bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ensemble-based evaluation for protein structure models
Authors: Jamroz Michal , Kolinski Andrzej , Kihara Daisuke 
Published: June 2016

Abstract
Motivation: Comparing protein tertiary structures is a fundamental procedure in structural biology and protein bioinformatics. Structure comparison is important particularly for evaluating computational protein structure models. Most of the model structure evaluation methods perform rigid body superimposition of a structure model to its crystal structure and measure the difference of the corresponding residue or atom positions between them. However, these methods neglect intrinsic flexibility of proteins by treating the native structure as a rigid molecule. Because different parts of proteins have different levels of flexibility, for example, exposed loop regions are usually more flexible than the core region of a protein structure, disagreement of a model to the native needs to be evaluated differently depending on the flexibility of residues in a protein.
Results: We propose a score named FlexScore for comparing protein structures that consider flexibility of each residue in the native state of proteins. Flexibility information may be extracted from experiments such as NMR or molecular dynamics simulation. FlexScore considers an ensemble of conformations of a protein described as a multivariate Gaussian distribution of atomic displacements and compares a query computational model with the ensemble. We compare FlexScore with other commonly used structure similarity scores over various examples. FlexScore agrees with experts’ intuitive assessment of computational models and provides information of practical usefulness of models.
Availability and implementation: https://bitbucket.org/mjamroz/flexscore
Contact: dkihara@purdue.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
deBWT: parallel construction of Burrows–Wheeler Transform for large collection of genomes with de Bruijn-branch encoding
Authors: Liu Bo , Zhu Dixian , Wang Yadong 
Published: June 2016

Abstract
Motivation : With the development of high-throughput sequencing, the number of assembled genomes continues to rise. It is critical to well organize and index many assembled genomes to promote future genomics studies. Burrows–Wheeler Transform (BWT) is an important data structure of genome indexing, which has many fundamental applications; however, it is still non-trivial to construct BWT for large collection of genomes, especially for highly similar or repetitive genomes. Moreover, the state-of-the-art approaches cannot well support scalable parallel computing owing to their incremental nature, which is a bottleneck to use modern computers to accelerate BWT construction.
Results : We propose de Bruijn branch-based BWT constructor (deBWT), a novel parallel BWT construction approach. DeBWT innovatively represents and organizes the suffixes of input sequence with a novel data structure, de Bruijn branch encoding. This data structure takes the advantage of de Bruijn graph to facilitate the comparison between the suffixes with long common prefix, which breaks the bottleneck of the BWT construction of repetitive genomic sequences. Meanwhile, deBWT also uses the structure of de Bruijn graph for reducing unnecessary comparisons between suffixes. The benchmarking suggests that, deBWT is efficient and scalable to construct BWT for large dataset by parallel computing. It is well-suited to index many genomes, such as a collection of individual human genomes, with multiple-core servers or clusters.
Availability and implementation : deBWT is implemented in C language, the source code is available at https://github.com/hitbc/deBWT or https://github.com/DixianZhu/deBWT
Contact: ydwang@hit.edu.cn
Supplementary information: Supplementary data are available at Bioinformatics online.
Linear effects models of signaling pathways from combinatorial perturbation data
Authors: Szczurek Ewa , Beerenwinkel Niko 
Published: June 2016

Abstract
Motivation: Perturbations constitute the central means to study signaling pathways. Interrupting components of the pathway and analyzing observed effects of those interruptions can give insight into unknown connections within the signaling pathway itself, as well as the link from the pathway to the effects. Different pathway components may have different individual contributions to the measured perturbation effects, such as gene expression changes. Those effects will be observed in combination when the pathway components are perturbed. Extant approaches focus either on the reconstruction of pathway structure or on resolving how the pathway components control the downstream effects.
Results: Here, we propose a linear effects model, which can be applied to solve both these problems from combinatorial perturbation data. We use simulated data to demonstrate the accuracy of learning the pathway structure as well as estimation of the individual contributions of pathway components to the perturbation effects. The practical utility of our approach is illustrated by an application to perturbations of the mitogen-activated protein kinase pathway in Saccharomyces cerevisiae .
Availability and Implementation: lem is available as a R package at http://www.mimuw.edu.pl/∼szczurek/lem .
Contact: szczurek@mimuw.edu.pl ; niko.beerenwinkel@bsse.ethz.ch
Supplementary information: Supplementary data are available at Bioinformatics online.
Using genomic annotations increases statistical power to detect eGenes
Authors: Duong Dat , Zou Jennifer , Hormozdiari Farhad , Sul Jae Hoon , Ernst Jason , Han Buhm , Eskin Eleazar 
Published: June 2016

