bluuebunny/crossref_metadata_2025 huggingface dataset:
Ligand- and mutation-induced conformational selection in the CCR5 chemokine G protein-coupled receptor
Authors: Abrol Ravinder , Trzaskowski Bartosz , Goddard William A. , Nesterov Alexandre , Olave Ivan , Irons Christopher
Published: August 2014

Significance

The C-C chemokine receptor type 5 (CCR5) G protein-coupled receptor (GPCR) is a prime target for preventing HIV invasion. A major difficulty in developing effective therapeutics is that the CCR5 exhibits an ensemble of
∼
10–20 distinct low-energy conformations, each of which might favor binding to different ligands and/or lead to different downstream functions. X-ray structures generally provide only one of these conformations. We applied the GEnSeMBLE methodology to predict this ensemble, and we designed and carried out 11 experiments to validate the ability of this ensemble to predict binding of an HIV therapeutic to CCR5. We found that each of the mutations changes the binding site. The predicted effects of mutations on binding are in excellent agreement with experiments, providing CCR5 structures for designing new ligands.
Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans
Authors: Ellebedy Ali H. , Krammer Florian , Li Gui-Mei , Miller Matthew S. , Chiu Christopher , Wrammert Jens , Chang Cathy Y. , Davis Carl W. , McCausland Megan , Elbein Rivka , Edupuganti Srilatha , Spearman Paul , Andrews Sarah F. , Wilson Patrick C. , García-Sastre Adolfo , Mulligan Mark J. , Mehta Aneesh K. , Palese Peter , Ahmed Rafi
Published: August 2014

Significance

Vaccination is the most effective means of attaining protection against influenza viruses. However, the constantly evolving nature of influenza viruses enables them to escape preexisting immune surveillance, and thus thwarts public health efforts to control influenza annual epidemics and occasional pandemics. One solution is to elicit antibodies directed against highly conserved epitopes, such as those within the stem region of influenza HA, the principal target of virus-neutralizing antibody responses. This study shows that annual influenza vaccines induce antibody responses that are largely directed against the highly variable HA head region. In contrast, heterologous immunization with HA derived from influenza strains that are currently not circulating in humans (e.g. H5N1) can substantially increase HA stem-specific responses.
Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir
Authors: Chun Tae-Wook , Murray Danielle , Justement Jesse S. , Blazkova Jana , Hallahan Claire W. , Fankuchen Olivia , Gittens Kathleen , Benko Erika , Kovacs Colin , Moir Susan , Fauci Anthony S.
Published: August 2014

Significance

A number of highly potent and broadly neutralizing HIV-specific monoclonal antibodies have recently been isolated from B cells of infected individuals. However, the effects of these antibodies on the persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We demonstrate that a select number of HIV-specific monoclonal antibodies potently suppressed entry into CD4
+
T cells of HIV isolated from the latent viral reservoir as well as replication of reservoir virus in autologous CD4
+
T cells derived from infected individuals receiving ART. These findings provide new opportunities for passive immunotherapy to prevent plasma viral rebound following discontinuation of antiretroviral drugs.
The class III ribonucleotide reductase from
Neisseria bacilliformis
can utilize thioredoxin as a reductant
Authors: Wei Yifeng , Funk Michael A. , Rosado Leonardo A. , Baek Jiyeon , Drennan Catherine L. , Stubbe JoAnne
Published: August 2014

Significance

Ribonucleotide reductases (RNRs) catalyze nucleotide reduction via complex radical chemistry, providing deoxynucleotides for DNA synthesis in all domains of life. Many anaerobic bacteria and archaea contain the class III O
2
-sensitive RNR, and those that have been studied to date couple nucleotide reduction to formate oxidation. Here we report the characterization of a second class III RNR subtype that couples nucleotide reduction to the oxidation of thioredoxin. Because of the central role of formate and thiols in many anaerobic processes, the distribution of class III RNRs among different organisms may shed light on aspects of anaerobic biochemistry.
Custos controls β-catenin to regulate head development during vertebrate embryogenesis
Authors: Komiya Yuko , Mandrekar Noopur , Sato Akira , Dawid Igor B. , Habas Raymond
Published: August 2014

Significance

Canonical Wnt pathway is essential for primary axis formation and establishment of basic body pattern during embryogenesis. Defects in Wnt signaling have also been implicated in tumorigenesis and birth defect disorders. Here we characterize a novel component of canonical Wnt signaling termed Custos and show that this protein binds to and modulates β-catenin nuclear translocation in the canonical Wnt signal transduction cascade. Our functional characterization of Custos further shows that this protein has a conserved role in development, being essential for organizer formation and subsequent anterior development in the
Xenopus
and zebrafish embryo. These studies unravel a new layer of regulation of canonical Wnt signaling that might provide insights into mechanisms by which deregulated Wnt signaling results in pathological disorders.
Surprisal analysis characterizes the free energy time course of cancer cells undergoing epithelial-to-mesenchymal transition
Authors: Zadran Sohila , Arumugam Rameshkumar , Herschman Harvey , Phelps Michael E. , Levine R. D.
Published: August 2014

