bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal design of gene knockout experiments for gene regulatory network inference
Authors: Ud-Dean S. M. Minhaz , Gunawan Rudiyanto
Published: November 2015

Motivation: We addressed the problem of inferring gene regulatory network (GRN) from gene expression data of knockout (KO) experiments. This inference is known to be underdetermined and the GRN is not identifiable from data. Past studies have shown that suboptimal design of experiments (DOE) contributes significantly to the identifiability issue of biological networks, including GRNs. However, optimizing DOE has received much less attention than developing methods for GRN inference.

Results: We developed REDuction of UnCertain Edges (REDUCE) algorithm for finding the optimal gene KO experiment for inferring directed graphs (digraphs) of GRNs. REDUCE employed ensemble inference to define uncertain gene interactions that could not be verified by prior data. The optimal experiment corresponds to the maximum number of uncertain interactions that could be verified by the resulting data. For this purpose, we introduced the concept of edge separatoid which gave a list of nodes (genes) that upon their removal would allow the verification of a particular gene interaction. Finally, we proposed a procedure that iterates over performing KO experiments, ensemble update and optimal DOE. The case studies including the inference of Escherichia coli GRN and DREAM 4 100-gene GRNs, demonstrated the efficacy of the iterative GRN inference. In comparison to systematic KOs, REDUCE could provide much higher information return per gene KO experiment and consequently more accurate GRN estimates.

Conclusions: REDUCE represents an enabling tool for tackling the underdetermined GRN inference. Along with advances in gene deletion and automation technology, the iterative procedure brings an efficient and fully automated GRN inference closer to reality.

Availability and implementation: MATLAB and Python scripts of REDUCE are available on www.cabsel.ethz.ch/tools/REDUCE.

Contact:  rudi.gunawan@chem.ethz.ch

Supplementary information:  Supplementary data are available at Bioinformatics online.
CHRONOS: a time-varying method for microRNA-mediated subpathway enrichment analysis
Authors: Vrahatis Aristidis G. , Dimitrakopoulou Konstantina , Balomenos Panos , Tsakalidis Athanasios K. , Bezerianos Anastasios
Published: November 2015

Motivation: In the era of network medicine and the rapid growth of paired time series mRNA/microRNA expression experiments, there is an urgent need for pathway enrichment analysis methods able to capture the time- and condition-specific ‘active parts’ of the biological circuitry as well as the microRNA impact. Current methods ignore the multiple dynamical ‘themes’—in the form of enriched biologically relevant microRNA-mediated subpathways—that determine the functionality of signaling networks across time.

Results: To address these challenges, we developed time-vaRying enriCHment integrOmics Subpathway aNalysis tOol (CHRONOS) by integrating time series mRNA/microRNA expression data with KEGG pathway maps and microRNA-target interactions. Specifically, microRNA-mediated subpathway topologies are extracted and evaluated based on the temporal transition and the fold change activity of the linked genes/microRNAs. Further, we provide measures that capture the structural and functional features of subpathways in relation to the complete organism pathway atlas. Our application to synthetic and real data shows that CHRONOS outperforms current subpathway-based methods into unraveling the inherent dynamic properties of pathways.

Availability and implementation: CHRONOS is freely available at http://biosignal.med.upatras.gr/chronos/.

Contact:  tassos.bezerianos@nus.edu.sg.

Supplementary information:  Supplementary data are available at Bioinformatics online.
Accurate estimation of isoelectric point of protein and peptide based on amino acid sequences
Authors: Audain Enrique , Ramos Yassel , Hermjakob Henning , Flower Darren R. , Perez-Riverol Yasset
Published: November 2015

Motivation: In any macromolecular polyprotic system—for example protein, DNA or RNA—the isoelectric point—commonly referred to as the pI—can be defined as the point of singularity in a titration curve, corresponding to the solution pH value at which the net overall surface charge—and thus the electrophoretic mobility—of the ampholyte sums to zero. Different modern analytical biochemistry and proteomics methods depend on the isoelectric point as a principal feature for protein and peptide characterization. Protein separation by isoelectric point is a critical part of 2-D gel electrophoresis, a key precursor of proteomics, where discrete spots can be digested in-gel, and proteins subsequently identified by analytical mass spectrometry. Peptide fractionation according to their pI is also widely used in current proteomics sample preparation procedures previous to the LC-MS/MS analysis. Therefore accurate theoretical prediction of pI would expedite such analysis. While such pI calculation is widely used, it remains largely untested, motivating our efforts to benchmark pI prediction methods.

Results: Using data from the database PIP-DB and one publically available dataset as our reference gold standard, we have undertaken the benchmarking of pI calculation methods. We find that methods vary in their accuracy and are highly sensitive to the choice of basis set. The machine-learning algorithms, especially the SVM-based algorithm, showed a superior performance when studying peptide mixtures. In general, learning-based pI prediction methods (such as Cofactor, SVM and Branca) require a large training dataset and their resulting performance will strongly depend of the quality of that data. In contrast with Iterative methods, machine-learning algorithms have the advantage of being able to add new features to improve the accuracy of prediction.

