its formation in a variable segment of distal bowel. Currently available surgical therapies for HSCR, although lifesaving, are associated with an unsatisfactory long‐term prognosis for many, highlighting the need for newer curative therapies. On the basis of our understanding of ENS development, 1 potential therapeutic tool relates to the cells that gave rise to the ENS during embryogenesis. Data from initial animal studies suggested that such “ENS stem cells” persist within postnatal gut, from which they can be harvested and used to replenish absent nerves within experimental models of gut aganglionosis. More recently, it has been shown that ENS stem cells can also be isolated from human postnatal gut. The early human studies, however, used full‐thickness gut tissue obtained at surgery to generate ENS stem cells, which in clinical terms poses practical problems. In an effort to directly address such obstacles our latest research has shown that ENS stem cells can also be harvested from gut mucosal biopsies obtained at routine endoscopy. Such gut mucosal ENS stem cells are capable of appropriately and fully colonizing aganglionic gut tissue, including from HSCR, to generate components of a mature and functional ENS.

Conclusions:

Current evidence suggests that transplantation of ENS stem cells, sourced from easily accessible postnatal gut, could be a viable alternative treatment for HSCR and ultimately for a number of other congenital or acquired ENS disorders.
Where do penguins go during the inter-breeding period? Using geolocation to track the winter dispersion of the macaroni penguin
Authors: Bost C. A. , Thiebot J. B. , Pinaud D. , Cherel Y. , Trathan P. N.
Published: May 2009

Although penguins are key marine predators from the Southern Ocean, their migratory behaviour during the inter-nesting period remains widely unknown. Here, we report for the first time, to our knowledge, the winter foraging movements and feeding habits of a penguin species by using geolocation sensors fitted on penguins with a new attachment method. We focused on the macaroni penguin
Eudyptes chrysolophus
at Kerguelen, the single largest consumer of marine prey among all seabirds. Overall, macaroni penguins performed very long winter trips, remaining at sea during approximately six months within the limits of the Southern Ocean. They departed from Kerguelen in an eastward direction and distributed widely, over more than 3.10
6
km
2
. The penguins spent most of their time in a previously unrecognized foraging area, i.e. a narrow latitudinal band (47–49° S) within the central Indian Ocean (70–110° E), corresponding oceanographically to the Polar Frontal Zone. There, their blood isotopic niche indicated that macaroni penguins preyed mainly upon crustaceans, but not on Antarctic krill
Euphausia superba
, which does not occur at these northern latitudes. Such winter information is a crucial step for a better integrative approach for the conservation of this species whose world population is known to be declining.
Darwin would have loved DNA: celebrating Darwin 200
Authors: Bromham Lindell
Published: May 2009

Analysis of DNA sequences now plays a key role in evolutionary biology research. If Darwin were to come back today, I think he would be absolutely delighted with molecular evolutionary genetics, for three reasons. First, it solved one of the greatest problems for his theory of evolution by natural selection. Second, it gives us a tool that can be used to investigate many of the questions he found the most fascinating. And third, DNA data confirm Darwin's grand view of evolution.
The ethical landscape: identifying the right way to think about the ethical and societal aspects of synthetic biology research and products
Authors: Yearley Steven
Published: May 2009

Synthetic biology promises to be highly innovative in its contribution to scientific understanding. But it offers other sorts of innovation too: in the variety of applications that could result and in the wide range of practitioners who could become involved. But directly corresponding to each of these is a kind of regulatory concern. If the entry barriers are low for a form of scientific practice with dramatic implications then the need for regulatory control over access is great since no one wants unlicensed operators releasing experimental organisms. If there are likely to be extensive opportunities for application within the human body and in the open environment (for energy production or novel forms of bioremediation) then the release and safety-testing implications are potentially enormous. Proponents of synthetic biology have been quick to realise that these challenges call for reviews of the societal and ethical aspects of synthetic biology. This paper shows that the template commonly adopted for such reviews draws on bioethics. It goes on to show that this template is far from ideal, both because of limitations in the way that bioethics has been institutionalized and because of key differences between the regulatory demands on synthetic biology and on bioethics. The paper concludes that broader models of societal and ethical review of synthetic biology are urgently required.
Mathematical modelling of the active hearing process in mosquitoes
Authors: Avitabile D. , Homer M. , Champneys A. R. , Jackson J. C. , Robert D.
Published: May 2009

Insects have evolved diverse and delicate morphological structures in order to capture the inherently low energy of a propagating sound wave. In mosquitoes, the capture of acoustic energy and its transduction into neuronal signals are assisted by the active mechanical participation of the scolopidia. We propose a simple microscopic mechanistic model of the active amplification in the mosquito speciesToxorhynchites brevipalpis. The model is based on the description of the antenna as a forced-damped oscillator coupled to a set of active threads (ensembles of scolopidia) that provide an impulsive force when they twitch. This twitching is in turn controlled by channels that are opened and closed if the antennal oscillation reaches a critical amplitude. The model matches both qualitatively and quantitatively with recent experiments: spontaneous oscillations, nonlinear amplification, hysteresis, 2 : 1 resonances, frequency response and gain loss owing to hypoxia. The numerical simulations presented here also generate new hypotheses. In particular, the model seems to indicate that scolopidia located towards the tip of Johnston's organ are responsible for the entrainment of the other scolopidia and that they give the largest contribution to the mechanical amplification.
North–South divide: contrasting impacts of climate change on crop yields in Scotland and England
Authors: Butterworth Michael H. , Semenov Mikhail A. , Barnes Andrew , Moran Dominic , West Jonathan S. , Fitt Bruce D. L.
Published: May 2009