Significance

Epithelial-to-mesenchymal transition (EMT) has been investigated extensively in cancer progression. Tumor cells induced to undergo an EMT acquire mesenchymal, invasive properties. We apply methods developed in chemical reaction dynamics to characterize the changing transcriptional profile during an EMT and trace the temporal unfolding of the transition on a free energy landscape. The analysis identifies three EMT stages, including passage through an intermediate, low-energy maturation state. The uphill energy requirements during the ascent past maturation correlate with an increase in ATP production. A stable cell machinery whose performance remains unperturbed underlies the EMT.
From paper to practice
Authors: Nyroos Lina , Sandlund Erica
Published: August 2014

This paper examines how a standardized question is launched and received in a corpus of performance appraisal interviews, with a focus on how pre-­formulated questions are translated into interaction. Using conversation analysis, we demonstrate that the same question becomes many different actions in practice. Prefaces as well as prosodic and lexical alterations make relevant different responses, and as such, the question can be recruited to initiate diverse interactional projects such as assessments and other socially delicate activities. As a consequence, goals of uniformity and standardization may be subverted. The interactional adaptations further evidence the strength of recipient design as reformulations also result in more fitted and personalized answers. Our study contributes to the understanding of standardization versus interactionalization, and points to the strong interrelationship between question design and the fitting of response options.
Medical record keeping as interactional accomplishment
Authors: Beck Nielsen Søren
Published: August 2014

Medical records are documents of tremendous social importance. They have been the subject of much medical and sociological research, in particular regarding validity, accessibility and readability. This paper uses Conversation Analysis to add an aspect to the understanding of medical records that has been missing so far, namely how medical records are produced as interactional accomplishments; specifically, how hospital staff members during meetings conversationally negotiate and reach conclusions, treatment recommendations, and other types of consequential decisions. The process involves four steps: assessing patients, interpreting implications, drawing conclusions, and dictating conclusions on tape. The key finding is that participants throughout the process orient towards a need for consensus, whilst at the same time acknowledging the doctors’ interactional leading roles. This insight can enhance our understanding of medical records in hospital settings as constructed and negotiated realities.
Dude, Alter!
Authors: Heyd Theresa
Published: August 2014

This paper takes a cross-linguistic look at two notorious examples of contemporary slang: American English dude and German Alter. Both have received considerable attention in the media and some initial sociolinguistic inquiry. It is shown here that both items share a number of properties, some quite obvious, others subtler and possibly less stable. This includes features from all levels of linguistic analysis and covers both formal and functional aspects. The seminal similarity between dude and Alter is of a syntactic nature: while both NPs can occur within argument structure, their default is in vocative position. Based on this structural parallelism, other domains are analyzed, including semantics and bleaching effects, phonological and orthographic variation. Particular attention is given to the sociocultural and sociopragmatic potential of dude and Alter, including their role as indexicals for certain youth groups and their subsequent stereotypization. This paper tracks both the similarities and the subtle differences in the usage and function of dude and Alter. It is argued that this lexical parallelism, albeit coincidental, highlights the role of vocative forms in the discursive makeup of both English and German.
Language and identity in a post-Soviet world: language of education and linguistic identity among Azerbaijani students
Authors: Luscombe Lisa Donohoe , Kazdal Vafa
Published: August 2014

Azerbaijan's complex history has weaved a tapestry of linguistic, cultural, and national identities among Azerbaijanis through centuries of political, social, and linguistic integration. In the current post-Soviet era, this identity is undergoing another period of change, with influences from intra-state ethnic, religious, and sociopolitical institutions as well as from regional and international powers. This article centers on linguistic identity among Azerbaijani youth at three types of schools: Azerbaijani-medium, Russian-medium, and English-medium. The authors seek to discover whether and to what extent the language of instruction in each type of school affects linguistic identity, which in turn has implications for national identity. The article first discusses the existing literature on language and identity in second language acquisition and socio-educational linguistics. It then examines Azerbaijan's linguistic and political history through the lens of the latter framework, as a context for an analysis of the data from surveys and focus groups. The article analyzes the relationship between medium of instruction in school and students' perceptions of language and identification with various language groups, and discusses the findings of a significant correlation between language of instruction and linguistic identity, with its implications for national identity.
What is the Impact of Comorbid Depression on Adolescent Substance Abuse Treatment?
Authors: Hersh Jacqueline , Curry John F. , Kaminer Yifrah
Published: August 2014

Background

Substance use disorders (SUDs) are among the most common psychiatric diagnoses in adolescents. Some research suggests that comorbid depression in adolescents with SUD is associated with increased likelihood of alcohol dependence, poorer social competence, and greater risk for suicide attempts. However, little is known about how depression influences adolescent substance abuse treatment retention and outcomes.