Contact: yperez@ebi.ac.uk

Availability and Implementation: The software and data are freely available at https://github.com/ypriverol/pIR.

Supplementary information:  Supplementary data are available at Bioinformatics online.
TCGA2STAT: simple TCGA data access for integrated statistical analysis in R
Authors: Wan Ying-Wooi , Allen Genevera I. , Liu Zhandong
Published: November 2015

Motivation: Massive amounts of high-throughput genomics data profiled from tumor samples were made publicly available by the Cancer Genome Atlas (TCGA).

Results: We have developed an open source software package, TCGA2STAT, to obtain the TCGA data, wrangle it, and pre-process it into a format ready for multivariate and integrated statistical analysis in the R environment. In a user-friendly format with one single function call, our package downloads and fully processes the desired TCGA data to be seamlessly integrated into a computational analysis pipeline. No further technical or biological knowledge is needed to utilize our software, thus making TCGA data easily accessible to data scientists without specific domain knowledge.

Availability and implementation: TCGA2STAT is available from the https://cran.r-project.org/web/packages/TCGA2STAT/index.html.

Supplementary information:  Supplementary data are available at Bioinformatics online.

Contact:  zhandong.liu@bcm.edu
Improving health care proxy documentation using a web-based interview through a patient portal
Authors: Bajracharya Adarsha S , Crotty Bradley H , Kowaloff Hollis B , Safran Charles , Slack Warner V
Published: November 2015

Objective Health care proxy (HCP) documentation is suboptimal. To improve rates of proxy selection and documentation, we sought to develop and evaluate a web-based interview to guide patients in their selection, and to capture their choices in their electronic health record (EHR).

Methods We developed and implemented a HCP interview within the patient portal of a large academic health system. We analyzed the experience, together with demographic and clinical factors, of the first 200 patients who used the portal to complete the interview. We invited users to comment about their experience and analyzed their comments using established qualitative methods.

Results From January 20, 2015 to March 13, 2015, 139 of the 200 patients who completed the interview submitted their HCP information for their clinician to review in the EHR. These patients had a median age of 57 years (Inter Quartile Range (IQR) 45–67) and most were healthy. The 99 patients who did not previously have HCP information in their EHR were more likely to complete and then submit their information than the 101 patients who previously had a proxy in their health record (odds ratio 2.4, P = .005). Qualitative analysis identified several ways in which the portal-based interview reminded, encouraged, and facilitated patients to complete their HCP.

Conclusions Patients found our online interview convenient and helpful in facilitating selection and documentation of an HCP. Our study demonstrates that a web-based interview to collect and share a patient’s HCP information is both feasible and useful.
Clinical element models in the SHARPn consortium
Authors: Oniki Thomas A , Zhuo Ning , Beebe Calvin E , Liu Hongfang , Coyle Joseph F , Parker Craig G , Solbrig Harold R , Marchant Kyle , Kaggal Vinod C , Chute Christopher G , Huff Stanley M
Published: November 2015

Objective The objective of the Strategic Health IT Advanced Research Project area four (SHARPn) was to develop open-source tools that could be used for the normalization of electronic health record (EHR) data for secondary use—specifically, for high throughput phenotyping. We describe the role of Intermountain Healthcare’s Clinical Element Models ([CEMs] Intermountain Healthcare Health Services, Inc, Salt Lake City, Utah) as normalization “targets” within the project.

Materials and Methods Intermountain’s CEMs were either repurposed or created for the SHARPn project. A CEM describes “valid” structure and semantics for a particular kind of clinical data. CEMs are expressed in a computable syntax that can be compiled into implementation artifacts. The modeling team and SHARPn colleagues agilely gathered requirements and developed and refined models.

Results Twenty-eight “statement” models (analogous to “classes”) and numerous “component” CEMs and their associated terminology were repurposed or developed to satisfy SHARPn high throughput phenotyping requirements. Model (structural) mappings and terminology (semantic) mappings were also created. Source data instances were normalized to CEM-conformant data and stored in CEM instance databases. A model browser and request site were built to facilitate the development.

Discussion The modeling efforts demonstrated the need to address context differences and granularity choices and highlighted the inevitability of iso-semantic models. The need for content expertise and “intelligent” content tooling was also underscored. We discuss scalability and sustainability expectations for a CEM-based approach and describe the place of CEMs relative to other current efforts.

