bluuebunny/crossref_metadata_2025 huggingface dataset:
Obesity and Lowered Cognitive Performance in a Canadian First Nations Population
Authors: Fergenbaum Jennifer H. , Bruce Sharon , Lou Wendy , Hanley Anthony J.G. , Greenwood Carol , Young T. Kue
Published: May 2009

The association between obesity, other cardiovascular risk factors, and cognitive function in a Canadian First Nations population was investigated using a cross‐sectional design. Eligible individuals were aged ≥18 years, without a history of stroke, nonpregnant, with First Nations status, and who had undergone cognitive function assessment by the Clock Drawing Test (CDT) and Trail Making Test Parts A and B. Parts A and B were combined into an Executive Function Score (TMT‐exec). Hypertension, a previous history of cardiovascular disease, dyslipidemia, metabolic syndrome, insulin resistance, and the presence and duration of diabetes were examined in addition to obesity. In the case of TMT‐exec only, obese individuals were at an approximately fourfold increased risk for lowered cognitive performance compared to those who were not obese in multivariable models (odds ratio (OR): 3.77, 95% confidence interval (CI): 1.46–9.72) whereas there was no effect for overweight individuals compared to those with a normal weight in unadjusted analysis. Those having an increased waist circumference also had 5 times the risk compared to those without an increased waist circumference (OR: 5.41, 95% CI: 1.83–15.99). Adjusted for age, sex, and insulin resistance, individuals having the metabolic syndrome were at an approximately fourfold increased risk compared to those without the metabolic syndrome (OR: 3.67, 95% CI: 1.34–10.07). No other cardiovascular risk factors were associated. Obesity and metabolic syndrome were associated with lowered cognitive performance. These results highlight the importance of studying the health effects of obesity beyond traditional disease endpoints, even in a relatively youthful population.
FAM20B is a kinase that phosphorylates xylose in the glycosaminoglycan–protein linkage region
Authors: Koike Toshiyasu , Izumikawa Tomomi , Tamura Jun-Ichi , Kitagawa Hiroshi
Published: May 2009

2-O-phosphorylation of xylose has been detected in the glycosaminoglycan–protein linkage region, GlcAβ1-3Galβ1-3Galβ1-4Xylβ1-O-Ser, of proteoglycans. Recent mutant analyses in zebrafish suggest that xylosyltransferase I and FAM20B, a protein of unknown function that shows weak similarity to a Golgi kinase encoded by four-jointed, operate in a linear pathway for proteoglycan production. In the present study, we identified FAM20B as a kinase that phosphorylates the xylose residue in the linkage region. Overexpression of FAM20B increased the amount of both chondroitin sulfate and heparan sulfate in HeLa cells, whereas the RNA interference of FAM20B resulted in a reduction of their amount in the cells. Gel-filtration analysis of the glycosaminoglycan chains synthesized in the overexpressing cells revealed that the glycosaminoglycan chains had a similar length to those in mock-transfected cells. These results suggest that FAM20B regulates the number of glycosaminoglycan chains by phosphorylating the xylose residue in the glycosaminoglycan–protein linkage region of proteoglycans.
Mobile Word-Of-Mouth - A Grounded Theory of Mobile Viral Marketing
Authors: Palka Wolfgang , Pousttchi Key , Wiedemann Dietmar G
Published: May 2009

Mobile devices as personal communication tools are used as platforms for viral marketing within existing social networks. Although there is some evidence on the usefulness of mobile viral marketing from the marketers’ perspective, little is known about the motivations, attitudes, and behaviors of consumers engaged in this marketing instrument. The purpose of this research is to better understand the motivations behind a consumer's decision to engage in mobile viral marketing strategies. The outcome is a grounded theory of mobile viral marketing with respect to the consumer and his social network, decomposing the mobile viral effect and identifying the determinants of reception, usage, and forwarding of mobile viral content. This result helps researchers and marketers to better understand the critical components of mobile viral marketing strategies and prepares the ground for further research in this emerging field.
Hydrogen in Ag-doped ZnO: Theoretical calculations
Authors: He H. Y. , Hu J. , Pan B. C.
Published: May 2009

Based on density functional theory calculations, we systematically investigate the behaviors of a H atom in Ag-doped ZnO involving the preference sites, diffusion behaviors, the electronic structures, and vibrational properties. We find that a H atom can migrate to the doped Ag to form a Ag–H complex by overcoming energy barriers of 0.3–1.0 eV. The lowest-energy site for H location is the bond center of a Ag–O in the basal plane. Moreover, H can migrate between this site and its equivalent sites with energy cost of less than 0.5 eV. In contrast, dissociation of such a Ag–H complex needs energy of about 1.1–1.3 eV. This implies that the Ag–H complexes can commonly exist in the Ag-doped ZnO, which have a negative effect on the desirable p-type carrier concentrations of Ag-doped ZnO. In addition, based on the frozen phonon calculation, the vibrational properties of ZnO with a Ag–H complex are predicted. Some new vibrational modes associated with the Ag–H complex present in the vibrational spectrum of the system.
Progesterone responses to intravenous and intrauterine infusions of prostaglandin F2α in mares
Authors: Ginther O. J. , Siddiqui M. A. R. , Beg M. A.
Published: May 2009

