Full Documentation Research Articles

Emergence, Agency, and Interaction-Notes from the Field.

This article describes the development of several interactive installations and robotic artworks developed through the 1990s and the technological, theoretical, and discursive context in which those works arose. The main works discussed are Petit Mal (1989-1995), Sympathetic Sentience (1996-1997), Fugitive I (1996-1997), Traces (1998-1999), and Fugitive II (2001-2004)-full documentation at ( www.simonpenny.net/works ). These works were motivated by a critical analysis of cognitivist computer science, which contrasted with notions of embodied experience arising from the arts. The works address questions of agency and interaction, informed by cybernetics and artificial life.

KMCLib 1.1: Extended random number support and technical updates to the KMCLib general framework for kinetic Monte-Carlo simulations

We here present a revised version, v1.1, of the KMCLib general framework for kinetic Monte-Carlo (KMC) simulations. The generation of random numbers in KMCLib now relies on the C++11 standard libra ...

Scikit-spectra: Explorative Spectroscopy in Python

Scikit-spectra is an intuitive framework for explorative spectroscopy in Python. Scikit-spectra leverages the Pandas library for powerful data processing to provide datastructures and an API designed for spectroscopy. Utilizing the new IPython Notebook widget system, scikit-spectra is headed towards a GUI when you want it, API when you need it approach to spectral analysis. As an application, analysis is presented of the surface-plasmon resonance shift in a solution of gold nanoparticles induced by proteins binding to the gold’s surface. Please refer to the scikit-spectra website for full documentation and support: http://hugadams.github.io/scikit-spectra/

NEW THEBAN TOMBS MAPPING PROJECT (NTTMP) PRELIMINARY REPORT, SEASONS 2014-2015 (a)

Thebes (Luxor) and its necropolis were involved in the world heritage list in 1979. The NTTMP project intends to contribute to the archaeological and topographical exploration of the Theban necropolis and it's layout as a world heritage site. Enhancing the value of newly discovered tombs will attract scholars and foreign missions to work and raise funds to preserve these tombs. Many maps were drawn for the Theban necropolis until the end of the 20th century. After the demolition of the modern village of al-Qurna and its houses in 2005, no up-to-date maps were established for the site including the newly discovered tombs. The last complete mapping project for the whole necropolis was accomplished by F. Kampp in 1989.Her results were published in 1996. In addition to previous surveys such as the Metropolitan Museum of Fine Arts mapping project and the survey of Porter & Moss, P. Piccione conducted another survey for the site of Sheikh Abdel-Qurna in 2005.One of the main issues of NTTMP therefore is to provide a general map of the entire necropolis including known and newly discovered tombs with full documentation and a consistent numbering system.

TcR: an R package for T cell receptor repertoire advanced data analysis.

BackgroundThe Immunoglobulins (IG) and the T cell receptors (TR) play the key role in antigen recognition during the adaptive immune response. Recent progress in next-generation sequencing technologies has provided an opportunity for the deep T cell receptor repertoire profiling. However, a specialised software is required for the rational analysis of massive data generated by next-generation sequencing.ResultsHere we introduce tcR, a new R package, representing a platform for the advanced analysis of T cell receptor repertoires, which includes diversity measures, shared T cell receptor sequences identification, gene usage statistics computation and other widely used methods. The tool has proven its utility in recent research studies.ConclusionstcR is an R package for the advanced analysis of T cell receptor repertoires after primary TR sequences extraction from raw sequencing reads. The stable version can be directly installed from The Comprehensive R Archive Network (http://cran.r-project.org/mirrors.html). The source code and development version are available at tcR GitHub (http://imminfo.github.io/tcr/) along with the full documentation and typical usage examples.

CoMET: visualisation of regional epigenome-wide association scan results and DNA co-methylation patterns.