Methods

This review aimed to summarize the effects of comorbid depression on treatment retention and outcomes across 13 adolescent SUD treatment studies.

Results

Results indicated that depression has a mixed relationship with treatment retention and outcomes, exerting a negative, positive, or nonsignificant effect depending on aspects of the study.

Conclusions

More research needs to be done, particularly addressing the potential mediators and moderators of the relationship between depression and SUD outcomes. Importantly, recognizing that the studies varied widely in hypotheses and research methods, the field needs to develop more standardized methods to allow for a clearer understanding of the role of comorbid depression.
Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin
Authors: Ashrafi Ghazaleh , Schlehe Julia S. , LaVoie Matthew J. , Schwarz Thomas L.
Published: August 2014

To minimize oxidative damage to the cell, malfunctioning mitochondria need to be removed by mitophagy. In neuronal axons, mitochondrial damage may occur in distal regions, far from the soma where most lysosomal degradation is thought to occur. In this paper, we report that PINK1 and Parkin, two Parkinson’s disease–associated proteins, mediate local mitophagy of dysfunctional mitochondria in neuronal axons. To reduce cytotoxicity and mimic physiological levels of mitochondrial damage, we selectively damaged a subset of mitochondria in hippocampal axons. Parkin was rapidly recruited to damaged mitochondria in axons followed by formation of LC3-positive autophagosomes and LAMP1-positive lysosomes. In PINK1−/− axons, damaged mitochondria did not accumulate Parkin and failed to be engulfed in autophagosomes. Similarly, initiation of mitophagy was blocked in Parkin−/− axons. Our findings demonstrate that the PINK1–Parkin-mediated pathway is required for local mitophagy in distal axons in response to focal damage. Local mitophagy likely provides rapid neuroprotection against oxidative stress without a requirement for retrograde transport to the soma.
BMP-regulated exosomes from Drosophila male reproductive glands reprogram female behavior
Authors: Corrigan Laura , Redhai Siamak , Leiblich Aaron , Fan Shih-Jung , Perera Sumeth M.W. , Patel Rachel , Gandy Carina , Wainwright S. Mark , Morris John F. , Hamdy Freddie , Goberdhan Deborah C.I. , Wilson Clive
Published: August 2014

Male reproductive glands secrete signals into seminal fluid to facilitate reproductive success. In Drosophila melanogaster, these signals are generated by a variety of seminal peptides, many produced by the accessory glands (AGs). One epithelial cell type in the adult male AGs, the secondary cell (SC), grows selectively in response to bone morphogenetic protein (BMP) signaling. This signaling is involved in blocking the rapid remating of mated females, which contributes to the reproductive advantage of the first male to mate. In this paper, we show that SCs secrete exosomes, membrane-bound vesicles generated inside late endosomal multivesicular bodies (MVBs). After mating, exosomes fuse with sperm (as also seen in vitro for human prostate-derived exosomes and sperm) and interact with female reproductive tract epithelia. Exosome release was required to inhibit female remating behavior, suggesting that exosomes are downstream effectors of BMP signaling. Indeed, when BMP signaling was reduced in SCs, vesicles were still formed in MVBs but not secreted as exosomes. These results demonstrate a new function for the MVB–exosome pathway in the reproductive tract that appears to be conserved across evolution.
Sequential and ordered assembly of a large DNA repair complex on undamaged chromatin
Authors: Ziani Salim , Nagy Zita , Alekseev Sergey , Soutoglou Evi , Egly Jean-Marc , Coin Frédéric
Published: August 2014

In nucleotide excision repair (NER), damage recognition by XPC-hHR23b is described as a critical step in the formation of the preincision complex (PInC) further composed of TFIIH, XPA, RPA, XPG, and ERCC1-XPF. To obtain new molecular insights into the assembly of the PInC, we analyzed its formation independently of DNA damage by using the lactose operator/repressor reporter system. We observed a sequential and ordered self-assembly of the PInC operating upon immobilization of individual NER factors on undamaged chromatin and mimicking that functioning on a bona fide NER substrate. We also revealed that the recruitment of the TFIIH subunit TTDA, involved in trichothiodystrophy group A disorder (TTD-A), was key in the completion of the PInC. TTDA recruits XPA through its first 15 amino acids, depleted in some TTD-A patients. More generally, these results show that proteins forming large nuclear complexes can be recruited sequentially on chromatin in the absence of their natural DNA target and with no reciprocity in their recruitment.
UNC-6 (netrin) stabilizes oscillatory clustering of the UNC-40 (DCC) receptor to orient polarity
Authors: Wang Zheng , Linden Lara M. , Naegeli Kaleb M. , Ziel Joshua W. , Chi Qiuyi , Hagedorn Elliott J. , Savage Natasha S. , Sherwood David R.
Published: August 2014