The hypotheses were tested that prostaglandin F2α (PGF) travels from the uterus to the ovaries via a systemic route in mares, as opposed to a local route in ruminants, and that one pulse of PGF produces only partial luteolysis. Intravenous (i.v.) and intrauterine (i.u.) infusions of PGF were performed 8 days after ovulation at a constant rate for 2 h. Plasma concentrations of PGF were assessed by assay of 13,14-dihydro-15-keto-PGF2α (PGFM). Total doses administered were as follows: 0, 0.05, 0.1, 0.5 and 1.0 mg, i.v., PGF and 0 and 0.5 mg, i.u., PGF (n = 4 mares per group). In addition, PGFM concentrations were determined for natural pulses from samples collected each hour during luteolysis (n = 5). Progesterone was similarly reduced by 4 days after treatment in the 0.5 mg i.v., 0.5 mg i.u. and 0.0 mg i.u. groups. The area under the PGFM curve in the 0.1 mg i.v. group was similar to the area for natural PGFM pulses. Progesterone decreased to a similar concentration by 12 h in the 0.1, 0.5 and 1.0 mg i.v. groups, but thereafter was greater (P < 0.05) in the 0.1 mg i.v. group. Progesterone concentrations reached <2 ng mL–1 6 days after treatment in the 0.05 and 0.1 mg i.v. groups and 2 days after treatment in the 0.5 and 1.0 mg i.v. groups. The results support the hypotheses of a systemic uteroluteal route for PGF transfer and that one pulse produces only partial luteolysis in mares.
Decision support tools to improve the effectiveness of hazardous fuel reduction treatments in the New Jersey Pine Barrens
Authors: Clark Kenneth L. , Skowronski Nicholas , Hom John , Duveneck Matthew , Pan Yude , Van Tuyl Stephen , Cole Jason , Patterson Matthew , Maurer Stephen
Published: May 2009

Our goal is to assist the New Jersey Forest Fire Service and federal wildland fire managers in the New Jersey Pine Barrens evaluate where and when to conduct hazardous fuel reduction treatments. We used remotely sensed LIDAR (Light Detection and Ranging System) data and field sampling to estimate fuel loads and consumption during prescribed fire treatments. This information was integrated with data on prescribed fire treatments conducted by the New Jersey Forest Fire Service over the last 15 years to produce and interpret maps of current fuel loads. Forest productivity measurements and models were then used to estimate rates of fuel accumulation through time. We could then calculate return intervals for desired fuel load conditions. Through formal workshops and frequent discussions with state and federal fire managers, our results enhance the ability of these agencies to make key decisions regarding the effectiveness and longevity of hazardous fuels treatments.
Interpreting federal policy at the local level: the wildland - urban interface concept in wildfire protection planning in the eastern United States
Authors: Grayzeck-Souter Stephanie A. , Nelson Kristen C. , Brummel Rachel F. , Jakes Pamela , Williams Daniel R.
Published: May 2009

In 2003, the Healthy Forests Restoration Act (HFRA) called for USA communities at risk of wildfire to develop Community Wildfire Protection Plans (CWPPs) requiring local, state and federal actors to work together to address hazardous fuels reduction and mitigation efforts. CWPPs can provide the opportunity for local government to influence actions on adjacent public land, by establishing local boundaries of the wildland–urban interface (WUI), the area where urban lands meet or intermix with wildlands. The present paper explores local response to the HFRA and CWPPs in the eastern USA, specifically if and how communities are using the policy incentive to identify the WUI. We conducted document reviews of eastern CWPPs, as well as qualitative analysis of in-depth interviews with participants in four case studies. We found tremendous variation in local response to HFRA, with plans completed at multiple scales and using different planning templates. The WUI policy incentive was not used in all CWPPs, suggesting that the incentive is not as useful in the eastern USA, where public land is less dominant and the perceived fire risk is lower than in the West. Even so, many communities in the East completed CWPPs to improve their wildfire preparedness.
Smoke incursions into urban areas: simulation of a Georgia prescribed burn
Authors: Liu Yongqiang , Goodrick Scott , Achtemeier Gary , Jackson William A. , Qu John J. , Wang Wanting
Published: May 2009

This study investigates smoke incursion into urban areas by examining a prescribed burn in central Georgia, USA, on 28 February 2007. Simulations were conducted with a regional modeling framework to understand transport, dispersion, and structure of smoke plumes, the air quality effects, sensitivity to emissions, and the roles of burn management strategy in mitigating the effects. The results indicate that smoke plumes first went west, but turned north-west at noon owing to a shift in wind direction. The smoke then invaded metropolitan Atlanta during the evening rush hour. The plumes caused severe air quality problems in Atlanta. Some hourly ground PM2.5 (particulate matter not greater than 2.5 μm in diameter) concentrations at three metropolitan Atlanta locations were three to four times as high as the daily (24-h) US National Ambient Air Quality Standard. The simulated shift in the smoke transport direction and the resultant effects on air quality are supported by the satellite and ambient air measurements. Two sensitivity simulations indicate a nearly linear relation between the emission intensities and PM2.5 concentrations. Two other simulations indicate that the impacts on air quality for the residents of Atlanta during the evening commute could have been reduced if the starting time of the burn had been altered.
FFI: a software tool for ecological monitoring
Authors: Lutes Duncan C. , Benson Nathan C. , Keifer MaryBeth , Caratti John F. , Streetman S. Austin
Published: May 2009