BackgroundEpigenome-wide association scans (EWAS) are an increasingly powerful and widely-used approach to assess the role of epigenetic variation in human complex traits. However, this rapidly emerging field lacks dedicated visualisation tools that can display features specific to epigenetic datasets.ResultWe developed coMET, an R package and online tool for visualisation of EWAS results in a genomic region of interest. coMET generates a regional plot of epigenetic-phenotype association results and the estimated DNA methylation correlation between CpG sites (co-methylation), with further options to visualise genomic annotations based on ENCODE data, gene tracks, reference CpG-sites, and user-defined features. The tool can be used to display phenotype association signals and correlation patterns of microarray or sequencing-based DNA methylation data, such as Illumina Infinium 450k, WGBS, or MeDIP-seq, as well as other types of genomic data, such as gene expression profiles. The software is available as a user-friendly online tool from http://epigen.kcl.ac.uk/cometand as an R Bioconductor package. Source code, examples, and full documentation are also available from GitHub.ConclusionOur new software allows visualisation of EWAS results with functional genomic annotations and with estimation of co-methylation patterns. coMET is available to a wide audience as an online tool and R package, and can be a valuable resource to interpret results in the fast growing field of epigenetics. The software is designed for epigenetic data, but can also be applied to genomic and functional genomic datasets in any species.

CCTop: An Intuitive, Flexible and Reliable CRISPR/Cas9 Target Prediction Tool.

Engineering of the CRISPR/Cas9 system has opened a plethora of new opportunities for site-directed mutagenesis and targeted genome modification. Fundamental to this is a stretch of twenty nucleotides at the 5’ end of a guide RNA that provides specificity to the bound Cas9 endonuclease. Since a sequence of twenty nucleotides can occur multiple times in a given genome and some mismatches seem to be accepted by the CRISPR/Cas9 complex, an efficient and reliable in silico selection and evaluation of the targeting site is key prerequisite for the experimental success. Here we present the CRISPR/Cas9 target online predictor (CCTop, http://crispr.cos.uni-heidelberg.de) to overcome limitations of already available tools. CCTop provides an intuitive user interface with reasonable default parameters that can easily be tuned by the user. From a given query sequence, CCTop identifies and ranks all candidate sgRNA target sites according to their off-target quality and displays full documentation. CCTop was experimentally validated for gene inactivation, non-homologous end-joining as well as homology directed repair. Thus, CCTop provides the bench biologist with a tool for the rapid and efficient identification of high quality target sites.

Lumbar Punctures at an Academic Level 4 NICU: Indications for a New Curriculum

Issue: Pediatric residents commonly perform lumbar punctures during their clinical training. The objective of this study was to assess residents’ rate of nontraumatic lumbar punctures, examine the adequacy of samples, and implement proper documentation of the procedure in an academic Level 4 Neonatal Intensive Care Unit. We hypothesize that traumatic taps are common and that documentation of the procedure is poor. Evidence: A retrospective chart review was done of infants admitted to the neonatal intensive care unit from January 2011 to November 2011 who underwent a lumbar puncture. Procedure notes were evaluated for completion of proper documentation, the lab specimen was assessed for red blood cell count less than 1,000 cells/mm3, and individuals were assessed for their ability to obtain a cerebrospinal fluid sample to send to the lab for analysis (i.e., sample of adequate volume and not clotted) and the total number of attempts to obtain a sample. A total of 184 charts were reviewed. Procedure notes were incomplete (58%) and lacked pertinent details. Eight percent of samples obtained had no record of the procedure being preformed. There was inadequate sample acquisition in 23% of the lumbar punctures. More than three attempts were noted in 14% of lumbar punctures performed. Many specimens contained very high red blood cell counts. Seventy-five percent of lumbar punctures with full documentation (n = 60), resulted in cerebrospinal fluid with more than 1,000 red blood cells/mm3 and 55% of underdocumented lumbar punctures resulted in cerebrospinal fluid with more than 1,000 red blood cells/mm3 (n = 71). Implications: We found that poorly documented lumbar punctures are common and the ability of residents to obtain satisfactory cerebrospinal fluid is low. The inability of residents to consistently perform nontraumatic lumbar punctures is likely a common phenomenon. New educational methods and evaluation criteria must be developed to address this gap in resident education.

Rock, paper, scissors: harnessing complementarity in ortholog detection methods improves comparative genomic inference.

