bluuebunny/crossref_metadata_2025 huggingface dataset:
On Free An-atomic or Transmissible Power
Authors: Wyld R. S.
Published: June 2016

In the first part of the paper I adduce probable, or prima facie, evidence in favour of the theory that the power which produces voluntary motion is not derived solely, nor even chiefly, from the decomposition of the muscular tissues, as has been generally, if not universally, held by recent investigators, but is derived primarily and principally from the decomposition of the cerebral tissues; and second, that this decomposition of the brain is effected by a direct voluntary mental effort.
7. On the Cell-Walls of Hepatic Cells
Authors: Haycraft John Berry
Published: June 2016

Since Henle and Purkinje first described the cells which form the great mass of the liver, microscopists have maintained that these are what are termed “naked protoplasts”—that is, they possess, like the white blood corpuscle, no differentiated cell-walls. I may mention the names of Dr Lionel Beale, Ewald Hering (“Stricker's Histology,” section on the Liver), and Dr Klein (“Atlas of Histology”), who all agree in denying its existence. Indeed, the absence of this structure is emphatically insisted upon in most works on microscopical anatomy.

If a liver-cell be examined with a power of about 300 diameters, it is seen to be a granular mass, of a somewhat spherical shape, containing a very distinct nucleus and nucleolus. The granules are but the optical expression of a delicate reticulum or stroma, which may be seen as such on using a higher power.
1. The Earthquake of 28th November 1880 in Scotland and Ireland
Authors: Stevenson Charles Alexander
Published: June 2016

In 1877, my father, Mr David Stevenson, communicated to the Society a notice of earthquake shocks in Argyllshire (see Proceedings, vol. ix.) from observations made by the keepers at several lighthouses, which the late Dr Bryce undertook to use in his intended visit to the west of Scotland, to trace the source of the earthquake waves of 1877, an intention which, however, was suddenly terminated by his lamented accidental death at Inverness.

Another earthquake shock, which visited Scotland and the north of Ireland on the 28th November 1880, has afforded the means of acquiring further observations, of which I think (in connection with those formerly given) the Society may consider it not unimportant to have a record in their Proceedings.
1. On the Colour of the Mediterranean and other Waters
Authors: Aitken John
Published: June 2016

The investigation was at first undertaken with a view of determining how the blue colour of the water of the Mediterranean is produced, and of finding the explanation of the different colour phenomena seen in that sea. The investigation was afterwards extended to other waters.

The experiments were made with a special view of determining whether the selective reflection or the selective absorption theory gave the correct explanation of the blueness seen in water.
3. On Voice-Effort and Rhythm
Authors: Blake J. L.
Published: June 2016

In this paper the author enunciates and illustrates the following propositions:—Speech is produced by distinctly separate jets of breath emitted under pressure; each such jet he names a monopressure. A monopressure may be used for the utterance of a single syllable, which may consist of a single vowel, or a vowel preceded or followed, or both, by consonants. In a monopressure the sound is weaker at the beginning and end, and stronger in the middle. The weak beginning, or the weak ending, of a monopressure, or both, may be used for the utterance of an unaccented syllable. There are thus four forms of a monopressure:—monosyllabic; dissyllabic, with the accent on the first; dissyllabic with the accent on the second; trissyllabic, with the accent on the second.
5. Vocalisation and Articulation
Authors: Blake J. L.
Published: June 2016

In this paper the author discusses the mechanism of speech, and the character of the vowels and consonants which occur in the English language. He points out the importance of attending to the proper division of words into syllables, and of clearly articulating consonants. He shows how his theory of monopressures facilitates the correct reading of poetry.
On the Comparative Histology and Physiology of the Spleen
Authors: Whiting Arthur J.
Published: June 2016

The principal subject of the author's research has been the comparative histology of the spleen in twenty-two different kinds of animals, embracing all the typical vertebrates from the fish to Man.

The capsule of a typical mammalian spleen, such as that of the cat, consists of two layers, the outer composed of ordinary fibrous tissue, the inner of nonstriped muscle. The splenic artery and vein, as they enter the organ at the hilum, are enclosed in a sheath formed by an inflexion of the capsule, and, like it, consisting of a fibrous and a muscular layer, the fibrous layer being next the vessels, and the muscular layer external to it, adjoining the pulp.
On certain Concretions from the Lower Coal Measures, and the Fossil Plants which they Contain
Authors: Stocks H. B.
Published: June 2016

Coal, we are all aware, is a remnant of the organic matter of plants which flourished long ago. Owing to the length of time that has elapsed since the remains were entombed, and the pressure the material has been subjected to by overlying strata of great thickness, coal now presents to the unaided eye little or no evidence of organic structure, but is a lustrous black product not at all like wood in appearance.
On some Observations made without a Dust Counter on the Hazing Effect of Atmospheric Dust
Authors: Aitken John
Published: June 2016