A new monitoring tool called FFI (FEAT/FIREMON Integrated) has been developed to assist managers with collection, storage and analysis of ecological information. The tool was developed through the complementary integration of two fire effects monitoring systems commonly used in the United States: FIREMON and the Fire Ecology Assessment Tool. FFI provides software components for: data entry, data storage, Geographic Information System, summary reports, analysis tools and Personal Digital Assistant use. In addition to a large set of standard FFI protocols, the Protocol Manager lets users define their own sampling protocol when custom data entry forms are needed. The standard FFI protocols and Protocol Manager allow FFI to be used for monitoring in a broad range of ecosystems. FFI is designed to help managers fulfil monitoring mandates set forth in land management policy. It supports scalable (project- to landscape-scale) monitoring at the field and research level, and encourages cooperative, interagency data management and information sharing. Though developed for application in the USA, FFI can potentially be used to meet monitoring needs internationally.
Generation of synthetic infrared remote-sensing scenes of wildland fire
Authors: Wang Zhen , Vodacek Anthony , Coen Janice
Published: May 2009

We describe a method for generating synthetic infrared remote-sensing scenes of wildland fire. These synthetic scenes are an important step in data assimilation, which is defined as the process of incorporating new data into an executing model. In our case, this is a fire propagation model. The scenes are built using the surface output of fire position from a fire propagation code and prior knowledge of fire physics and behavior to estimate the shape of the flame. The scene radiance is then estimated by employing a physics-based ray-tracing model called DIRSIG to render the radiation that would reach a sensor on an airborne platform. Values of the Fire Radiated Energy calculated from the synthetic radiance scene compare well with previously published values, providing validation of the method.
Protein tyrosine phosphatases PTP-1B and TC-PTP play nonredundant roles in macrophage development and IFN-γ signaling
Authors: Heinonen Krista M. , Bourdeau Annie , Doody Karen M. , Tremblay Michel L.
Published: May 2009

The control of tyrosine phosphorylation depends on the fine balance between kinase and phosphatase activities. Protein tyrosine phosphatase 1B (PTP-1B) and T cell protein tyrosine phosphatase (TC-PTP) are 2 closely related phosphatases known to control cytokine signaling. We studied the functional redundancy of PTP-1B and TC-PTP by deleting 1 or both copies of these genes by interbreeding TC-PTP and PTP-1B parental lines. Our results indicate that the double mutant (
tcptp
−/−
ptp1b
−/−
) is lethal at day E9.5–10.5 of embryonic development with constitutive phosphorylation of Stat1. Mice heterozygous for TC-PTP on a PTP-1B–deficient background (
tcptp
+/−
ptp1b
−/−
) developed signs of inflammation. Macrophages from these animals were highly sensitive to IFN-γ, as demonstrated by increased Stat1 phosphorylation and nitric oxide production. In addition, splenic T cells demonstrated increased IFN-γ secretion capacity. Mice with deletions of single copies of TC-PTP and PTP-1B (
tcptp
+/−
ptp1b
+/−
) exhibited normal development, confirming that these genes are not interchangeable. Together, these data indicate a nonredundant role for PTP-1B and TC-PTP in the regulation of IFN signaling.
Functional and shunt states of bacteriorhodopsin resolved by 250 GHz dynamic nuclear polarization–enhanced solid-state NMR
Authors: Bajaj Vikram S. , Mak-Jurkauskas Melody L. , Belenky Marina , Herzfeld Judith , Griffin Robert G.
Published: May 2009

Observation and structural studies of reaction intermediates of proteins are challenging because of the mixtures of states usually present at low concentrations. Here, we use a 250 GHz gyrotron (cyclotron resonance maser) and cryogenic temperatures to perform high-frequency dynamic nuclear polarization (DNP) NMR experiments that enhance sensitivity in magic-angle spinning NMR spectra of cryo-trapped photocycle intermediates of bacteriorhodopsin (bR) by a factor of ≈90. Multidimensional spectroscopy of U-
13
C,
15
N-labeled samples resolved coexisting states and allowed chemical shift assignments in the retinylidene chromophore for several intermediates not observed previously. The correlation spectra reveal unexpected heterogeneity in dark-adapted bR, distortion in the K state, and, most importantly, 4 discrete L substates. Thermal relaxation of the mixture of L's showed that 3 of these substates revert to bR
568
and that only the 1 substate with both the strongest counterion and a fully relaxed 13-
cis
bond is functional. These definitive observations of functional and shunt states in the bR photocycle provide a preview of the mechanistic insights that will be accessible in membrane proteins via sensitivity-enhanced DNP NMR. These observations would have not been possible absent the signal enhancement available from DNP.
Brain-size evolution and sociality in Carnivora
Authors: Finarelli John A. , Flynn John J.
Published: May 2009