Abstract
Motivation: Expression quantitative trait loci (eQTLs) are genetic variants that affect gene expression. In eQTL studies, one important task is to find eGenes or genes whose expressions are associated with at least one eQTL. The standard statistical method to determine whether a gene is an eGene requires association testing at all nearby variants and the permutation test to correct for multiple testing. The standard method however does not consider genomic annotation of the variants. In practice, variants near gene transcription start sites (TSSs) or certain histone modifications are likely to regulate gene expression. In this article, we introduce a novel eGene detection method that considers this empirical evidence and thereby increases the statistical power.
Results: We applied our method to the liver Genotype-Tissue Expression (GTEx) data using distance from TSSs, DNase hypersensitivity sites, and six histone modifications as the genomic annotations for the variants. Each of these annotations helped us detected more candidate eGenes. Distance from TSS appears to be the most important annotation; specifically, using this annotation, our method discovered 50% more candidate eGenes than the standard permutation method.
Contact: buhm.han@amc.seoul.kr or eeskin@cs.ucla.edu
Data-driven mechanistic analysis method to reveal dynamically evolving regulatory networks
Authors: Intosalmi Jukka , Nousiainen Kari , Ahlfors Helena , Lähdesmäki Harri 
Published: June 2016

AbstractMotivation: Mechanistic models based on ordinary differential equations provide powerful and accurate means to describe the dynamics of molecular machinery which orchestrates gene regulation. When combined with appropriate statistical techniques, mechanistic models can be calibrated using experimental data and, in many cases, also the model structure can be inferred from time–course measurements. However, existing mechanistic models are limited in the sense that they rely on the assumption of static network structure and cannot be applied when transient phenomena affect, or rewire, the network structure. In the context of gene regulatory network inference, network rewiring results from the net impact of possible unobserved transient phenomena such as changes in signaling pathway activities or epigenome, which are generally difficult, but important, to account for.Results: We introduce a novel method that can be used to infer dynamically evolving regulatory networks from time–course data. Our method is based on the notion that all mechanistic ordinary differential equation models can be coupled with a latent process that approximates the network structure rewiring process. We illustrate the performance of the method using simulated data and, further, we apply the method to study the regulatory interactions during T helper 17 (Th17) cell differentiation using time–course RNA sequencing data. The computational experiments with the real data show that our method is capable of capturing the experimentally verified rewiring effects of the core Th17 regulatory network. We predict Th17 lineage specific subnetworks that are activated sequentially and control the differentiation process in an overlapping manner.Availability and Implementation: An implementation of the method is available at http://research.ics.aalto.fi/csb/software/lem/ .Contacts: jukka.intosalmi@aalto.fi or harri.lahdesmaki@aalto.fi
Read-based phasing of related individuals
Authors: Garg Shilpa , Martin Marcel , Marschall Tobias 
Published: June 2016

Abstract
Motivation: Read-based phasing deduces the haplotypes of an individual from sequencing reads that cover multiple variants, while genetic phasing takes only genotypes as input and applies the rules of Mendelian inheritance to infer haplotypes within a pedigree of individuals. Combining both into an approach that uses these two independent sources of information—reads and pedigree—has the potential to deliver results better than each individually.
Results: We provide a theoretical framework combining read-based phasing with genetic haplotyping, and describe a fixed-parameter algorithm and its implementation for finding an optimal solution. We show that leveraging reads of related individuals jointly in this way yields more phased variants and at a higher accuracy than when phased separately, both in simulated and real data. Coverages as low as 2× for each member of a trio yield haplotypes that are as accurate as when analyzed separately at 15× coverage per individual.
Availability and Implementation: https://bitbucket.org/whatshap/whatshap
Contact: t.marschall@mpi-inf.mpg.de
Compacting de Bruijn graphs from sequencing data quickly and in low memory
Authors: Chikhi Rayan , Limasset Antoine , Medvedev Paul 
Published: June 2016