Conclusions The SHARPn effort demonstrated the normalization and secondary use of EHR data. CEMs proved capable of capturing data originating from a variety of sources within the normalization pipeline and serving as suitable normalization targets.
The vulnerabilities of computerized physician order entry systems: a qualitative study
Authors: Slight Sarah P , Eguale Tewodros , Amato Mary G , Seger Andrew C , Whitney Diana L , Bates David W , Schiff Gordon D
Published: November 2015

Objective To test the vulnerabilities of a wide range of computerized physician order entry (CPOE) systems to different types of medication errors, and develop a more comprehensive qualitative understanding of how their design could be improved.

Materials and Methods The authors reviewed a random sample of 63 040 medication error reports from the US Pharmacopeia (USP) MEDMARX reporting system where CPOE systems were considered a “contributing factor” to errors and flagged test scenarios that could be tested in current CPOE systems. Testers entered these orders in 13 commercial and homegrown CPOE systems across 16 different sites in the United States and Canada, using both usual practice and where-needed workarounds. Overarching themes relevant to interface design and usability/workflow issues were identified.

Results CPOE systems often failed to detect and prevent important medication errors. Generation of electronic alert warnings varied widely between systems, and depended on a number of factors, including how the order information was entered. Alerts were often confusing, with unrelated warnings appearing on the same screen as those more relevant to the current erroneous entry. Dangerous drug-drug interaction warnings were displayed only after the order was placed rather than at the time of ordering. Testers illustrated various workarounds that allowed them to enter these erroneous orders.

Discussion and Conclusion The authors found high variability in ordering approaches between different CPOE systems, with major deficiencies identified in some systems. It is important that developers reflect on these findings and build in safeguards to ensure safer prescribing for patients.
Effects of health information technology on patient outcomes: a systematic review
Authors: Brenner Samantha K , Kaushal Rainu , Grinspan Zachary , Joyce Christine , Kim Inho , Allard Rhonda J , Delgado Diana , Abramson Erika L
Published: November 2015

Objective To systematically review studies assessing the effects of health information technology (health IT) on patient safety outcomes.

Materials and Methods The authors employed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement methods. MEDLINE, Cumulative Index to Nursing Allied Health (CINAHL), EMBASE, and Cochrane Library databases, from 2001 to June 2012, were searched. Descriptive and comparative studies were included that involved use of health IT in a clinical setting and measured effects on patient safety outcomes.

Results Data on setting, subjects, information technology implemented, and type of patient safety outcomes were all abstracted. The quality of the studies was evaluated by 2 independent reviewers (scored from 0 to 10). A total of 69 studies met inclusion criteria. Quality scores ranged from 1 to 9. There were 25 (36%) studies that found benefit of health IT on direct patient safety outcomes for the primary outcome measured, 43 (62%) studies that either had non-significant or mixed findings, and 1 (1%) study for which health IT had a detrimental effect. Neither the quality of the studies nor the rate of randomized control trials performed changed over time. Most studies that demonstrated a positive benefit of health IT on direct patient safety outcomes were inpatient, single-center, and either cohort or observational trials studying clinical decision support or computerized provider order entry.

Discussion and Conclusion Many areas of health IT application remain understudied and the majority of studies have non-significant or mixed findings. Our study suggests that larger, higher quality studies need to be conducted, particularly in the long-term care and ambulatory care settings.
Strategizing EHR use to achieve patient-centered care in exam rooms: a qualitative study on primary care providers
Authors: Zhang Jing , Chen Yunan , Ashfaq Shazia , Bell Kristin , Calvitti Alan , Farber Neil J , Gabuzda Mark T , Gray Barbara , Liu Lin , Rick Steven , Street Richard L , Zheng Kai , Zuest Danielle , Agha Zia
Published: November 2015

Objective Electronic health records (EHRs) have great potential to improve quality of care. However, their use may diminish “patient-centeredness” in exam rooms by distracting the healthcare provider from focusing on direct patient interaction. The authors conducted a qualitative interview study to understand the magnitude of this issue, and the strategies that primary care providers devised to mitigate the unintended adverse effect associated with EHR use.

Methods and Materials Semi-structured interviews were conducted with 21 healthcare providers at 4 Veterans Affairs (VAs) outpatient primary care clinics in San Diego County. Data analysis was performed using the grounded theory approach.

Results The results show that providers face demands from both patients and the EHR system. To cope with these demands, and to provide patient-centered care, providers attempt to perform EHR work outside of patient encounters and create templates to streamline documentation work. Providers also attempt to use the EHR to engage patients, establish patient buy-in for EHR use, and multitask between communicating with patients and using the EHR.

Discussion and Conclusion This study has uncovered the challenges that primary care providers face in integrating the EHR into their work practice, and the strategies they use to overcome these challenges in order to maintain patient-centered care. These findings illuminate the importance of developing “best” practices to improve patient-centered care in today’s highly “wired” health environment. These findings also show that more user-centered EHR design is needed to improve system usability.
Equiosmolar Solutions of Hypertonic Saline and Mannitol Do Not Impair Blood Coagulation During Elective Intracranial Surgery
Authors: Hernández-Palazón Joaquín , Fuentes-García Diego , Doménech-Asensi Paloma , Piqueras-Pérez Claudio , Falcón-Araña Luis , Burguillos-López Sebastián
Published: November 2015

Background:

The authors investigated the effect of equiosmolar, equivolemic solutions of 3% hypertonic saline (HS) and 20% mannitol on blood coagulation assessed by rotational thromboelastometry (ROTEM) and standard coagulation tests during elective craniotomy.