Increased encephalization, or larger brain volume relative to body mass, is a repeated theme in vertebrate evolution. Here we present an extensive sampling of relative brain sizes in fossil and extant taxa in the mammalian order Carnivora (cats, dogs, bears, weasels, and their relatives). By using Akaike Information Criterion model selection and endocranial volume and body mass data for 289 species (including 125 fossil taxa), we document clade-specific evolutionary transformations in encephalization allometries. These evolutionary transformations include multiple independent encephalization increases and decreases in addition to a remarkably static basal Carnivora allometry that characterizes much of the suborder Feliformia and some taxa in the suborder Caniformia across much of their evolutionary history, emphasizing that complex processes shaped the modern distribution of encephalization across Carnivora. This analysis also permits critical evaluation of the social brain hypothesis (SBH), which predicts a close association between sociality and increased encephalization. Previous analyses based on living species alone appeared to support the SBH with respect to Carnivora, but those results are entirely dependent on data from modern Canidae (dogs). Incorporation of fossil data further reveals that no association exists between sociality and encephalization across Carnivora and that support for sociality as a causal agent of encephalization increase disappears for this clade.
Neural deficits contribute to respiratory insufficiency in Pompe disease
Authors: DeRuisseau Lara R. , Fuller David D. , Qiu Kai , DeRuisseau Keith C. , Donnelly William H. , Mah Cathryn , Reier Paul J. , Byrne Barry J.
Published: May 2009

Pompe disease is a severe form of muscular dystrophy due to glycogen accumulation in all tissues, especially striated muscle. Disease severity is directly related to the deficiency of acid α-glucosidase (GAA), which degrades glycogen in the lysosome. Respiratory dysfunction is a hallmark of the disease, muscle weakness has been viewed as the underlying cause, and the possibility of an associated neural contribution has not been evaluated previously. Therefore, we examined behavioral and neurophysiological aspects of breathing in 2 animal models of Pompe disease—the
Gaa
−/−
mouse and a transgenic line (MTP) expressing GAA only in skeletal muscle, as well as a detailed analysis of the CNS in a Pompe disease patient. Glycogen content was elevated in the
Gaa
−/−
mouse cervical spinal cord. Retrograde labeling of phrenic motoneurons showed significantly greater soma size in
Gaa
−/−
mice vs. isogenic controls, and glycogen was observed in
Gaa
−/−
phrenic motoneurons. Ventilation, assessed via plethysmography, was attenuated during quiet breathing and hypercapnic challenge in
Gaa
−/−
mice (6 to >21 months of age) vs. controls. We confirmed that MTP mice had normal diaphragmatic contractile properties; however, MTP mice had ventilation similar to the
Gaa
−/−
mice during quiet breathing. Neurophysiological recordings indicated that efferent phrenic nerve inspiratory burst amplitudes were substantially lower in
Gaa
−/−
and MTP mice vs. controls. In human samples, we demonstrated similar pathology in the cervical spinal cord and greater accumulation of glycogen in spinal cord compared with brain. We conclude that neural output to the diaphragm is deficient in
Gaa
−/−
mice, and therapies targeting muscle alone may be ineffective in Pompe disease.
Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
Authors: Hindorff Lucia A. , Sethupathy Praveen , Junkins Heather A. , Ramos Erin M. , Mehta Jayashri P. , Collins Francis S. , Manolio Teri A.
Published: May 2009

We have developed an online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs). Reported TASs were common [median risk allele frequency 36%, interquartile range (IQR) 21%−53%] and were associated with modest effect sizes [median odds ratio (OR) 1.33, IQR 1.20–1.61]. Among 20 genomic annotation sets, reported TASs were significantly overrepresented only in nonsynonymous sites [OR = 3.9 (2.2−7.0),
p
= 3.5 × 10
−7
] and 5kb-promoter regions [OR = 2.3 (1.5−3.6),
p
= 3 × 10
−4
] compared to SNPs randomly selected from genotyping arrays. Although 88% of TASs were intronic (45%) or intergenic (43%), TASs were not overrepresented in introns and were significantly depleted in intergenic regions [OR = 0.44 (0.34−0.58),
p
= 2.0 × 10
−9
]. Only slightly more TASs than expected by chance were predicted to be in regions under positive selection [OR = 1.3 (0.8−2.1),
p
= 0.2]. This new online resource, together with bioinformatic predictions of the underlying functionality at trait/disease-associated loci, is well-suited to guide future investigations of the role of common variants in complex disease etiology.
Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses
Authors: Slonim Donna K. , Koide Keiko , Johnson Kirby L. , Tantravahi Umadevi , Cowan Janet M. , Jarrah Zina , Bianchi Diana W.
Published: May 2009

To characterize the differences between second trimester Down syndrome (DS) and euploid fetuses, we used Affymetrix microarrays to compare gene expression in uncultured amniotic fluid supernatant samples. Functional pathway analysis highlighted the importance of oxidative stress, ion transport, and G protein signaling in the DS fetuses. Further evidence supporting these results was derived by correlating the observed gene expression patterns to those of small molecule drugs via the Connectivity Map. Our results suggest that there are secondary adverse consequences of DS evident in the second trimester, leading to testable hypotheses about possible antenatal therapy for DS.
Arkawāzī and His Baweyaļ: A Feylî Elegiac Verse from Piştiku
Authors: Dehqan Mustafa
Published: May 2009