Abstract
Motivation : As the quantity of data per sequencing experiment increases, the challenges of fragment assembly are becoming increasingly computational. The de Bruijn graph is a widely used data structure in fragment assembly algorithms, used to represent the information from a set of reads. Compaction is an important data reduction step in most de Bruijn graph based algorithms where long simple paths are compacted into single vertices. Compaction has recently become the bottleneck in assembly pipelines, and improving its running time and memory usage is an important problem.
Results : We present an algorithm and a tool bcalm 2 for the compaction of de Bruijn graphs. bcalm 2 is a parallel algorithm that distributes the input based on a minimizer hashing technique, allowing for good balance of memory usage throughout its execution. For human sequencing data, bcalm 2 reduces the computational burden of compacting the de Bruijn graph to roughly an hour and 3 GB of memory. We also applied bcalm 2 to the 22 Gbp loblolly pine and 20 Gbp white spruce sequencing datasets. Compacted graphs were constructed from raw reads in less than 2 days and 40 GB of memory on a single machine. Hence, bcalm 2 is at least an order of magnitude more efficient than other available methods.
Availability and Implementation : Source code of bcalm 2 is freely available at: https://github.com/GATB/bcalm
Contact: rayan.chikhi@univ-lille1.fr
Analysis of differential splicing suggests different modes of short-term splicing regulation
Authors: Topa Hande , Honkela Antti 
Published: June 2016

Abstract
Motivation: Alternative splicing is an important mechanism in which the regions of pre-mRNAs are differentially joined in order to form different transcript isoforms. Alternative splicing is involved in the regulation of normal physiological functions but also linked to the development of diseases such as cancer. We analyse differential expression and splicing using RNA-sequencing time series in three different settings: overall gene expression levels, absolute transcript expression levels and relative transcript expression levels.
Results: Using estrogen receptor α signaling response as a model system, our Gaussian process-based test identifies genes with differential splicing and/or differentially expressed transcripts. We discover genes with consistent changes in alternative splicing independent of changes in absolute expression and genes where some transcripts change whereas others stay constant in absolute level. The results suggest classes of genes with different modes of alternative splicing regulation during the experiment.
Availability and Implementation: R and Matlab codes implementing the method are available at https://github.com/PROBIC/diffsplicing . An interactive browser for viewing all model fits is available at http://users.ics.aalto.fi/hande/splicingGP/
Contact: hande.topa@helsinki.fi or antti.honkela@helsinki.fi
Supplementary information: Supplementary data are available at Bioinformatics online.
Creating a scalable clinical pharmacogenomics service with automated interpretation and medical record result integration – experience from a pediatric tertiary care facility
Authors: Manzi Shannon F , Fusaro Vincent A , Chadwick Laura , Brownstein Catherine , Clinton Catherine , Mandl Kenneth D , Wolf Wendy A , Hawkins Jared B 
Published: June 2016

Objective: This paper outlines the implementation of a comprehensive clinical pharmacogenomics (PGx) service within a pediatric teaching hospital and the integration of clinical decision support in the electronic health record (EHR).
Materials and Methods: An approach to clinical decision support for medication ordering and dispensing driven by documented PGx variant status in an EHR is described. A web-based platform was created to automatically generate a clinical report from either raw assay results or specified diplotypes, able to parse and combine haplotypes into an interpretation for each individual and compared to the reference lab call for accuracy.
Results: Clinical decision support rules built within an EHR provided guidance to providers for 31 patients (100%) who had actionable PGx variants and were written for interacting medications. A breakdown of the PGx alerts by practitioner service, and alert response for the initial cohort of patients tested is described. In 90% (355/394) of the cases, thiopurine methyltranferase genotyping was ordered pre-emptively.
Discussion: This paper outlines one approach to implementing a clinical PGx service in a pediatric teaching hospital that cares for a heterogeneous patient population. There is a focus on incorporation of PGx clinical decision support rules and a program to standardize report text within the electronic health record with subsequent exploration of clinician behavior in response to the alerts.
Conclusion: The incorporation of PGx data at the time of prescribing and dispensing, if done correctly, has the potential to impact the incidence of adverse drug events, a significant cause of morbidity and mortality.
Electronic tools to support medication reconciliation: a systematic review
Authors: Marien Sophie , Krug Bruno , Spinewine Anne 
Published: June 2016