Methods:

In a prospective, randomized, double-blind trial, 40 patients undergoing elective craniotomy were randomized to receive 5 mL/kg of either 20% mannitol or 3% HS for intraoperative brain relaxation. Fibrinogen, activated partial thromboplastin time, prothrombin time, hemoglobin, hematocrit, and platelet count were simultaneously measured intraoperatively with ROTEM for EXTEM, INTEM, and FIBTEM analysis. ROTEM parameters were: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and α-angle.

Results:

No significant differences between groups were found in ROTEM variables CT, CFT, MCF, α-angle (EXTEM and INTEM), and MCF (FIBTEM) nor standard coagulation tests. ROTEM parameters did not show changes after administration of hyperosmolar solutions relating to basal values, except for an increase of CFT EXTEM (118±28 vs. 128±26 s) and decrease of CT INTEM (160±18 vs. 148±15 s) with values within normal range. Significant decreases from baseline levels were observed for hematocrit (−7%), platelet count (−10%), and fibrinogen (−13%) after HS infusion, and hematocrit (−9%), platelet count (−13%), and fibrinogen (−9%) after mannitol infusion, but remaining normal.

Conclusions:

The use of 5 mL/kg of equiosmolar solutions of 3% HS and 20% mannitol applied to reach a brain relaxation during elective craniotomy does not induce coagulation impairment as evidenced by ROTEM and standard coagulation tests.
A Dopamine Pathway Gene Risk Score for Cognitive Recovery Following Traumatic Brain Injury: Methodological Considerations, Preliminary Findings, and Interactions With Sex
Authors: Myrga John M. , Failla Michelle D. , Ricker Joseph H. , Dixon C. Edward , Conley Yvette P. , Arenth Patricia M. , Wagner Amy K.
Published: November 2015

Objectives:

With evidence of sexual dimorphism involving the dopamine (DA)-pathway, and the importance of DA pathways in traumatic brain injury (TBI) recovery, we hypothesized that sex × DA-gene interactions may influence cognition post-TBI.

Participants:

Adult survivors of severe TBI (n = 193) consecutively recruited from a level 1 trauma center.

Design:

Risk allele assignments were made for multiple DA pathway genes using a sex-specific stratified approach. Genetic risk alleles, and their impacts on cognition, were assessed at 6 and 12 months postinjury using unweighted, semiweighted, and weighted gene risk score (GRS) approaches.

Main Measures:

A cognitive composite score generated from 8 standardized neuropsychological tests targeting multiple cognitive domains.

Results:

A significant sex × gene interaction was observed at 6 and 12 months for ANKK1 rs1800497 (6M: P = .002, 12M: P = .001) and COMT rs4680 (6M: P = .048; 12M: P = .004); DRD2 rs6279 (P = .001) and VMAT rs363226 (P = .043) genotypes were independently associated with cognition at 6 months, with trends for a sex × gene interaction at 12 months. All GRS methods were significant predictors of cognitive performance in multivariable models. Weighted GRS multivariate models captured the greatest variance in cognition: R
2 = 0.344 (6 months); R
2 = 0.441 (12 months), significantly increasing the variance captured from the base prediction models.

Conclusions:

A sex-specific DA-pathway GRS may be a valuable tool when predicting cognitive recovery post-TBI. Future work should validate these findings and explore how DA-pathway genetics may guide therapeutic intervention.
Consistency of Recall for Deployment-Related Traumatic Brain Injury
Authors: Alosco Michael L. , Aslan Mihaela , Du Mengtian , Ko John , Grande Laura , Proctor Susan P. , Concato John , Vasterling Jennifer J.
Published: November 2015

Objective:

To examine the temporal consistency of self-reported deployment-related traumatic brain injury (TBI) and its association with posttraumatic stress disorder (PTSD) symptom severity.

Setting:

In-person interviews at US Army installations (postdeployment); phone interviews (long-term follow-up).

Participants:

A total of 378 US Army soldiers and veterans deployed to Iraq; 14.3% (n = 54) reported TBI with loss of consciousness during an index deployment.

Design:

Participants were evaluated after returning from deployment and again 5 to 9 years later.

Main Measures:

Temporal consistency of TBI endorsement based on TBI screening interviews; PTSD Checklist, Civilian Version.