Effects of climate change on productivity of agricultural crops in relation to diseases that attack them are difficult to predict because they are complex and nonlinear. To investigate these crop–disease–climate interactions, UKCIP02 scenarios predicting UK temperature and rainfall under high- and low-CO
2
emission scenarios for the 2020s and 2050s were combined with a crop-simulation model predicting yield of fungicide-treated winter oilseed rape and with a weather-based regression model predicting severity of phoma stem canker epidemics. The combination of climate scenarios and crop model predicted that climate change will increase yield of fungicide-treated oilseed rape crops in Scotland by up to 0.5 t ha
−1
(15%). In contrast, in southern England the combination of climate scenarios, crop, disease and yield loss models predicted that climate change will increase yield losses from phoma stem canker epidemics to up to 50 per cent (1.5 t ha
−1
) and greatly decrease yield of untreated winter oilseed rape. The size of losses is predicted to be greater for winter oilseed rape cultivars that are susceptible than for those that are resistant to the phoma stem canker pathogen
Leptosphaeria maculans
. Such predictions illustrate the unexpected, contrasting impacts of aspects of climate change on crop–disease interactions in agricultural systems in different regions.
Deformable wing kinematics in free-flying hoverflies
Authors: Walker Simon M. , Thomas Adrian L. R. , Taylor Graham K.
Published: May 2009

Here, we present a detailed analysis of the deforming wing kinematics of free-flying hoverflies (Eristalis tenax, Linnaeus) during hovering flight. We used four high-speed digital video cameras to reconstruct the motion of approximately 22 points on each wing using photogrammetric techniques. While the root-flapping motion of the wing is similar in both the downstroke and upstroke, and is well modelled as a simple harmonic motion, other wing kinematic parameters show substantial variation between the downstroke and upstroke. Whereas the magnitude of the angle of incidence varies considerably within and between different hoverflies, the twist distribution along the wing is highly stereotyped. The angle of incidence and camber both show a recoil effect as they change abruptly at stroke reversal. Pronation occurs consistently after stroke reversal, which is perhaps surprising, because this has been found to reduce lift production in modelling studies. We find that the alula, a hinged flap near the base of the wing, operates in two discrete states: either in plane with the wing, or flipped approximately normal to it. We hypothesize that the alula may be acting as a flow-control device.
Overlapping pools for high-throughput targeted resequencing
Authors: Prabhu Snehit , Pe'er Itsik
Published: May 2009

Resequencing genomic DNA from pools of individuals is an effective strategy to detect new variants in targeted regions and compare them between cases and controls. There are numerous ways to assign individuals to the pools on which they are to be sequenced. The naïve, disjoint pooling scheme (many individuals to one pool) in predominant use today offers insight into allele frequencies, but does not offer the identity of an allele carrier. We present a framework for overlapping pool design, where each individual sample is resequenced in several pools (many individuals to many pools). Upon discovering a variant, the set of pools where this variant is observed reveals the identity of its carrier. We formalize the mathematical framework for such pool designs and list the requirements from such designs. We specifically address three practical concerns for pooled resequencing designs: (1) false-positives due to errors introduced during amplification and sequencing; (2) false-negatives due to undersampling particular alleles aggravated by nonuniform coverage; and consequently, (3) ambiguous identification of individual carriers in the presence of errors. We build on theory of error-correcting codes to design pools that overcome these pitfalls. We show that in practical parameters of resequencing studies, our designs guarantee high probability of unambiguous singleton carrier identification while maintaining the features of naïve pools in terms of sensitivity, specificity, and the ability to estimate allele frequencies. We demonstrate the ability of our designs in extracting rare variations using short read data from the 1000 Genomes Pilot 3 project.
Combinatorial algorithms for structural variation detection in high-throughput sequenced genomes
Authors: Hormozdiari Fereydoun , Alkan Can , Eichler Evan E. , Sahinalp S. Cenk
Published: May 2009