Ortholog detection (OD) is a lynchpin of most statistical methods in comparative genomics. This task involves accurately identifying genes across species that descend from a common ancestral sequence. OD methods comprise a wide variety of approaches, each with their own benefits and costs under a variety of evolutionary and practical scenarios. In this article, we examine the proteomes of ten mammals by using four methodologically distinct, rigorously filtered OD methods. In head-to-head comparisons, we find that these algorithms significantly outperform one another for 38–45% of the genes analyzed. We leverage this high complementarity through the development MOSAIC, or Multiple Orthologous Sequence Analysis and Integration by Cluster optimization, the first tool for integrating methodologically diverse OD methods. Relative to the four methods examined, MOSAIC more than quintuples the number of alignments for which all species are present while simultaneously maintaining or improving functional-, phylogenetic-, and sequence identity-based measures of ortholog quality. Further, this improvement in alignment quality yields more confidently aligned sites and higher levels of overall conservation, while simultaneously detecting of up to 180% more positively selected sites. We close by highlighting a MOSAIC-specific positively selected sites near the active site of TPSAB1, an enzyme linked to asthma, heart disease, and irritable bowel disease. MOSAIC alignments, source code, and full documentation are available at http://pythonhosted.org/bio-MOSAIC.

Factors underlying short sales

The short sale process has emerged as the most common alternative to the traditional foreclosure process in the recent mortgage crisis. This paper examines the factors that affect the liquidation outcome between these two ways of disposing the housing asset. We find that better quality borrowers such as those with higher credit scores and with full documentation status are more likely to prefer and obtain approval of short sales, involvement of mortgage insurance firms and second lien holders reduces short sales, and that state foreclosure laws such as longer foreclosure delay and the statutory right of redemption reduce short sales. The results have implications for ostensibly borrower-friendly measures promoted by governmental entities.

Inflammatory bowel disease in pediatric patients: Characteristics of newly diagnosed patients from the CEDATA-GPGE Registry.

Inflammatory bowel disease (IBD) can arise at any age, with peak incidence in adolescence and young adulthood. A registry of pediatric cases of IBD offers the opportunity to document their diagnosis and treatment, with the ultimate aim of improving diagnosis and treatment in the future. In the German-language CEDATA-GPGE registry, 3991 cases of IBD in patients less than 18 years of age were documented from 2004 to 2014. The 1257 patients who were prospectively included in the registry upon diagnosis and whose further course was documented for at least three months were analyzed in two separate groups--under 10 years old, and 10 years and above--with respect to the type and duration of their symptoms until diagnosis, the completeness of the diagnostic evaluation, the disease phenotype, and the initial treatment. Of the 958 patients for whom full documentation was available, 616 (64.3%) had Crohn's disease (CD), 278 (29%) had ulcerative colitis (UC), 64 (6.7%) had an unclassified IBD, and 23.2% were under 10 years old. The latency to diagnosis was longer for CD than for UC (0.5 versus 0.3 years), regardless of age. 62.5% of the CD patients had ileocolonic involvement, and more than half had involvement of the upper gastrointestinal tract. 71% of the patients with UC had subtotal colitis or pancolitis. Continuous improvement was seen in diagnostic assessment according to published guidelines. For example, in 2004/2005, 69% of patients were evaluated endoscopically with ileocolonoscopy and esophagogastroduodenoscopy; this fraction had risen to nearly 100% by 2013/2014. Similarly, the percentage of patients who underwent a diagnostic evaluation of the small intestine, as recommended, rose from 41.2% to 60.9% over the same period. The most common initial treatments were 5- amino - salicylates (86.8% CD, 100% UC) and glucocorticoids (60.6% CD, 65.6% UC). 32% of the patients with CD received exclusive enteral nutrition therapy. Most of these pediatric patients with IBD, whether in the younger or the older age group, had extensive bowel involvement at the time of diagnosis. The registry data imply that improvement in clinical course may be achieved by shortening the time to diagnosis and by closer adherence to the diagnostic and therapeutic guidelines.

Mobility-based prediction of hydration structures of protein surfaces.