The receptor deleted in colorectal cancer (DCC) directs dynamic polarizing activities in animals toward its extracellular ligand netrin. How DCC polarizes toward netrin is poorly understood. By performing live-cell imaging of the DCC orthologue UNC-40 during anchor cell invasion in Caenorhabditis elegans, we have found that UNC-40 clusters, recruits F-actin effectors, and generates F-actin in the absence of UNC-6 (netrin). Time-lapse analyses revealed that UNC-40 clusters assemble, disassemble, and reform at periodic intervals in different regions of the cell membrane. This oscillatory behavior indicates that UNC-40 clusters through a mechanism involving interlinked positive (formation) and negative (disassembly) feedback. We show that endogenous UNC-6 and ectopically provided UNC-6 orient and stabilize UNC-40 clustering. Furthermore, the UNC-40–binding protein MADD-2 (a TRIM family protein) promotes ligand-independent clustering and robust UNC-40 polarization toward UNC-6. Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing UNC-40 clustering. We propose that ligand-independent UNC-40 clustering provides a robust and adaptable mechanism to polarize toward netrin.
Netrin puts an end to the anchor cell’s vacillations
Authors: Short Ben
Published: August 2014

The guidance cue orients cell invasion by stabilizing the oscillations of its receptor UNC-40.
Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD
Authors: Ward Michael E. , Taubes Alice , Chen Robert , Miller Bruce L. , Sephton Chantelle F. , Gelfand Jeffrey M. , Minami Sakura , Boscardin John , Martens Lauren Herl , Seeley William W. , Yu Gang , Herz Joachim , Filiano Anthony J. , Arrant Andrew E. , Roberson Erik D. , Kraft Timothy W. , Farese Robert V. , Green Ari , Gan Li
Published: August 2014

Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of familial FTLD-TDP. Grn-KO mice were developed as an FTLD model, but lack cortical TDP-43 mislocalization and neurodegeneration. Here, we report retinal thinning as an early disease phenotype in humans with GRN mutations that precedes dementia onset and an age-dependent retinal neurodegenerative phenotype in Grn-KO mice. Retinal neuron loss in Grn-KO mice is preceded by nuclear depletion of TDP-43 and accompanied by reduced expression of the small GTPase Ran, which is a master regulator of nuclear import required for nuclear localization of TDP-43. In addition, TDP-43 regulates Ran expression, likely via binding to its 3′-UTR. Augmented expression of Ran in progranulin-deficient neurons restores nuclear TDP-43 levels and improves their survival. Our findings establish retinal neurodegeneration as a new phenotype in progranulin-deficient FTLD, and suggest a pathological loop involving reciprocal loss of Ran and nuclear TDP-43 as an underlying mechanism.
Towards a piRNA prediction using multiple kernel fusion and support vector machine
Authors: Brayet Jocelyn , Zehraoui Farida , Jeanson-Leh Laurence , Israeli David , Tahi Fariza
Published: August 2014

Motivation: Piwi-interacting RNA (piRNA) is the most recently discovered and the least investigated class of Argonaute/Piwi protein-interacting small non-coding RNAs. The piRNAs are mostly known to be involved in protecting the genome from invasive transposable elements. But recent discoveries suggest their involvement in the pathophysiology of diseases, such as cancer. Their identification is therefore an important task, and computational methods are needed. However, the lack of conserved piRNA sequences and structural elements makes this identification challenging and difficult.

Results: In the present study, we propose a new modular and extensible machine learning method based on multiple kernels and a support vector machine (SVM) classifier for piRNA identification. Very few piRNA features are known to date. The use of a multiple kernels approach allows editing, adding or removing piRNA features that can be heterogeneous in a modular manner according to their relevance in a given species. Our algorithm is based on a combination of the previously identified features [sequence features (k-mer motifs and a uridine at the first position) and piRNAs cluster feature] and a new telomere/centromere vicinity feature. These features are heterogeneous, and the kernels allow to unify their representation. The proposed algorithm, named piRPred, gives promising results on Drosophila and Human data and outscores previously published piRNA identification algorithms.

Availability and implementation: piRPred is freely available to non-commercial users on our Web server EvryRNA http://EvryRNA.ibisc.univ-evry.fr

Contact:  tahi@ibisc.univ-evry.fr
Estimating the activity of transcription factors by the effect on their target genes
Authors: Schacht Theresa , Oswald Marcus , Eils Roland , Eichmüller Stefan B. , König Rainer
Published: August 2014

Motivation: Understanding regulation of transcription is central for elucidating cellular regulation. Several statistical and mechanistic models have come up the last couple of years explaining gene transcription levels using information of potential transcriptional regulators as transcription factors (TFs) and information from epigenetic modifications. The activity of TFs is often inferred by their transcription levels, promoter binding and epigenetic effects. However, in principle, these methods do not take hard-to-measure influences such as post-transcriptional modifications into account.