The study of southern Kurdish literature is largely dominated by a bipolar perspective. Literature in southern Kurdistan is mostly, if not exclusively viewed in the context of relations between Iran on the one hand and, on the other, Iraq, the local states of the eighteenth and nineteenth centuries. To be sure, Iran acquired a dominant role in southern Kurdistan, yet it is also considered to have been the only dynamic factor in southern Kurdish dialect, while the Iraqi regions are supposed to have fulfilled an essentially passive one. This article presents the most well-known poem of Arkawāzī, a southern Kurdish poet from Piştiku, an Iranian region of southern Kurdistan. It transcribes, translates, and glosses a Feylî elegiac text in which the poet describes the death of his son. Notwithstanding my dialectological purpose, the article may also provide some raw material for the historians.
A Phosphatidylinositol-Transfer Protein and Phosphatidylinositol-4-phosphate 5-Kinase Control Cdc42 to Regulate the Actin Cytoskeleton and Secretory Pathway in Yeast
Authors: Yakir-Tamang Liat , Gerst Jeffrey E.
Published: May 2009

The actin cytoskeleton rapidly depolarizes in yeast secretory (sec) mutants at restrictive temperatures. Thus, an unknown signal conferred upon secretion is necessary for actin polarity and exocytosis. Here, we show that a phosphatidylinositol (PI) transfer protein, Sfh5, and a phosphatidylinositol-4-phosphate 5-kinase, Mss4, facilitate Cdc42 activation to concomitantly regulate both actin and protein trafficking. Defects in Mss4 function led to actin depolarization, an inhibition of secretion, reduced levels of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] in membranes, mislocalization of a pleckstrin homology domain fused to green fluorescent protein, and the mislocalization of Cdc42. Similar defects were observed in sec, myo2-66, and cdc42-6 mutants at elevated temperatures and were rescued by the overexpression of MSS4. Likewise, the overexpression of SFH5 or CDC42 could ameliorate these defects in many sec mutants, most notably in sec3Δ cells, indicating that Cdc42-mediated effects upon actin and secretion do not necessitate Sec3 function. Moreover, mutation of the residues involved in PI binding in Sfh5 led to the mislocalization and loss of function of both Sfh5 and Cdc42. Based upon these findings, we propose that the exocytic signal involves PI delivery to the PI kinases (i.e., Mss4) by Sfh5, generation of PI(4,5)P2, and PI(4,5)P2-dependent regulation of Cdc42 and the actin cytoskeleton.
Efficient exact motif discovery
Authors: Marschall Tobias , Rahmann Sven
Published: May 2009

Motivation: The motif discovery problem consists of finding over-represented patterns in a collection of biosequences. It is one of the classical sequence analysis problems, but still has not been satisfactorily solved in an exact and efficient manner. This is partly due to the large number of possibilities of defining the motif search space and the notion of over-representation. Even for well-defined formalizations, the problem is frequently solved in an ad hoc manner with heuristics that do not guarantee to find the best motif.

Results: We show how to solve the motif discovery problem (almost) exactly on a practically relevant space of IUPAC generalized string patterns, using the p-value with respect to an i.i.d. model or a Markov model as the measure of over-representation. In particular, (i) we use a highly accurate compound Poisson approximation for the null distribution of the number of motif occurrences. We show how to compute the exact clump size distribution using a recently introduced device called probabilistic arithmetic automaton (PAA). (ii) We define two p-value scores for over-representation, the first one based on the total number of motif occurrences, the second one based on the number of sequences in a collection with at least one occurrence. (iii) We describe an algorithm to discover the optimal pattern with respect to either of the scores. The method exploits monotonicity properties of the compound Poisson approximation and is by orders of magnitude faster than exhaustive enumeration of IUPAC strings (11.8 h compared with an extrapolated runtime of 4.8 years). (iv) We justify the use of the proposed scores for motif discovery by showing our method to outperform other motif discovery algorithms (e.g. MEME, Weeder) on benchmark datasets. We also propose new motifs on Mycobacterium tuberculosis.

Availability and Implementation: The method has been implemented in Java. It can be obtained from http://ls11-www.cs.tu-dortmund.de/people/marschal/paa_md/

Contact:  tobias.marschall@tu-dortmund.de; sven.rahmann@tu-dortmund.de
Graph theoretical approach to study eQTL: a case study of Plasmodium falciparum
Authors: Huang Yang , Wuchty Stefan , Ferdig Michael T. , Przytycka Teresa M.
Published: May 2009

Motivation: Analysis of expression quantitative trait loci (eQTL) significantly contributes to the determination of gene regulation programs. However, the discovery and analysis of associations of gene expression levels and their underlying sequence polymorphisms continue to pose many challenges. Methods are limited in their ability to illuminate the full structure of the eQTL data. Most rely on an exhaustive, genome scale search that considers all possible locus–gene pairs and tests the linkage between each locus and gene.

Result: To analyze eQTLs in a more comprehensive and efficient way, we developed the Graph based eQTL Decomposition method (GeD) that allows us to model genotype and expression data using an eQTL association graph. Through graph-based heuristics, GeD identifies dense subgraphs in the eQTL association graph. By identifying eQTL association cliques that expose the hidden structure of genotype and expression data, GeD effectively filters out most locus–gene pairs that are unlikely to have significant linkage. We apply GeD on eQTL data from Plasmodium falciparum, the human malaria parasite, and show that GeD reveals the structure of the relationship between all loci and all genes on a whole genome level. Furthermore, GeD allows us to uncover additional eQTLs with lower FDR, providing an important complement to traditional eQTL analysis methods.