Results:

The concordance of deployment-related TBI endorsement from the postdeployment to long-term follow-up assessment was moderate (κ = 0.53). Of the 54 participants reporting (predominantly mild) TBI occurring during an index deployment, 32 endorsed TBI inconsistently over time. More severe PTSD symptoms at postdeployment assessment were independently associated with discordant reporting (P = .0004); each 10-point increase in PCL scores increasing odds of discordance by 69% (odds ratio = 1.69; 95% confidence interval, 1.26-2.26).

Conclusions:

Deployment-related TBI may not be reported reliably over time, particularly among war-zone veterans with greater PTSD symptoms. Results of screening evaluations for TBI history should be viewed with caution in the context of PTSD symptom history.
Import of proteins into peroxisomes: piggybacking to a new home away from home
Authors: Thoms Sven
Published: November 2015

Peroxisomes are capable of importing folded and oligomeric proteins. However, it is a matter of dispute whether oligomer import by peroxisomes is the exception or the rule. Here, I argue for a clear distinction between homo-oligomeric proteins that are essentially peroxisomal, and dually localized hetero-oligomers that access the peroxisome by piggyback import, localizing there in limited number, whereas the majority remain in the cytosol. Homo-oligomeric proteins comprise the majority of all peroxisomal matrix proteins. There is evidence that binding by Pex5 in the cytosol can regulate their oligomerization state before import. The hetero-oligomer group is made up of superoxide dismutase and lactate dehydrogenase. These proteins have evolved mechanisms that render import inefficient and retain the majority of proteins in the cytosol.
The E-music box: an empirical method for exploring the universal capacity for musical production and for social interaction through music
Authors: Novembre Giacomo , Varlet Manuel , Muawiyath Shujau , Stevens Catherine J. , Keller Peter E.
Published: November 2015

Humans are assumed to have a natural—universal—predisposition for making music and for musical interaction. Research in this domain is, however, typically conducted with musically trained individuals, and therefore confounded with expertise. Here, we present a rediscovered and updated invention—the E-music box—that we establish as an empirical method to investigate musical production and interaction in everyone. The E-music box transforms rotatory cyclical movements into pre-programmable digital musical output, with tempo varying according to rotation speed. The user’s movements are coded as continuous oscillatory data, which can be analysed using linear or nonlinear analytical tools. We conducted a proof-of-principle experiment to demonstrate that, using this method, pairs of non-musically trained individuals can interact according to conventional musical practices (leader/follower roles and lower-pitch dominance). The results suggest that the E-music box brings ‘active’ and ‘interactive’ musical capacities within everyone’s reach. We discuss the potential of this method for exploring the universal predisposition for music making and interaction in developmental and cross-cultural contexts, and for neurologic musical therapy and rehabilitation.
Summation of a Schlömilch type series
Authors: Asatryan A. A.
Published: November 2015

The ability to accurately and efficiently characterize multiple scattering of waves of different nature attracts substantial interest in physics. The advent of photonic crystals has created additional impetus in this direction. An efficient approach in the study of multiple scattering originates from the Rayleigh method, which often requires the summation of conditionally converging series. Here summation formulae have been derived for conditionally convergent Schlömilch type series

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. These series arise in two-dimensional scattering problems on diffraction gratings with multiple inclusions per unit cell. It is shown that the Schlömilch series involving Hankel functions or Neumann functions can be expressed as an absolutely converging series of elementary functions and a finite sum of Lerch transcendent functions, while the Schlömilch series of Bessel functions can be transformed into a finite sum of elementary functions. The closed-form expressions for the Coates's integrals of integer order have also been found. The derived equations have been verified numerically and their accuracy and efficiency has been demonstrated.
Towards extracting supporting information about predicted protein-protein interactions
Authors: Roth Adam , Subramanian Sandeep , Ganapathiraju Madhavi K.
Published: November 2015

One of the goals of relation extraction is to identify protein-protein interactions (PPIs) in biomedical literature. Current systems are capturing binary relations and also the direction and type of an interaction. Besides assisting in the curation PPIs into databases, there has been little real-world application of these algorithms. We describe UPSITE, a text mining tool for extracting evidence in support of a hypothesized interaction. Given a predicted PPI, UPSITE uses a binary relation detector to check whether a PPI is found in abstracts in PubMed. If it is not found, UPSITE retrieves documents relevant to each of the two proteins separately, and extracts contextual information about biological events surrounding each protein, and calculates semantic similarity of the two proteins to provide evidential support for the predicted PPI. In evaluations, relation extraction achieved an Fscore of 0.88 on the HPRD50 corpus, and semantic similarity measured with angular distance was found to be statistically significant. With the development of PPI prediction algorithms, the burden of interpreting the validity and relevance of novel PPIs is on biologists. We suggest that presenting annotations of the two proteins in a PPI side-by-side and a score that quantifies their similarity lessens this burden to some extent.
Health and population effects of rare gene knockouts in adult humans with related parents
Authors: Narasimhan V. , Hunt K.A. , Mason D. , Baker C.L. , Karczewski K.J. , Barnes M.R. , Barnett A.H. , Bates C. , Bellary S. , Bockett N.A. , Giorda K. , Griffiths C.J. , Hemingway H. , Jia Z. , Kelly M.A. , Khawaja H.A. , Lek Monkol , McCarthy S. , McEachan R. , Paigen K. , Parisinos C. , Sheridan E. , Southgate Laura , Tee L. , Thomas M. , Xue Y. , Schnall-Levin M. , Petkov P.M. , Tyler-Smith C. , Maher E.R. , Trembath R.C. , MacArthur D.G. , Wright J. , Durbin R. , van Heel D.A.
Published: November 2015

Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani-heritage adults with high parental relatedness, discovering 1,111 rare-variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription- or doctor-consultation rate, and no disease-related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthyPRDM9knockout mother, her child and controls, showed meiotic recombination sites localised away fromPRDM9-dependent hotspots, demonstratingPRDM9redundancy in humans.
DataJoint: managing big scientific data using MATLAB or Python
Authors: Yatsenko Dimitri , Reimer Jacob , Ecker Alexander S. , Walker Edgar Y. , Sinz Fabian , Berens Philipp , Hoenselaar Andreas , James Cotton R. , Siapas Athanassios S. , Tolias Andreas S.
Published: November 2015

The rise of big data in modern research poses serious challenges for data management: Large and intricate datasets from diverse instrumentation must be precisely aligned, annotated, and processed in a variety of ways to extract new insights. While high levels of data integrity are expected, research teams have diverse backgrounds, are geographically dispersed, and rarely possess a primary interest in data science. Here we describe DataJoint, an open-source toolbox designed for manipulating and processing scientific data under the relational data model. Designed for scientists who need a flexible and expressive database language with few basic concepts and operations, DataJoint facilitates multiuser access, efficient queries, and distributed computing. With implementations in both MATLAB and Python, DataJoint is not limited to particular file formats, acquisition systems, or data modalities and can be quickly adapted to new experimental designs. DataJoint and related resources are available athttp://datajoint.github.com.
A new model of human dispersal
Authors: Underwood Trevor G.
Published: November 2015

Analysis of previously unpublished allele counts obtained from the French-San-Neanderthal-Chimpanzee alignment of the high quality DNA sequence of a Neanderthal from the Altai Mountains raises significant questions about the currently accepted phylogenetic model of the origins of Europeans. Previous estimates of the proportion of Neanderthal ancestry in present-day Europeans ranged between 1.3% and 2.7% supporting a recent Out-of Africa dispersal model followed by a low level of admixture with Neanderthals. However, analysis of the allele counts indicates the existence of an unidentified third archaic ancestor of Europeans, which diverged from its common ancestor with sub-Saharan Africans around 900 thousand years ago. This analysis shows that the relative proportions of derived alleles in the 0.0826% of the European genome that is not shared with the common ancestor of humans and chimpanzee are 13.6% Neanderthal, 32.3% sub-Saharan African and 54.2% third archaic ancestor. This analysis together with anthropological and archaeological evidence suggests a new model of human dispersal based on a Eurasian lineage in the Levant, which admixed with Neanderthals and descendants of African mtDNA haplogroup L3, followed by radiation from a basal admixed population around 55–50 Kya, with no subsequent major contribution to the European genome.
Depletion of Abundant Sequences by Hybridization (DASH): Using Cas9 to remove unwanted high-abundance species in sequencing libraries and molecular counting applications
Authors: Gu Wei , Crawford Emily D , O'Donovan Brian D , Wilson Michael R , Chow Eric D , Retallack Hanna , DeRisi Joseph L
Published: November 2015

Background: With widespread adoption of next-generation sequencing (NGS) technologies, the need has arisen for a broadly applicable method to remove unwanted high-abundance species prior to sequencing. We introduce DASH (Depletion of Abundant Sequences by Hybridization), a facile technique for targeted depletion of undesired sequences. Results: Sequencing libraries are DASHed with recombinant Cas9 protein complexed with a library of single guide RNAs (sgRNAs) programmed to target unwanted species for cleavage, thus preventing them from consuming sequencing space. We demonstrate up to 99% reduction of mitochondrial ribosomal RNA (rRNA) in HeLa cells, and enrichment of pathogen sequences up to 4-fold in metagenomic samples from patients with infectious diseases. Similarly, we demonstrate the utility of DASH in the context of cancer diagnostics by significantly increasing the detectable fraction of KRAS mutant sequences over the predominant wild-type allele. Conclusion: This simple single-tube method is reprogrammable for virtually any sample type to increase sequencing yield without additional cost. [Note: Wei Gu and Emily Crawford contributed equally to this work.]
Shared generative rules of locomotor behavior in arthropods and vertebrates
Authors: Gomez-Marin Alex , Oron Efrat , Gakamsky Anna , Valente Dan , Benjamini Yoav , Golani Ilan
Published: November 2015