Objectives: Medication reconciliation (MedRec) is essential for reducing patient harm caused by medication discrepancies across care transitions. Electronic support has been described as a promising approach to moving MedRec forward. We systematically reviewed the evidence about electronic tools that support MedRec, by (a) identifying tools; (b) summarizing their characteristics with regard to context, tool, implementation, and evaluation; and (c) summarizing key messages for successful development and implementation.Materials and Methods: We searched PubMed, the Cumulative Index to Nursing and Allied Health Literature, Embase, PsycINFO, and the Cochrane Library, and identified additional reports from reference lists, reviews, and patent databases. Reports were included if the electronic tool supported medication history taking and the identification and resolution of medication discrepancies. Two researchers independently selected studies, evaluated the quality of reporting, and extracted data.Results: Eighteen reports relative to 11 tools were included. There were eight quality improvement projects, five observational effectiveness studies, three randomized controlled trials (RCTs) or RCT protocols (ie, descriptions of RCTs in progress), and two patents. All tools were developed in academic environments in North America. Most used electronic data from multiple sources and partially implemented functionalities considered to be important. Relevant information on functionalities and implementation features was frequently missing. Evaluations mainly focused on usability, adherence, and user satisfaction. One RCT evaluated the effect on potential adverse drug events.Conclusion: Successful implementation of electronic tools to support MedRec requires favorable context, properly designed tools, and attention to implementation features. Future research is needed to evaluate the effect of these tools on the quality and safety of healthcare.
A Novel Strategy to Reverse General Anesthesia by Scavenging with the Acyclic Cucurbit[n]uril-type Molecular Container Calabadion 2
Authors: Diaz-Gil Daniel , Haerter Friederike , Falcinelli Shane , Ganapati Shweta , Hettiarachchi Gaya K. , Simons Jeroen C. P. , Zhang Ben , Grabitz Stephanie D. , Moreno Duarte Ingrid , Cotten Joseph F. , Eikermann-Haerter Katharina , Deng Hao , Chamberlin Nancy L. , Isaacs Lyle , Briken Volker , Eikermann Matthias 
Published: June 2016

Abstract

Background
Calabadion 2 is a new drug-encapsulating agent. In this study, the authors aim to assess its utility as an agent to reverse general anesthesia with etomidate and ketamine and facilitate recovery.

Methods
To evaluate the effect of calabadion 2 on anesthesia recovery, the authors studied the response of rats to calabadion 2 after continuous and bolus intravenous etomidate or ketamine and bolus intramuscular ketamine administration. The authors measured electroencephalographic predictors of depth of anesthesia (burst suppression ratio and total electroencephalographic power), functional mobility impairment, blood pressure, and toxicity.

Results
Calabadion 2 dose-dependently reverses the effects of ketamine and etomidate on electroencephalographic predictors of depth of anesthesia, as well as drug-induced hypotension, and shortens the time to recovery of righting reflex and functional mobility. Calabadion 2 displayed low cytotoxicity in MTS-3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium–based cell viability and adenylate kinase release cell necrosis assays, did not inhibit the human ether-à-go-go-related channel, and was not mutagenic (Ames test). On the basis of maximum tolerable dose and acceleration of righting reflex recovery, the authors calculated the therapeutic index of calabadion 2 in recovery as 16:1 (95% CI, 10 to 26:1) for the reversal of ketamine and 3:1 (95% CI, 2 to 5:1) for the reversal of etomidate.