Results: For TFs, we present a novel concept circumventing this problem. We estimate the regulatory activity of TFs using their cumulative effects on their target genes. We established our model using expression data of 59 cell lines from the National Cancer Institute. The trained model was applied to an independent expression dataset of melanoma cells yielding excellent expression predictions and elucidated regulation of melanogenesis.

Availability and implementation: Using mixed-integer linear programming, we implemented a switch-like optimization enabling a constrained but optimal selection of TFs and optimal model selection estimating their effects. The method is generic and can also be applied to further regulators of transcription.

Contact:  rainer.koenig@uni-jena.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Personalized identification of altered pathways in cancer using accumulated normal tissue data
Authors: Ahn TaeJin , Lee Eunjin , Huh Nam , Park Taesung
Published: August 2014

Motivation: Identifying altered pathways in an individual is important for understanding disease mechanisms and for the future application of custom therapeutic decisions. Existing pathway analysis techniques are mainly focused on discovering altered pathways between normal and cancer groups and are not suitable for identifying the pathway aberrance that may occur in an individual sample. A simple way to identify individual’s pathway aberrance is to compare normal and tumor data from the same individual. However, the matched normal data from the same individual are often unavailable in clinical situation. Therefore, we suggest a new approach for the personalized identification of altered pathways, making special use of accumulated normal data in cases when a patient’s matched normal data are unavailable. The philosophy behind our method is to quantify the aberrance of an individual sample's pathway by comparing it with accumulated normal samples. We propose and examine personalized extensions of pathway statistics, overrepresentation analysis and functional class scoring, to generate individualized pathway aberrance score.

Results: Collected microarray data of normal tissue of lung and colon mucosa are served as reference to investigate a number of cancer individuals of lung adenocarcinoma (LUAD) and colon cancer, respectively. Our method concurrently captures known facts of cancer survival pathways and identifies the pathway aberrances that represent cancer differentiation status and survival. It also provides more improved validation rate of survival-related pathways than when a single cancer sample is interpreted in the context of cancer-only cohort. In addition, our method is useful in classifying unknown samples into cancer or normal groups. Particularly, we identified ‘amino acid synthesis and interconversion’ pathway is a good indicator of LUAD (Area Under the Curve (AUC) 0.982 at independent validation). Clinical importance of the method is providing pathway interpretation of single cancer, even though its matched normal data are unavailable.

Availability and implementation: The method was implemented using the R software, available at our Web site: http://bibs.snu.ac.kr/ipas.

Contact:  tspark@stat.snu.ac.kr or namhuh@samsung.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
Effects of small particle numbers on long-term behaviour in discrete biochemical systems
Authors: Kreyssig Peter , Wozar Christian , Peter Stephan , Veloz Tomás , Ibrahim Bashar , Dittrich Peter
Published: August 2014

Motivation: The functioning of many biological processes depends on the appearance of only a small number of a single molecular species. Additionally, the observation of molecular crowding leads to the insight that even a high number of copies of species do not guarantee their interaction. How single particles contribute to stabilizing biological systems is not well understood yet. Hence, we aim at determining the influence of single molecules on the long-term behaviour of biological systems, i.e. whether they can reach a steady state.

Results: We provide theoretical considerations and a tool to analyse Systems Biology Markup Language models for the possibility to stabilize because of the described effects. The theory is an extension of chemical organization theory, which we called discrete chemical organization theory. Furthermore we scanned the BioModels Database for the occurrence of discrete chemical organizations. To exemplify our method, we describe an application to the Template model of the mitotic spindle assembly checkpoint mechanism.

Availability and implementation:  http://www.biosys.uni-jena.de/Services.html.

Contact:  bashar.ibrahim@uni-jena.de or dittrich@minet.uni-jena.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
A new statistical framework to assess structural alignment quality using information compression
Authors: Collier James H. , Allison Lloyd , Lesk Arthur M. , Garcia de la Banda Maria , Konagurthu Arun S.
Published: August 2014

Motivation: Progress in protein biology depends on the reliability of results from a handful of computational techniques, structural alignments being one. Recent reviews have highlighted substantial inconsistencies and differences between alignment results generated by the ever-growing stock of structural alignment programs. The lack of consensus on how the quality of structural alignments must be assessed has been identified as the main cause for the observed differences. Current methods assess structural alignment quality by constructing a scoring function that attempts to balance conflicting criteria, mainly alignment coverage and fidelity of structures under superposition. This traditional approach to measuring alignment quality, the subject of considerable literature, has failed to solve the problem. Further development along the same lines is unlikely to rectify the current deficiencies in the field.