Contact:  przytyck@ncbi.nlm.nih.gov
Identifying novel constrained elements by exploiting biased substitution patterns
Authors: Garber Manuel , Guttman Mitchell , Clamp Michele , Zody Michael C. , Friedman Nir , Xie Xiaohui
Published: May 2009

Motivation: Comparing the genomes from closely related species provides a powerful tool to identify functional elements in a reference genome. Many methods have been developed to identify conserved sequences across species; however, existing methods only model conservation as a decrease in the rate of mutation and have ignored selection acting on the pattern of mutations.

Results: We present a new approach that takes advantage of deeply sequenced clades to identify evolutionary selection by uncovering not only signatures of rate-based conservation but also substitution patterns characteristic of sequence undergoing natural selection. We describe a new statistical method for modeling biased nucleotide substitutions, a learning algorithm for inferring site-specific substitution biases directly from sequence alignments and a hidden Markov model for detecting constrained elements characterized by biased substitutions. We show that the new approach can identify significantly more degenerate constrained sequences than rate-based methods. Applying it to the ENCODE regions, we identify as much as 10.2% of these regions are under selection.

Availability: The algorithms are implemented in a Java software package, called SiPhy, freely available at http://www.broadinstitute.org/science/software/.

Contact:  xhx@ics.uci.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Ontology quality assurance through analysis of term transformations
Authors: Verspoor Karin , Dvorkin Daniel , Cohen K. Bretonnel , Hunter Lawrence
Published: May 2009

Motivation: It is important for the quality of biological ontologies that similar concepts be expressed consistently, or univocally. Univocality is relevant for the usability of the ontology for humans, as well as for computational tools that rely on regularity in the structure of terms. However, in practice terms are not always expressed consistently, and we must develop methods for identifying terms that are not univocal so that they can be corrected.

Results: We developed an automated transformation-based clustering methodology for detecting terms that use different linguistic conventions for expressing similar semantics. These term sets represent occurrences of univocality violations. Our method was able to identify 67 examples of univocality violations in the Gene Ontology.

Availability: The identified univocality violations are available upon request. We are preparing a release of an open source version of the software to be available at http://bionlp.sourceforge.net.

Contact:  karin.verspoor@ucdenver.edu
Inference of locus-specific ancestry in closely related populations
Authors: Paşaniuc Bogdan , Sankararaman Sriram , Kimmel Gad , Halperin Eran
Published: May 2009

A characterization of the genetic variation of recently admixed populations may reveal historical population events, and is useful for the detection of single nucleotide polymorphisms (SNPs) associated with diseases through association studies and admixture mapping. Inference of locus-specific ancestry is key to our understanding of the genetic variation of such populations. While a number of methods for the inference of locus-specific ancestry are accurate when the ancestral populations are quite distant (e.g. African–Americans), current methods incur a large error rate when inferring the locus-specific ancestry in admixed populations where the ancestral populations are closely related (e.g. Americans of European descent).

Results: In this work, we extend previous methods for the inference of locus-specific ancestry by the incorporation of a refined model of recombination events. We present an efficient dynamic programming algorithm to infer the locus-specific ancestries in this model, resulting in a method that attains improved accuracies; the improvement is most significant when the ancestral populations are closely related. An evaluation on a wide range of scenarios, including admixtures of the 52 population groups from the Human Genome Diversity Project demonstrates that locus-specific ancestry can indeed be accurately inferred in these admixtures using our method. Finally, we demonstrate that imputation methods can be improved by the incorporation of locus-specific ancestry, when applied to admixed populations.

Availability: The implementation of the WINPOP model is available as part of the LAMP package at http://lamp.icsi.berkeley.edu/lamp

Contact:  heran@icsi.berkeley.edu
IsoRankN: spectral methods for global alignment of multiple protein networks
Authors: Liao Chung-Shou , Lu Kanghao , Baym Michael , Singh Rohit , Berger Bonnie
Published: May 2009

Motivation: With the increasing availability of large protein–protein interaction networks, the question of protein network alignment is becoming central to systems biology. Network alignment is further delineated into two sub-problems: local alignment, to find small conserved motifs across networks, and global alignment, which attempts to find a best mapping between all nodes of the two networks. In this article, our aim is to improve upon existing global alignment results. Better network alignment will enable, among other things, more accurate identification of functional orthologs across species.

Results: We introduce IsoRankN (IsoRank-Nibble) a global multiple-network alignment tool based on spectral clustering on the induced graph of pairwise alignment scores. IsoRankN outperforms existing algorithms for global network alignment in coverage and consistency on multiple alignments of the five available eukaryotic networks. Being based on spectral methods, IsoRankN is both error tolerant and computationally efficient.

Availability: Our software is available freely for non-commercial purposes on request from: http://isorank.csail.mit.edu/

Contact:  bab@mit.edu
Family classification without domain chaining
Authors: Joseph Jacob M. , Durand Dannie
Published: May 2009

Motivation: Classification of gene and protein sequences into homologous families, i.e. sets of sequences that share common ancestry, is an essential step in comparative genomic analyses. This is typically achieved by construction of a sequence homology network, followed by clustering to identify dense subgraphs corresponding to families. Accurate classification of single domain families is now within reach due to major algorithmic advances in remote homology detection and graph clustering. However, classification of multidomain families remains a significant challenge. The presence of the same domain in sequences that do not share common ancestry introduces false edges in the homology network that link unrelated families and stymy clustering algorithms.