Hydration largely determines solubility, aggregation of proteins and influences interactions between proteins and drug molecules. Despite the importance of hydration, structural determination of hydration structure of protein surfaces is still challenging from both experimental and theoretical viewpoints. The precision of experimental measurements is often affected by fluctuations and mobility of water molecules resulting in uncertain assignment of water positions. Our method can utilize mobility as an information source for the prediction of hydration structure. The necessary information can be produced by molecular dynamics simulations accounting for all atomic interactions including water-water contacts. The predictions were validated and tested by comparison to more than 1500 crystallographic water positions in 20 hydrated protein molecules including enzymes of biomedical importance such as cyclin-dependent kinase 2. The agreement with experimental water positions was larger than 80% on average. The predictions can be particularly useful in situations where no or limited experimental knowledge is available on hydration structures of molecular surfaces. The method is implemented in a standalone C program MobyWat released under the GNU General Public License, freely accessible with full documentation at http://www.mobywat.com.

Comparison of classifications of vascular plants of China

AbstractChina has 31,362 species of vascular plants, more than any country on the planet except Brazil and Colombia, and this number represents 8%–12% of the world diversity of vascular plants. With the two largest completed floristic projects in the world, a full documentation of the vascular plants of China has been published twice over the past 54 years: the Chinese‐language Flora Reipublicae Popularis Sinicae (FRPS), 1959–2004, and the English‐language Flora of China (FOC), 1994–2013. With the advent of molecular phylogenetics the past half century has witnessed dramatical changes of classifications of vascular plants. In this paper, we compare the circumscriptions of all families of vascular plants occurring within China in FRPS, FOC, and the Angiosperm Phylogeny Group (APG) III system when applicable, and summarize familial assignments of all controversial genera in the different classifications. Such comparison to some extent reflects the history of classification of vascular plants and differences between classical morphology‐based classifications and modern DNA (mainly chloroplast) sequence data‐based classifications of vascular plants.

ValWorkBench: An open source Java library for cluster validation, with applications to microarray data analysis

The prediction of the number of clusters in a dataset, in particular microarrays, is a fundamental task in biological data analysis, usually performed via validation measures. Unfortunately, it has received very little attention and in fact there is a growing need for software tools/libraries dedicated to it. Here we present ValWorkBench, a software library consisting of eleven well known validation measures, together with novel heuristic approximations for some of them. The main objective of this paper is to provide the interested researcher with the full software documentation of an open source cluster validation platform having the main features of being easily extendible in a homogeneous way and of offering software components that can be readily re-used. Consequently, the focus of the presentation is on the architecture of the library, since it provides an essential map that can be used to access the full software documentation, which is available at the supplementary material website [1]. The mentioned main features of ValWorkBench are also discussed and exemplified, with emphasis on software abstraction design and re-usability. A comparison with existing cluster validation software libraries, mainly in terms of the mentioned features, is also offered. It suggests that ValWorkBench is a much needed contribution to the microarray software development/algorithm engineering community. For completeness, it is important to mention that previous accurate algorithmic experimental analysis of the relative merits of each of the implemented measures [19,23,25], carried out specifically on microarray data, gives useful insights on the effectiveness of ValWorkBench for cluster validation to researchers in the microarray community interested in its use for the mentioned task.

A Diffuse Large B-Cell Lymphoma Classification System That Associates Normal B-Cell Subset Phenotypes with Prognosis