Results: This paper proposes a new statistical framework to assess structural alignment quality and significance based on lossless information compression. This is a radical departure from the traditional approach of formulating scoring functions. It links the structural alignment problem to the general class of statistical inductive inference problems, solved using the information-theoretic criterion of minimum message length. Based on this, we developed an efficient and reliable measure of structural alignment quality, I-value. The performance of I-value is demonstrated in comparison with a number of popular scoring functions, on a large collection of competing alignments. Our analysis shows that I-value provides a rigorous and reliable quantification of structural alignment quality, addressing a major gap in the field.

Availability: http://lcb.infotech.monash.edu.au/I-value

Contact: arun.konagurthu@monash.edu

Supplementary information:  Online supplementary data are available at http://lcb.infotech.monash.edu.au/I-value/suppl.html
Point estimates in phylogenetic reconstructions
Authors: Benner Philipp , Bačák Miroslav , Bourguignon Pierre-Yves
Published: August 2014

Motivation: The construction of statistics for summarizing posterior samples returned by a Bayesian phylogenetic study has so far been hindered by the poor geometric insights available into the space of phylogenetic trees, and ad hoc methods such as the derivation of a consensus tree makeup for the ill-definition of the usual concepts of posterior mean, while bootstrap methods mitigate the absence of a sound concept of variance. Yielding satisfactory results with sufficiently concentrated posterior distributions, such methods fall short of providing a faithful summary of posterior distributions if the data do not offer compelling evidence for a single topology.

Results: Building upon previous work of Billera et al., summary statistics such as sample mean, median and variance are defined as the geometric median, Fréchet mean and variance, respectively. Their computation is enabled by recently published works, and embeds an algorithm for computing shortest paths in the space of trees. Studying the phylogeny of a set of plants, where several tree topologies occur in the posterior sample, the posterior mean balances correctly the contributions from the different topologies, where a consensus tree would be biased. Comparisons of the posterior mean, median and consensus trees with the ground truth using simulated data also reveals the benefits of a sound averaging method when reconstructing phylogenetic trees.

Availability and implementation: We provide two independent implementations of the algorithm for computing Fréchet means, geometric medians and variances in the space of phylogenetic trees. TFBayes: https://github.com/pbenner/tfbayes, TrAP: https://github.com/bacak/TrAP.

Contact:  philipp.benner@mis.mpg.de
Transcriptome-guided amyloid imaging genetic analysis via a novel structured sparse learning algorithm
Authors: Yan Jingwen , Du Lei , Kim Sungeun , Risacher Shannon L. , Huang Heng , Moore Jason H. , Saykin Andrew J. , Shen Li ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2014

Motivation: Imaging genetics is an emerging field that studies the influence of genetic variation on brain structure and function. The major task is to examine the association between genetic markers such as single-nucleotide polymorphisms (SNPs) and quantitative traits (QTs) extracted from neuroimaging data. The complexity of these datasets has presented critical bioinformatics challenges that require new enabling tools. Sparse canonical correlation analysis (SCCA) is a bi-multivariate technique used in imaging genetics to identify complex multi-SNP–multi-QT associations. However, most of the existing SCCA algorithms are designed using the soft thresholding method, which assumes that the input features are independent from one another. This assumption clearly does not hold for the imaging genetic data. In this article, we propose a new knowledge-guided SCCA algorithm (KG-SCCA) to overcome this limitation as well as improve learning results by incorporating valuable prior knowledge.

Results: The proposed KG-SCCA method is able to model two types of prior knowledge: one as a group structure (e.g. linkage disequilibrium blocks among SNPs) and the other as a network structure (e.g. gene co-expression network among brain regions). The new model incorporates these prior structures by introducing new regularization terms to encourage weight similarity between grouped or connected features. A new algorithm is designed to solve the KG-SCCA model without imposing the independence constraint on the input features. We demonstrate the effectiveness of our algorithm with both synthetic and real data. For real data, using an Alzheimer’s disease (AD) cohort, we examine the imaging genetic associations between all SNPs in the APOE gene (i.e. top AD gene) and amyloid deposition measures among cortical regions (i.e. a major AD hallmark). In comparison with a widely used SCCA implementation, our KG-SCCA algorithm produces not only improved cross-validation performances but also biologically meaningful results.

Availability: Software is freely available on request.

Contact: shenli@iu.edu
ContrastRank: a new method for ranking putative cancer driver genes and classification of tumor samples
Authors: Tian Rui , Basu Malay K. , Capriotti Emidio
Published: August 2014

Motivation: The recent advance in high-throughput sequencing technologies is generating a huge amount of data that are becoming an important resource for deciphering the genotype underlying a given phenotype. Genome sequencing has been extensively applied to the study of the cancer genomes. Although a few methods have been already proposed for the detection of cancer-related genes, their automatic identification is still a challenging task. Using the genomic data made available by The Cancer Genome Atlas Consortium (TCGA), we propose a new prioritization approach based on the analysis of the distribution of putative deleterious variants in a large cohort of cancer samples.