Results: Here, we investigate a network-rewiring strategy designed to eliminate edges due to promiscuous domains. We show that this strategy can reduce noise in and restore structure to artificial networks with simulated noise, as well as to the yeast genome homology network. We further evaluate this approach on a hand-curated set of multidomain sequences in mouse and human, and demonstrate that classification using the rewired network delivers dramatic improvement in Precision and Recall, compared with current methods. Families in our test set exhibit a broad range of domain architectures and sequence conservation, demonstrating that our method is flexible, robust and suitable for high-throughput, automated processing of heterogeneous, genome-scale data.

contact:  jacobmj@cmu.edu
Probabilistic retrieval and visualization of biologically relevant microarray experiments
Authors: Caldas José , Gehlenborg Nils , Faisal Ali , Brazma Alvis , Kaski Samuel
Published: May 2009

Motivation: As ArrayExpress and other repositories of genome-wide experiments are reaching a mature size, it is becoming more meaningful to search for related experiments, given a particular study. We introduce methods that allow for the search to be based upon measurement data, instead of the more customary annotation data. The goal is to retrieve experiments in which the same biological processes are activated. This can be due either to experiments targeting the same biological question, or to as yet unknown relationships.

Results: We use a combination of existing and new probabilistic machine learning techniques to extract information about the biological processes differentially activated in each experiment, to retrieve earlier experiments where the same processes are activated and to visualize and interpret the retrieval results. Case studies on a subset of ArrayExpress show that, with a sufficient amount of data, our method indeed finds experiments relevant to particular biological questions. Results can be interpreted in terms of biological processes using the visualization techniques.

Availability: The code is available from http://www.cis.hut.fi/projects/mi/software/ismb09.

Contact:  jose.caldas@tkk.fi
Modeling interactions between adjacent nucleosomes improves genome-wide predictions of nucleosome occupancy
Authors: Lubliner Shai , Segal Eran
Published: May 2009

Motivation: Understanding the mechanisms that govern nucleosome positioning over genomes in vivo is essential for unraveling the role of chromatin organization in transcriptional regulation. Until now, models for predicting genome-wide nucleosome occupancy have assumed that the DNA associations of neighboring nucleosomes on the genome are independent. We present a new model that relaxes this independence assumption by modeling interactions between adjacent nucleosomes.

Results: We show that modeling interactions between adjacent nucleosomes improves genome-wide nucleosome occupancy predictions in an in vitro system that includes only nucleosomes and purified DNA, where the resulting model has a preference for short spacings (linkers) of less than 20 bp in length between neighboring nucleosomes. Since nucleosome occupancy in vitro depends only on properties intrinsic to nucleosomes, these results suggest that the interactions we find are intrinsic to nucleosomes and do not depend on other factors, such as transcription factors and chromatin remodelers. We also show that modeling these intrinsic interactions significantly improves genome-wide predictions of nucleosome occupancy in vivo.

Contact:  eran.segal@weizmann.ac.il

Supplementary information:  Supplementary data are available at Bioinformatics online.
PICKY: a novel SVD-based NMR spectra peak picking method
Authors: Alipanahi Babak , Gao Xin , Karakoc Emre , Donaldson Logan , Li Ming
Published: May 2009

Motivation: Picking peaks from experimental NMR spectra is a key unsolved problem for automated NMR protein structure determination. Such a process is a prerequisite for resonance assignment, nuclear overhauser enhancement (NOE) distance restraint assignment, and structure calculation tasks. Manual or semi-automatic peak picking, which is currently the prominent way used in NMR labs, is tedious, time consuming and costly.

Results: We introduce new ideas, including noise-level estimation, component forming and sub-division, singular value decomposition (SVD)-based peak picking and peak pruning and refinement. PICKY is developed as an automated peak picking method. Different from the previous research on peak picking, we provide a systematic study of the proposed method. PICKY is tested on 32 real 2D and 3D spectra of eight target proteins, and achieves an average of 88% recall and 74% precision. PICKY is efficient. It takes PICKY on average 15.7 s to process an NMR spectrum. More important than these numbers, PICKY actually works in practice. We feed peak lists generated by PICKY to IPASS for resonance assignment, feed IPASS assignment to SPARTA for fragments generation, and feed SPARTA fragments to FALCON for structure calculation. This results in high-resolution structures of several proteins, for example, TM1112, at 1.25 Å.

Availability: PICKY is available upon request. The peak lists of PICKY can be easily loaded by SPARKY to enable a better interactive strategy for rapid peak picking.