▪BackgroundRecent findings have introduced biological classification of non-Hodgkin lymphomas as exemplified by the “activated B-cell-like” (ABC) and “germinal-center B-cell–like” (GCB) subgroups of diffuse large B-cell lymphoma (DLBCL).AimsThe goal is to generate a refined cell of origin (COO) classification that includes B-cell subset associated gene signatures (BAGS) from the normal B-cell hierarchy.MethodsWe have combined fluorescence activated cell sorting and gene expression profiling by Gene Chip HG U133 Plus 2.0 to generate five BAGS for naïve, germinal centrocytes and centroblasts, post germinal memory B-cells, and plasmablasts of normal human tonsils. Clinical data sets are the Aalborg Project CHEPRETRO (N=89), the Lymphoma/Leukemia Molecular Profiling Project LLMPP (N=233), the International DLBCL Rituximab-CHOP Consortium MD Anderson Project IDRC (N=460), the Mayo Clinic, Brigham & Women Hospital, and Dana-Farber Cancer Institute Project MDFCI (N=88) available on the GEO website. All statistical analyses were done with R version 3.0.1 and full documentation is provided by a Sweave document.ResultsFirst, we verified the quality of the sampled B-cell subsets based on the expression patterns of differentiation molecules, transcription factors, and genes matching biological knowledge. Next, we constructed a BAGS-classifier provided by 77-115 gene probe sets, capable of assigning samples to each of the five COO subtypes.Second, we assigned individual lymphoma cases in 5 patient cohorts including a total of 1063 patient. BAGS identified COO subtypes with frequencies of 2-7 % naïve (N), 35-41 % centrocytes (CC), 18-21 % centroblasts (CB), 4-15 % memory (M), 12-18 % plasmablast (PB), and 15-16 % unclassified (UC) subtypes. The frequencies was not different between cohorts (p=0.41).Third, the BAGS subtypes was associated significantly with overall survival and time to progression for R-CHOP–treated patients in clinical cohorts from the LLMPPN (p=0.0441/0.0358) and the IDRC Program (p=0.002/8e-04).Fourth, we found a very high fraction of GCB samples to be of CC or CB subtypes. On the contrary, a major fraction of BAGS-unclassified subtypes were of the ABC class. In a multiple Cox proportional hazards model we identified the BAGS subtypes to be a prognostic variables independent of ABC/GCB subtypes but not of IPI and age. The most significant impact was observed within the GCB subclass, where the GCB-CC subtype had superior prognosis compared to the GCB-CB subtype, in accordance with individual assignments for drug specific sensitivity to hydroxydaunomycin and vincristine.Fifth, we performed genetic evaluation of the BAGS subtypes by mutation analysis within the CHEPRETRO cohort for EZH2, CD79B, and MYD88 identifying frequencies of 6.3%, 10.1% and 14.7%, respectively. The EZH2 mutation was only identified in the GCBN-CC and -CB subtypes. Mutations of CD79B and MYD88 were preferential in ABC, present in all subtypes. The CC subtype had high p53 mutation and indel frequencies, whereas the CB subtype had high Chr12q15 amplification frequencies and a complex genotype. Finally, the CC subtype expressed LMO2, NF-κB targets, CD58, Stroma1, and MHCII genes, known to have prognostic impact.SummaryIn summary, this study addresses an unmet medical need for a new diagnostic platform for individual DLBCL classification of “cell of origin” phenotyping attempting to design new strategies and more effective disease management. DisclosuresNo relevant conflicts of interest to declare.

Integrating protein structural dynamics and evolutionary analysis with Bio3D.

BackgroundPopular bioinformatics approaches for studying protein functional dynamics include comparisons of crystallographic structures, molecular dynamics simulations and normal mode analysis. However, determining how observed displacements and predicted motions from these traditionally separate analyses relate to each other, as well as to the evolution of sequence, structure and function within large protein families, remains a considerable challenge. This is in part due to the general lack of tools that integrate information of molecular structure, dynamics and evolution.ResultsHere, we describe the integration of new methodologies for evolutionary sequence, structure and simulation analysis into the Bio3D package. This major update includes unique high-throughput normal mode analysis for examining and contrasting the dynamics of related proteins with non-identical sequences and structures, as well as new methods for quantifying dynamical couplings and their residue-wise dissection from correlation network analysis. These new methodologies are integrated with major biomolecular databases as well as established methods for evolutionary sequence and comparative structural analysis. New functionality for directly comparing results derived from normal modes, molecular dynamics and principal component analysis of heterogeneous experimental structure distributions is also included. We demonstrate these integrated capabilities with example applications to dihydrofolate reductase and heterotrimeric G-protein families along with a discussion of the mechanistic insight provided in each case.ConclusionsThe integration of structural dynamics and evolutionary analysis in Bio3D enables researchers to go beyond a prediction of single protein dynamics to investigate dynamical features across large protein families. The Bio3D package is distributed with full source code and extensive documentation as a platform independent R package under a GPL2 license from http://thegrantlab.org/bio3d/.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-014-0399-6) contains supplementary material, which is available to authorized users.