Results: In this paper, we present ContastRank, a new method for the prioritization of putative impaired genes in cancer. The method is based on the comparison of the putative defective rate of each gene in tumor versus normal and 1000 genome samples. We show that the method is able to provide a ranked list of putative impaired genes for colon, lung and prostate adenocarcinomas. The list significantly overlaps with the list of known cancer driver genes previously published. More importantly, by using our scoring approach, we can successfully discriminate between TCGA normal and tumor samples. A binary classifier based on ContrastRank score reaches an overall accuracy >90% and the area under the curve (AUC) of receiver operating characteristics (ROC) >0.95 for all the three types of adenocarcinoma analyzed in this paper. In addition, using ContrastRank score, we are able to discriminate the three tumor types with a minimum overall accuracy of 77% and AUC of 0.83.

Conclusions: We describe ContrastRank, a method for prioritizing putative impaired genes in cancer. The method is based on the comparison of exome sequencing data from different cohorts and can detect putative cancer driver genes.

ContrastRank can also be used to estimate a global score for an individual genome about the risk of adenocarcinoma based on the genetic variants information from a whole-exome VCF (Variant Calling Format) file. We believe that the application of ContrastRank can be an important step in genomic medicine to enable genome-based diagnosis.

Availability and implementation: The lists of ContrastRank scores of all genes in each tumor type are available as supplementary materials. A webserver for evaluating the risk of the three studied adenocarcinomas starting from whole-exome VCF file is under development.

Contact:  emidio@uab.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
OncodriveROLE classifies cancer driver genes in loss of function and activating mode of action
Authors: Schroeder Michael P. , Rubio-Perez Carlota , Tamborero David , Gonzalez-Perez Abel , Lopez-Bigas Nuria
Published: August 2014

Motivation: Several computational methods have been developed to identify cancer drivers genes—genes responsible for cancer development upon specific alterations. These alterations can cause the loss of function (LoF) of the gene product, for instance, in tumor suppressors, or increase or change its activity or function, if it is an oncogene. Distinguishing between these two classes is important to understand tumorigenesis in patients and has implications for therapy decision making. Here, we assess the capacity of multiple gene features related to the pattern of genomic alterations across tumors to distinguish between activating and LoF cancer genes, and we present an automated approach to aid the classification of novel cancer drivers according to their role.

Result: OncodriveROLE is a machine learning-based approach that classifies driver genes according to their role, using several properties related to the pattern of alterations across tumors. The method shows an accuracy of 0.93 and Matthew's correlation coefficient of 0.84 classifying genes in the Cancer Gene Census. The OncodriveROLE classifier, its results when applied to two lists of predicted cancer drivers and TCGA-derived mutation and copy number features used by the classifier are available at http://bg.upf.edu/oncodrive-role.

Availability and implementation: The R implementation of the OncodriveROLE classifier is available at http://bg.upf.edu/oncodrive-role.

Contact:  abel.gonzalez@upf.edu or nuria.lopez@upf.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Integration of molecular network data reconstructs Gene Ontology
Authors: Gligorijević Vladimir , Janjić Vuk , Pržulj Nataša
Published: August 2014

Motivation: Recently, a shift was made from using Gene Ontology (GO) to evaluate molecular network data to using these data to construct and evaluate GO. Dutkowski et al. provide the first evidence that a large part of GO can be reconstructed solely from topologies of molecular networks. Motivated by this work, we develop a novel data integration framework that integrates multiple types of molecular network data to reconstruct and update GO. We ask how much of GO can be recovered by integrating various molecular interaction data.

Results: We introduce a computational framework for integration of various biological networks using penalized non-negative matrix tri-factorization (PNMTF). It takes all network data in a matrix form and performs simultaneous clustering of genes and GO terms, inducing new relations between genes and GO terms (annotations) and between GO terms themselves. To improve the accuracy of our predicted relations, we extend the integration methodology to include additional topological information represented as the similarity in wiring around non-interacting genes. Surprisingly, by integrating topologies of bakers’ yeasts protein–protein interaction, genetic interaction (GI) and co-expression networks, our method reports as related 96% of GO terms that are directly related in GO. The inclusion of the wiring similarity of non-interacting genes contributes 6% to this large GO term association capture. Furthermore, we use our method to infer new relationships between GO terms solely from the topologies of these networks and validate 44% of our predictions in the literature. In addition, our integration method reproduces 48% of cellular component, 41% of molecular function and 41% of biological process GO terms, outperforming the previous method in the former two domains of GO. Finally, we predict new GO annotations of yeast genes and validate our predictions through GIs profiling.

Availability and implementation: Supplementary Tables of new GO term associations and predicted gene annotations are available at http://bio-nets.doc.ic.ac.uk/GO-Reconstruction/.