The discovery of shared behavioral processes across phyla is an essential step in the establishment of a comparative study of behavior. We use immobility as an origin and reference for the measurement of locomotor behavior; speed, direction of walking and direction of facing as the three degrees of freedom shaping fly locomotor behavior; and cocaine as the parameter inducing a progressive transition in and out of immobility. In this way we expose and quantify the generative rules that shape part of fruit fly locomotor behavior, bringing about a gradual buildup of freedom during the transition from immobility to normal behavior and a precisely opposite narrowing down during the transition into immobility. During buildup the fly exhibits enhancement and then reduction to normal values of movement along each degree of freedom: first, body rotation in the horizontal plane, then path curvature and then speed of translation. Transition into immobility unfolds by narrowing down of the repertoire in the opposite sequential order, showing reciprocal relations during both buildup and narrowing down. The same generative rules apply to vertebrate locomotor behavior in a variety of contexts involving transition out and into immobility. Recent claims for deep homology between the arthropod central complex and the vertebrate basal ganglia provide an opportunity to examine whether the generative rules we discovered also share common descent. Neurochemical processes mediating the buildup of locomotor behavior in vertebrates could guide the search for equivalent processes in arthropods. The measurement methodology we use prompts the discovery of candidate behavioral homologies.

Significance Statement

Do flies and mice share the same behavior? By defining immobility as an intrinsic reference point for locomotor behavior we show that the rules that generate the transition from immobility to full blown normal behavior, and from full blown behavior to immobility are shared by fruit flies and mice. These rules constitute a much desired aim of evolutionary biology: the discovery of behavioral homologies across distant phyla. The methodology we use facilitates the discovery of cross-phyletic behavioral homologies, shedding light on the problem of the evolution of behavior.
Estimating Error Models for Whole Genome Sequencing Using Mixtures of Dirichlet-Multinomial Distributions
Authors: Wu Steven H. , Schwartz Rachel S. , Winter David J. , Conrad Donald F. , Cartwright Reed A.
Published: November 2015

Motivation

Accurate identification of genotypes is critical in identifying de novo mutations, linking mutations with disease, and determining mutation rates. Because de novo mutations are rare, even low levels of genotyping error can cause a large fraction of false positive de novo mutations. Biological and technical processes that adversely affect genotyping include copy-number-variation, paralogous sequences, library preparation, sequencing error, and reference-mapping biases, among others.

Results

We modeled the read depth for all data as a mixture of Dirichlet-multinomial distributions, resulting in significant improvements over previously used models. In most cases the best model was comprised of two distributions. The major-component distribution is similar to a binomial distribution with low error and low reference bias. The minor-component distribution is overdispersed with higher error and reference bias. We also found that sites fitting the minor component are enriched for copy number variants and low complexity region. We expect that this approach to modeling the distribution of NGS data, will lead to improved genotyping. For example, this approach provides an expected distribution of reads that can be incorporated into a model to estimate de novo mutations using reads across a pedigree.

Availability

Methods and data files are available athttps://github.com/CartwrightLab/WuEtAl2016/.

Contact

cartwright@asu.edu
A short remark on Ontogenetic model and its analytical solution
Authors: Li Ya , He Ji-Huan
Published: November 2015

The ontogenetic growth modeling has been of conspicuously scientific interest, as well as its practical importance in many industrial activities for optimal design. Much work has been done recently to understand the growth mechanism of living organism with a nonlinear time dependence. Some quantitative metabolic models which have been provided to describe organism growth curves are in comparison with what for ontogenetic growth represented by G.B. West et al. (West et al., 2001) in his basic formulations used to discuss the application on different growth patterns. Herein the analytical solution is also involved. In this paper we re-analyzed the assumptions underlying them to find whether the basic relation of organism growth estimated can inosculate with the equation we have proposed.
Natural selection reduces linked neutral divergence between distantly related species
Authors: Phung Tanya N. , Huber Christian D. , Lohmueller Kirk E.
Published: November 2015

Much work has been devoted to understanding the evolutionary processes shaping genetic variation across genomes. Studies have found neutral polymorphism is reduced close to genes and in regions of low recombination, suggesting the effects of natural selection. However, the effect of selection on neutral sequence divergence between species remains ambiguous. While studies have reported correlations between divergence and recombination, theoretical arguments suggest selection may not affect divergence at linked neutral sites. Here we address these outstanding issues by examining how natural selection has affected divergence between distantly related species. We show that neutral divergence is negatively correlated with functional content and positively correlated with estimates of background selection from primates. These patterns persist even when comparing humans and mice, species that split 75 million years ago. Further, neutral divergence is positively correlated with recombination rate. The correlation increases when focusing on genic regions, and biased gene conversion cannot explain all of this correlation. These signatures suggest that natural selection has affected linked divergence between distantly related species. Coalescent models indicate that background selection can generate these patterns. Even when the contribution of ancestral polymorphism to divergence is small, background selection in the ancestral population can still explain a large proportion of the variance in divergence across the genome. Thus, the view that selection does not affect divergence at linked neutral sites needs to be reconsidered. Our work has important implications for understanding evolution of genomes and interpreting patterns of genetic variation.
An integrated metagenomics pipeline for strain profiling reveals novel patterns of transmission and global biogeography of bacteria
Authors: Nayfach Stephen , Rodriguez-Mueller Beltran , Garud Nandita , Pollard Katherine S.
Published: November 2015