There was considerable difficulty in selecting a proper title for this paper. It may appear to some, after reading it, that a shorter and better title would have been, “On the Hazing Effects of Smoke.” But as smoke particles generally reflect a reddish-brown light, they do not therefore seem to be the cause of the whitish light which we call haze; and further, smoke particles generally condense into little masses of such a size that they fall to the ground before they are carried to any great distance. It was thought that as this paper is a continuation of previous work, and is founded on results already communicated to this Society, it would be better to keep to the use of the same terms, and as usual, under the name of “dust particles,” to include all the solid and liquid products of combustion, of whatever size or colour they may be.
The Rise and Progress of Anthropology
Authors: Munro Robert
Published: June 2016

However far back written records conduct us in an investigation of the early history of mankind, it can no longer be maintained that they cover but a small portion of man's existence on the globe. That human racial characters were broadly marked, some 6000 years ago, has been surmised from an analysis of the ancient wall paintings of Egypt. Thus, in the tombs of the kings at Thebes are to be seen, to this day, coloured and highly expressive portraits of the four principal races who then frequented the Nile valley; and it is a remarkable fact that their distinguishing peculiarities, as depicted in the conventional eye and reddish-brown colour of the Egyptian, the fair-skinned and blue-eyed Lybian, the aquiline profile of the Semite, and the thick lip and curly hair of the Negro, are equally descriptive of their modern representatives.
Note on the Action of Sodium Mercaptide on Dibromo-Malonic Ether
Authors: Brown Crum , Fairbairn Robert
Published: June 2016

We examined the action of sodium mercaptide on dibromomalonic ether in the hope that in this way we might obtain the substance C(S—C2H5)2(COOC2H5)2. We found, however, that the reaction takes a different direction, and that what happens is represented by the equation
Editor's Introduction
Authors: CHRISTAKIS THÉODORE
Published: June 2016

The present symposium follows on from a forum held at the University of Oslo on 11 September 2015 during the 11th Annual Conference of the European Society of International Law. This forum, sponsored by the ESIL Interest Group on Peace and Security, was particularly successful and led to a very interesting debate between the members of the European Society of International Law. The Leiden Journal of International Law has today the pleasure to publish, after the usual process of peer review, the complete and updated versions of the four papers presented during this event.
Fazıl Say: A Turkish Musician in Europe
Authors: Durugönül Esma
Published: June 2016

Identity isn’t given once and for all:

it is built up and changes throughout a person’s lifetime.1

The aim of this paper is to determine how and to what extent Fazıl Say, whose inspiration, according to his own words, is the bridge between Europe and Asia, has become an ambassador between Europe and Turkey.2 A further aim is to determine whether Fazıl Say may be referred to as ‘hybrid’ concerning both his person and his works. This will be done first by describing his background and then the conditions which led not only to his European, but also his global success. Assuming that not only his family, social environment and education were decisive in this process, the social changes that took place in Turkey following the foundation of the Turkish Republic in 1923 are detailed, with special consideration of the reforms directly affecting art and music. To offer more insight into this context, the mutual influences on music between the Ottoman Empire and Europe are outlined.
Report Touts White House Science Impact
Authors: Showstack Randy
Published: June 2016

The Obama administration also announced a milestone for White House science adviser John Holdren, who on 18 June set a new record for longevity in the science advisory role.
Prenatal programming: adverse cardiac programming by gestational testosterone excess
Authors: Vyas Arpita K. , Hoang Vanessa , Padmanabhan Vasantha , Gilbreath Ebony , Mietelka Kristy A.
Published: June 2016

Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30–90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells –c3 (NFATc3) and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess.
Specification of jaw identity by the Hand2 transcription factor
Authors: Funato Noriko , Kokubo Hiroki , Nakamura Masataka , Yanagisawa Hiromi , Saga Yumiko
Published: June 2016

Acquisition of the lower jaw (mandible) was evolutionarily important for jawed vertebrates. In humans, syndromic craniofacial malformations often accompany jaw anomalies. The basic helix-loop-helix transcription factor Hand2, which is conserved among jawed vertebrates, is expressed in the neural crest in the mandibular process but not in the maxillary process of the first branchial arch. Here, we provide evidence that Hand2 is sufficient for upper jaw (maxilla)-to-mandible transformation by regulating the expression of homeobox transcription factors in mice. Altered Hand2 expression in the neural crest transformed the maxillae into mandibles with duplicated Meckel’s cartilage, which resulted in an absence of the secondary palate. In Hand2-overexpressing mutants, non-Hox homeobox transcription factors were dysregulated. These results suggest that Hand2 regulates mandibular development through downstream genes of Hand2 and is therefore a major determinant of jaw identity. Hand2 may have influenced the evolutionary acquisition of the mandible and secondary palate.
Direct amidation of unprotected amino acids using B(OCH2CF3)3
Authors: Lanigan Rachel M. , Karaluka Valerija , Sabatini Marco T. , Starkov Pavel , Badland Matthew , Boulton Lee , Sheppard Tom D.
Published: June 2016