Contact:  natasha@imperial.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Extracting patterns of database and software usage from the bioinformatics literature
Authors: Duck Geraint , Nenadic Goran , Brass Andy , Robertson David L. , Stevens Robert
Published: August 2014

Motivation: As a natural consequence of being a computer-based discipline, bioinformatics has a strong focus on database and software development, but the volume and variety of resources are growing at unprecedented rates. An audit of database and software usage patterns could help provide an overview of developments in bioinformatics and community common practice, and comparing the links between resources through time could demonstrate both the persistence of existing software and the emergence of new tools.

Results: We study the connections between bioinformatics resources and construct networks of database and software usage patterns, based on resource co-occurrence, that correspond to snapshots of common practice in the bioinformatics community. We apply our approach to pairings of phylogenetics software reported in the literature and argue that these could provide a stepping stone into the identification of scientific best practice.

Availability and implementation: The extracted resource data, the scripts used for network generation and the resulting networks are available at http://bionerds.sourceforge.net/networks/

Contact:  robert.stevens@manchester.ac.uk
Prespawning herring distribution in the Irish Celtic Sea between 2005 and 2012
Authors: Volkenandt Mareike , Berrow Simon , O’Connor Ian , Guarini Jean-Marc , O’Donnell Ciaran
Published: August 2014

Knowledge of the spatial distribution of species is fundamental to understanding trophic interactions and ecosystem structure. Intraspecies-specific dynamics and environmental factors shape species distribution within an ecosystem. Distribution patterns and the realized habitat of Atlantic herring (Clupea harengus), a key fish species in the Celtic Sea, were examined using distribution data collected during annual acoustic stock assessment surveys during 2005–2012. Distribution patterns during migration to spawning grounds were analysed using geostatistical methods, including modelling of variograms and comparing the centre of gravity (CG). Distribution patterns were further linked to oceanographic variables collected with the acoustic data to describe habitat. Herring density was greatest inshore along the spawning grounds and lower farther offshore. Herring shoals were clustered and randomly distributed during spawning migration. Variograms of fish densities described the global structure, with high local variability of the same order of magnitude as variability at a regional scale, indicating that no continuous structure can be found within the study area. The CG values showed that the average position of the population was located northeast. The realized habitat for herring encompassed a wide range of temperatures and salinities; therefore, oceanographic features were not a limiting factor for herring distribution during spawning migration. The present study changes the perception of the spatial distribution of the Celtic Sea herring stock from a more continuous distribution to a discrete model, with implications for trophic ecosystem modelling on local scales. Future studies of herring distribution and its influence within the Celtic Sea ecosystem would benefit from using the approach employed in the present study for analysing aggregation patterns.
Slow science: the value of long ocean biogeochemistry records
Authors: Henson Stephanie A.
Published: August 2014

Sustained observations (SOs) have provided invaluable information on the ocean's biology and biogeochemistry for over 50 years. They continue to play a vital role in elucidating the functioning of the marine ecosystem, particularly in the light of ongoing climate change. Repeated, consistent observations have provided the opportunity to resolve temporal and/or spatial variability in ocean biogeochemistry, which has driven exploration of the factors controlling biological parameters and processes. Here, I highlight some of the key breakthroughs in biological oceanography that have been enabled by SOs, which include areas such as trophic dynamics, understanding variability, improved biogeochemical models and the role of ocean biology in the global carbon cycle. In the near future, SOs are poised to make progress on several fronts, including detecting climate change effects on ocean biogeochemistry, high-resolution observations of physical–biological interactions and greater observational capability in both the mesopelagic zone and harsh environments, such as the Arctic. We are now entering a new era for biological SOs, one in which our motivations have evolved from the need to acquire basic understanding of the ocean's state and variability, to a need to understand ocean biogeochemistry in the context of increasing pressure in the form of climate change, overfishing and eutrophication.
The role of sustained observations in tracking impacts of environmental change on marine biodiversity and ecosystems
Authors: Mieszkowska N. , Sugden H. , Firth L. B. , Hawkins S. J.
Published: August 2014

Marine biodiversity currently faces unprecedented threats from multiple pressures arising from human activities. Global drivers such as climate change and ocean acidification interact with regional eutrophication, exploitation of commercial fish stocks and localized pressures including pollution, coastal development and the extraction of aggregates and fuel, causing alteration and degradation of habitats and communities. Segregating natural from anthropogenically induced change in marine ecosystems requires long-term, sustained observations of marine biota. In this review, we outline the history of biological recording in the coastal and shelf seas of the UK and Ireland and highlight where sustained observations have contributed new understanding of how anthropogenic activities have impacted on marine biodiversity. The contributions of sustained observations, from those collected at observatories, single station platforms and multiple-site programmes to the emergent field of multiple stressor impacts research, are discussed, along with implications for management and sustainable governance of marine resources in an era of unprecedented use of the marine environment.