Conclusions
Calabadion 2 reverses etomidate and ketamine anesthesia in rats by chemical encapsulation at nontoxic concentrations.
Contrast MRI Findings for Spinal Schwannoma as Predictors of Tumor Proliferation and Motor Status
Authors: Kobayashi Kazuyoshi , Imagama Shiro , Ando Kei , Hida Tetsuro , Ito Kenyu , Tsushima Mikito , Ishikawa Yoshimoto , Matsumoto Akiyuki , Morozumi Masayoshi , Tanaka Satoshi , Ishiguro Naoki 
Published: June 2016

Study Design.
Retrospective analysis.

Objective.
The goal of this study was to examine the relationship of the proliferation potency based on the MIB-1 index and motor status with features of T2-weighted images (T2WI) and contrast T1-weighted images (T1WI) of spinal schwannoma.

Summary of Background Data.
Spinal schwannomas account for 55% of spinal tumors, but the relationship of cellular proliferation with MRI findings for spinal schwannoma is unknown.

Methods.
The subjects were 48 patients (22 males and 26 females) with spinal schwannoma who were classified into three subgroups: iso/homo, high/rim, and hetero/hetero, based on T2WI/contrast T1WI. A retrospective analysis of tumor size and MIB-1 index was performed in the context of these MRI findings. Intraoperative findings and pre- and postoperative motor performance were also examined.

Results.
The average tumor size was 32.4 mm (range 10–130 mm) and the average MIB-1 index was 3.8% (range 1–12). In the three subgroups, there were no significant differences in sex, age, duration of disease, tumor lesion, and dumbbell type. In the hetero/hetero group, the tumor size was significantly greater and the MIB-1 index was significantly higher (both P < 0.05), than the other two groups. The tumor adherence rate was significantly higher for hetero tumors (P < 0.05) and preoperative paralysis was more common in cases with tumor adhesion. The rate of paralysis improvement at 1 month was significantly lower for hetero tumors, but all cases had improved at 6 months.

Conclusion.
Contrast T1WI MRI was useful for prediction of the proliferative activity and growth of spinal schwannomas, which are associated with increased tumor size and adhesion. A heterogeneous pattern on contrast T1WI indicated an increase in size and adhesion of the tumor. This pattern reflected the preoperative motor status and postoperative motor recovery.

Level of Evidence: 4
Intrathecal Versus Intravenous Morphine in Minimally Invasive Posterior Lumbar Fusion
Authors: Araimo Morselli Fabio Silvio Mario , Zuccarini Francesco , Caporlingua Federico , Scarpa Ilaria , Imperiale Carmela , Caporlingua Alessandro , De Biase Lorenzo , Tordiglione Paolo 
Published: June 2016

Study Design.
A blinded, randomized, comparative prospective study.

Objective.
The aim of this study was to compare the use of intrathecal morphine to endovenous morphine on postoperative pain after posterior lumbar surgery.

Summary of Background Data.
Intrathecal morphine can provide significant safe analgesia for at least 12 hours and up to 24 hours in patients undergoing major surgery. Its dosages have been decreasing in the last 30 years, but currently, the optimal dose remains unknown. As of today, there are no studies comparing the efficacy and the side effects of this technique with intravenous morphine administration after minimally invasive lumbar fusion surgery.

Methods.
We randomized and compared two groups of 25 patients, who were given either 100 μg intrathecal (ITM group) or 5 ± 2 mg intravenous morphine delivered intravenously for 24 hours at 2 mL/h (IVM group) after minimally invasive posterior lumbar fusion. VAS score at 0, 6, 12, 24 hours, mobilization out of bed at 6 hours, hospitalization duration and complications as lower limbs paresthesia, urinary retention at 6 and 12 hours, nausea, vomit, itch, and constipation were evaluated.

Results.
Data showed a lower VAS score, a reduction of constipation, lower limbs paresthesia, or urinary retention at 12 hours in ITM rather than in the IVM group. None suffered of vomit, itch, or nausea in both groups. Urinary retention was observed more frequently in ITM group at 6 hours. Patients of ITM group were mobilized out bed earlier than those from IVM group.

Conclusion.
A low dosage of intrathecal morphine is safe and effective after minimally invasive lumbar fusion surgery. The reduction of pain in the study group permitted a shorter hospitalization and earlier mobilization out of bed, augmenting patients’ comfort.

Level of Evidence: 2