We present theMetagenomic Intra-species Diversity Analysis System (MIDAS), which is an integrated computational pipeline for quantifying bacterial species abundance and strain-level genomic variation, including gene content and single nucleotide polymorphisms, from shotgun metagenomes. Our method leverages a database of >30,000 bacterial reference genomes which we clustered into species groups. These cover the majority of abundant species in the human microbiome but only a small proportion of microbes in other environments, including soil and seawater. We appliedMIDASto stool metagenomes from 98 Swedish mothers and their infants over one year and used rare single nucleotide variants to reveal extensive vertical transmission of strains at birth but colonization with strains unlikely to derive from the mother at later time points. This pattern was missed with species-level analysis, because the infant gut microbiome composition converges towards that of an adult over time. We also appliedMIDASto 198 globally distributed marine metagenomes and used gene content to show that many prevalent bacterial species have population structure that correlates with geographic location. Strain-level genetic variants present in metagenomes clearly reveal extensive structure and dynamics that are obscured when data is analyzed at a higher taxonomic resolution.
Cortical state and natural movie responses in cat visual cortex
Authors: Spacek Martin A. , Swindale Nicholas V.
Published: November 2015

How does cortical state affect neural responses to naturalistic stimuli, and is it analogous between anesthetized and awake animals? We recorded spikes and local field potential (LFP) from all layers of isoflurane-anesthetized cat primary visual cortex (V1) while repeatedly presenting wide-field natural scene movie clips. Spiking responses of single units were remarkably precise, reliable and sparse, with lognormally distributed mean firing rates. Many units had distinct barcode-like firing patterns, with features as little as 10 ms wide. LFP-derived cortical state switched spontaneously between synchronized (1/f) and desynchronized (broadband). Surprisingly, responses were more precise, reliable and sparse during the synchronized than desynchronized state. Because the desynchronized state under anesthesia is thought to correspond to attending periods in awake animals, during which responses are enhanced, our results complicate the analogy between cortical states in anesthetized and awake animals. The presenceof orientation maps in cat V1 may explain contrary reports in anesthetized rodents, and predicts a similar result in anesthetized ferret and primate V1.

Significance Statement

Global brain activity changes spontaneously over time and can be characterized along a spectrum from slow synchronized activity, to fast desynchronized activity. This spectrum is similar in awake, asleep and anesthetized animals, but is its effect on neural responses the same in all cases? Here we show that neural responses to natural movies in anesthetized cat visual cortex are more precise during synchronized activity. This is contrary to reports in anesthetized rodents, which we suggest may be due to greater columnar organization in cat visual cortex. Since this is also contrary to enhanced responses and behavioural performance during attention, when activity is desynchronized, our results suggest that similar brain states in awake and anesthetized animals may not be functionally analogous.
Biomechanics of shear-sensitive adhesion in climbing animals: peeling, pre-tension and sliding-induced changes in interface strength
Authors: Labonte David , Federle Walter
Published: November 2015

Rapid control of adhesive forces is one of the key benchmarks where footpads of climbing animals outperform conventional adhesives, promising novel bio-inspired attachment systems. All climbing animals use shear forces to switch rapidly between firm attachment and easy detachment, but the detailed mechanisms underlying ‘shear-sensitive adhesion’ have remained unclear. Here, we show that attachment forces of stick insects follow classic peeling theory when shear forces are small, but strongly exceed predictions as soon as their pads start to slide due to high shear forces. Pad sliding dramatically increases the critical peel forceviaa combination of two distinct mechanisms. First, partial sliding will pre-stretch the pads, so that they are effectively stiffer upon detachment and peel increasingly like inextensible tape. We demonstrate how this effect can be directly related to peeling theories which account for frictional dissipation. Second, pad sliding reduces the thickness of the secretion layer in the contact zone, thereby decreasing the interfacial mobility, and increasing the stress levels required for peeling. The approximately linear increase of adhesion with friction results in a sharp increase of adhesion at peel angles less than ca. 30°, allowing rapid switching between attachment and detachment during locomotion. Our results may apply to diverse climbing animals independent of pad morphology and adhesive mechanism, and highlight that control of adhesion is not solely achieved by direction-dependence and morphological anisotropy, suggesting promising new routes for the development of bio-inspired adhesives.