Contact:  mli@uwaterloo.ca
A Classifier-based approach to identify genetic similarities between diseases
Authors: Schaub Marc A. , Kaplow Irene M. , Sirota Marina , Do Chuong B. , Butte Atul J. , Batzoglou Serafim
Published: May 2009

Motivation: Genome-wide association studies are commonly used to identify possible associations between genetic variations and diseases. These studies mainly focus on identifying individual single nucleotide polymorphisms (SNPs) potentially linked with one disease of interest. In this work, we introduce a novel methodology that identifies similarities between diseases using information from a large number of SNPs. We separate the diseases for which we have individual genotype data into one reference disease and several query diseases. We train a classifier that distinguishes between individuals that have the reference disease and a set of control individuals. This classifier is then used to classify the individuals that have the query diseases. We can then rank query diseases according to the average classification of the individuals in each disease set, and identify which of the query diseases are more similar to the reference disease. We repeat these classification and comparison steps so that each disease is used once as reference disease.

Results: We apply this approach using a decision tree classifier to the genotype data of seven common diseases and two shared control sets provided by the Wellcome Trust Case Control Consortium. We show that this approach identifies the known genetic similarity between type 1 diabetes and rheumatoid arthritis, and identifies a new putative similarity between bipolar disease and hypertension.

Contact:  serafim@cs.stanford.edu
Predictions of RNA secondary structure by combining homologous sequence information
Authors: Hamada Michiaki , Sato Kengo , Kiryu Hisanori , Mituyama Toutai , Asai Kiyoshi
Published: May 2009

Motivation: Secondary structure prediction of RNA sequences is an important problem. There have been progresses in this area, but the accuracy of prediction from an RNA sequence is still limited. In many cases, however, homologous RNA sequences are available with the target RNA sequence whose secondary structure is to be predicted.

Results: In this article, we propose a new method for secondary structure predictions of individual RNA sequences by taking the information of their homologous sequences into account without assuming the common secondary structure of the entire sequences. The proposed method is based on posterior decoding techniques, which consider all the suboptimal secondary structures of the target and homologous sequences and all the suboptimal alignments between the target sequence and each of the homologous sequences. In our computational experiments, the proposed method provides better predictions than those performed only on the basis of the formation of individual RNA sequences and those performed by using methods for predicting the common secondary structure of the homologous sequences. Remarkably, we found that the common secondary predictions sometimes give worse predictions for the secondary structure of a target sequence than the predictions from the individual target sequence, while the proposed method always gives good predictions for the secondary structure of target sequences in all tested cases.

Availability: Supporting information and software are available online at: http://www.ncrna.org/software/centroidfold/ismb2009/.

Contact:  hamada-michiaki@aist.go.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
DISCOVER: a feature-based discriminative method for motif search in complex genomes
Authors: Fu Wenjie , Ray Pradipta , Xing Eric P.
Published: May 2009

Motivation: Identifying transcription factor binding sites (TFBSs) encoding complex regulatory signals in metazoan genomes remains a challenging problem in computational genomics. Due to degeneracy of nucleotide content among binding site instances or motifs, and intricate ‘grammatical organization’ of motifs within cis-regulatory modules (CRMs), extant pattern matching-based in silico motif search methods often suffer from impractically high false positive rates, especially in the context of analyzing large genomic datasets, and noisy position weight matrices which characterize binding sites. Here, we try to address this problem by using a framework to maximally utilize the information content of the genomic DNA in the region of query, taking cues from values of various biologically meaningful genetic and epigenetic factors in the query region such as clade-specific evolutionary parameters, presence/absence of nearby coding regions, etc. We present a new method for TFBS prediction in metazoan genomes that utilizes both the CRM architecture of sequences and a variety of features of individual motifs. Our proposed approach is based on a discriminative probabilistic model known as conditional random fields that explicitly optimizes the predictive probability of motif presence in large sequences, based on the joint effect of all such features.

Results: This model overcomes weaknesses in earlier methods based on less effective statistical formalisms that are sensitive to spurious signals in the data. We evaluate our method on both simulated CRMs and real Drosophila sequences in comparison with a wide spectrum of existing models, and outperform the state of the art by 22% in F1 score.

Availability and Implementation: The code is publicly available at http://www.sailing.cs.cmu.edu/discover.html.

Contact:  epxing@cs.cmu.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Proteome coverage prediction with infinite Markov models
Authors: Claassen Manfred , Aebersold Ruedi , Buhmann Joachim M.
Published: May 2009

Motivation: Liquid chromatography tandem mass spectrometry (LC-MS/MS) is the predominant method to comprehensively characterize complex protein mixtures such as samples from prefractionated or complete proteomes. In order to maximize proteome coverage for the studied sample, i.e. identify as many traceable proteins as possible, LC-MS/MS experiments are typically repeated extensively and the results combined. Proteome coverage prediction is the task of estimating the number of peptide discoveries of future LC-MS/MS experiments. Proteome coverage prediction is important to enhance the design of efficient proteomics studies. To date, there does not exist any method to reliably estimate the increase of proteome coverage at an early stage.

Results: We propose an extended infinite Markov model DiriSim to extrapolate the progression of proteome coverage based on a small number of already performed LC-MS/MS experiments. The method explicitly accounts for the uncertainty of peptide identifications. We tested DiriSim on a set of 37 LC-MS/MS experiments of a complete proteome sample and demonstrated that DiriSim correctly predicts the coverage progression already from a small subset of experiments. The predicted progression enabled us to specify maximal coverage for the test sample. We demonstrated that quality requirements on the final proteome map impose an upper bound on the number of useful experiment repetitions and limit the achievable proteome coverage.

Contact:  manfredc@inf.ethz.ch; jbuhmann@inf.ethz.ch