Recent studies show that along with single nucleotide polymorphisms and small indels, larger structural variants among human individuals are common. The Human Genome Structural Variation Project aims to identify and classify deletions, insertions, and inversions (>5 Kbp) in a small number of normal individuals with a fosmid-based paired-end sequencing approach using traditional sequencing technologies. The realization of new ultra-high-throughput sequencing platforms now makes it feasible to detect the full spectrum of genomic variation among many individual genomes, including cancer patients and others suffering from diseases of genomic origin. Unfortunately, existing algorithms for identifying structural variation (SV) among individuals have not been designed to handle the short read lengths and the errors implied by the “next-gen” sequencing (NGS) technologies. In this paper, we give combinatorial formulations for the SV detection between a reference genome sequence and a next-gen-based, paired-end, whole genome shotgun-sequenced individual. We describe efficient algorithms for each of the formulations we give, which all turn out to be fast and quite reliable; they are also applicable to all next-gen sequencing methods (Illumina, 454 Life Sciences [Roche], ABI SOLiD, etc.) and traditional capillary sequencing technology. We apply our algorithms to identify SV among individual genomes very recently sequenced by Illumina technology.
Shifted Transversal Design smart-pooling for high coverage interactome mapping
Authors: Xin Xiaofeng , Rual Jean-François , Hirozane-Kishikawa Tomoko , Hill David E. , Vidal Marc , Boone Charles , Thierry-Mieg Nicolas
Published: May 2009

“Smart-pooling,” in which test reagents are multiplexed in a highly redundant manner, is a promising strategy for achieving high efficiency, sensitivity, and specificity in systems-level projects. However, previous applications relied on low redundancy designs that do not leverage the full potential of smart-pooling, and more powerful theoretical constructions, such as the Shifted Transversal Design (STD), lack experimental validation. Here we evaluate STD smart-pooling in yeast two-hybrid (Y2H) interactome mapping. We employed two STD designs and two established methods to perform ORFeome-wide Y2H screens with 12 baits. We found that STD pooling achieves similar levels of sensitivity and specificity as one-on-one array-based Y2H, while the costs and workloads are divided by three. The screening-sequencing approach is the most cost- and labor-efficient, yet STD identifies about twofold more interactions. Screening-sequencing remains an appropriate method for quickly producing low-coverage interactomes, while STD pooling appears as the method of choice for obtaining maps with higher coverage.
DNA Sudoku—harnessing high-throughput sequencing for multiplexed specimen analysis
Authors: Erlich Yaniv , Chang Kenneth , Gordon Assaf , Ronen Roy , Navon Oron , Rooks Michelle , Hannon Gregory J.
Published: May 2009

Next-generation sequencers have sufficient power to analyze simultaneously DNAs from many different specimens, a practice known as multiplexing. Such schemes rely on the ability to associate each sequence read with the specimen from which it was derived. The current practice of appending molecular barcodes prior to pooling is practical for parallel analysis of up to many dozen samples. Here, we report a strategy that permits simultaneous analysis of tens of thousands of specimens. Our approach relies on the use of combinatorial pooling strategies in which pools rather than individual specimens are assigned barcodes. Thus, the identity of each specimen is encoded within the pooling pattern rather than by its association with a particular sequence tag. Decoding the pattern allows the sequence of an original specimen to be inferred with high confidence. We verified the ability of our encoding and decoding strategies to accurately report the sequence of individual samples within a large number of mixed specimens in two ways. First, we simulated data both from a clone library and from a human population in which a sequence variant associated with cystic fibrosis was present. Second, we actually pooled, sequenced, and decoded identities within two sets of 40,000 bacterial clones comprising approximately 20,000 different artificial microRNAs targetingArabidopsisor human genes. We achieved greater than 97% accuracy in these trials. The strategies reported here can be applied to a wide variety of biological problems, including the determination of genotypic variation within large populations of individuals.
The Organization Pattern of Root Border-Like Cells of Arabidopsis Is Dependent on Cell Wall Homogalacturonan
Authors: Durand Caroline , Vicré-Gibouin Maïté , Follet-Gueye Marie Laure , Duponchel Ludovic , Moreau Myriam , Lerouge Patrice , Driouich Azeddine
Published: May 2009

Border-like cells are released by Arabidopsis (Arabidopsis thaliana) root tips as organized layers of several cells that remain attached to each other rather than completely detached from each other, as is usually observed in border cells of many species. Unlike border cells, cell attachment between border-like cells is maintained after their release into the external environment. To investigate the role of cell wall polysaccharides in the attachment and organization of border-like cells, we have examined their release in several well-characterized mutants defective in the biosynthesis of xyloglucan, cellulose, or pectin. Our data show that among all mutants examined, only quasimodo mutants (qua1-1 and qua2-1), which have been characterized as producing less homogalacturonan, had an altered border-like cell phenotype as compared with the wild type. Border-like cells in both lines were released as isolated cells separated from each other, with the phenotype being much more pronounced in qua1-1 than in qua2-1. Further analysis of border-like cells in the qua1-1 mutant using immunocytochemistry and a set of anti-cell wall polysaccharide antibodies showed that the loss of the wild-type phenotype was accompanied by (1) a reduction in homogalacturonan-JIM5 epitope in the cell wall of border-like cells, confirmed by Fourier transform infrared microspectrometry, and (2) the secretion of an abundant mucilage that is enriched in xylogalacturonan and arabinogalactan-protein epitopes, in which the cells are trapped in the vicinity of the root tip.