MOST: a software environment for constraint-based metabolic modeling and strain design.

MOST (metabolic optimization and simulation tool) is a software package that implements GDBB (genetic design through branch and bound) in an intuitive user-friendly interface with excel-like editing functionality, as well as implementing FBA (flux balance analysis), and supporting systems biology markup language and comma-separated values files. GDBB is currently the fastest algorithm for finding gene knockouts predicted by FBA to increase production of desired products, but GDBB has only been available on a command line interface, which is difficult to use for those without programming knowledge, until the release of MOST. MOST is distributed for free on the GNU General Public License. The software and full documentation are available at http://most.ccib.rutgers.edu/. dslun@rutgers.edu.

Adaptation of the ToxRTool to Assess the Reliability of Toxicology Studies Conducted with Genetically Modified Crops and Implications for Future Safety Testing

To determine the reliability of food safety studies carried out in rodents with genetically modified (GM) crops, a Food Safety Study Reliability Tool (FSSRTool) was adapted from the European Centre for the Validation of Alternative Methods’ (ECVAM) ToxRTool. Reliability was defined as the inherent quality of the study with regard to use of standardized testing methodology, full documentation of experimental procedures and results, and the plausibility of the findings. Codex guidelines for GM crop safety evaluations indicate toxicology studies are not needed when comparability of the GM crop to its conventional counterpart has been demonstrated. This guidance notwithstanding, animal feeding studies have routinely been conducted with GM crops, but their conclusions on safety are not always consistent. To accurately evaluate potential risks from GM crops, risk assessors need clearly interpretable results from reliable studies. The development of the FSSRTool, which provides the user with a means of assessing the reliability of a toxicology study to inform risk assessment, is discussed. Its application to the body of literature on GM crop food safety studies demonstrates that reliable studies report no toxicologically relevant differences between rodents fed GM crops or their non-GM comparators.

Evaluation of matched control algorithms in EHR-based phenotyping studies: A case study of inflammatory bowel disease comorbidities

The success of many population studies is determined by proper matching of cases to controls. Some of the confounding and bias that afflict electronic health record (EHR)-based observational studies may be reduced by creating effective methods for finding adequate controls. We implemented a method to match case and control populations to compensate for sparse and unequal data collection practices common in EHR data. We did this by matching the healthcare utilization of patients after observing that more complete data was collected on high healthcare utilization patients vs. low healthcare utilization patients. In our results, we show that many of the anomalous differences in population comparisons are mitigated using this matching method compared to other traditional age and gender-based matching. As an example, the comparison of the disease associations of ulcerative colitis and Crohn’s disease show differences that are not present when the controls are chosen in a random or even a matched age/gender/race algorithm. In conclusion, the use of healthcare utilization-based matching algorithms to find adequate controls greatly enhanced the accuracy of results in EHR studies. Full source code and documentation of the control matching methods is available at https://community.i2b2.org/wiki/display/conmat/.

Jvenn: an interactive Venn diagram viewer.

BackgroundVenn diagrams are commonly used to display list comparison. In biology, they are widely used to show the differences between gene lists originating from different differential analyses, for instance. They thus allow the comparison between different experimental conditions or between different methods. However, when the number of input lists exceeds four, the diagram becomes difficult to read. Alternative layouts and dynamic display features can improve its use and its readability.Resultsjvenn is a new JavaScript library. It processes lists and produces Venn diagrams. It handles up to six input lists and presents results using classical or Edwards-Venn layouts. User interactions can be controlled and customized. Finally, jvenn can easily be embeded in a web page, allowing to have dynamic Venn diagrams.Conclusionsjvenn is an open source component for web environments helping scientists to analyze their data. The library package, which comes with full documentation and an example, is freely available at http://bioinfo.genotoul.fr/jvenn.