A commercially available borate ester, B(OCH2CF3)3, can be used to achieve protecting-group free direct amidation of α-amino acids with a range of amines in cyclopentyl methyl ether.
Synchronised photoreversion of spirooxazine ring opening in thin crystals to uncover ultrafast dynamics
Authors: Siddiqui Khalid M. , Corthey Gastón , Hayes Stuart A. , Rossos Andreas , Badali Daniel S. , Xian Rui , Murphy R. Scott , Whitaker Benjamin J. , Miller R. J. Dwayne
Published: June 2016

A ‘recover before destroy’ approach to minimise photoproduct build-up in solid state enables ultrafast studies of chemical reactions.
Vibrational dynamics (IR, Raman, NRVS) and a DFT study of a new antitumor tetranuclearstannoxane cluster, Sn(iv)-oxo-{di-o-vanillin} dimethyl dichloride
Authors: Arjmand F. , Sharma S. , Usman M. , Leu B. M. , Hu M. Y. , Toupet L. , Gosztola D. , Tabassum S.
Published: June 2016

Complex 1 showing NRVS, Raman spectra and antitumor activity.
Quantifying the landscape and kinetic paths for epithelial–mesenchymal transition from a core circuit
Authors: Li Chunhe , Hong Tian , Nie Qing
Published: June 2016

The landscape and path provide a new physical and quantitative way to understand the mechanisms of epithelial–mesenchymal transition.
Studies in organic and physical photochemistry – an interdisciplinary approach
Authors: Oelgemöller Michael , Hoffmann Norbert
Published: June 2016

Organic photochemistry when applied to synthesis strongly interacts in a very fruitful way with physical chemistry. A profound understanding of the photochemical reaction mechanisms is indispensable for optimization and application of these reactions.
Preparation and characterization of calcium phosphate/pectin scaffolds for bone tissue engineering
Authors: Zhao Lisheng , Li Junjie , Zhang Liang , Wang Yu , Wang Jiexin , Gu Bin , Chen Jianfeng , Hao Tong , Wang Changyong , Wen Ning
Published: June 2016

A calcium phosphate cement (CPC) scaffold has been used to repair bone defects, but its low compressive strength and poor osteogenesis greatly hinder its clinical application.
MXene: a promising photocatalyst for water splitting
Authors: Guo Zhonglu , Zhou Jian , Zhu Linggang , Sun Zhimei
Published: June 2016

Identifying suitable photocatalysts for photocatalytic water splitting to produce hydrogen fuelviasunlight is an arduous task by the traditional trial-and-error method.
Solvent effects on the absorption spectrum and first hyperpolarizability of keto-enol tautomeric forms of anil derivatives: A Monte Carlo/quantum mechanics study
Authors: Adriano Junior L. , Fonseca T. L. , Castro M. A.
Published: June 2016

Theoretical results for the absorption spectrum and electric properties of the enol and keto tautomeric forms of anil derivatives in the gas-phase and in solution are presented. The electronic properties in chloroform, acetonitrile, methanol, and water were determined by carrying out sequential Monte Carlo simulations and quantum mechanics calculations based on the time dependent density functional theory and on the second-order Møller–Plesset perturbation theory method. The results illustrate the role played by electrostatic interactions in the electronic properties of anil derivatives in a liquid environment. There is a significant increase of the dipole moment in solution (20%-100%) relative to the gas-phase value. Solvent effects are mild for the absorption spectrum and linear polarizability but they can be particularly important for first hyperpolarizability. A large first hyperpolarizability contrast between the enol and keto forms is observed when absorption spectra present intense lowest-energy absorption bands. Dynamic results for the first hyperpolarizability are in qualitative agreement with the available experimental results.
Fault detection, isolation, and diagnosis of self-validating multifunctional sensors
Authors: Yang Jing-li , Chen Yin-sheng , Zhang Li-li , Sun Zhen
Published: June 2016

A novel fault detection, isolation, and diagnosis (FDID) strategy for self-validating multifunctional sensors is presented in this paper. The sparse non-negative matrix factorization-based method can effectively detect faults by using the squared prediction error (SPE) statistic, and the variables contribution plots based on SPE statistic can help to locate and isolate the faulty sensitive units. The complete ensemble empirical mode decomposition is employed to decompose the fault signals to a series of intrinsic mode functions (IMFs) and a residual. The sample entropy (SampEn)-weighted energy values of each IMFs and the residual are estimated to represent the characteristics of the fault signals. Multi-class support vector machine is introduced to identify the fault mode with the purpose of diagnosing status of the faulty sensitive units. The performance of the proposed strategy is compared with other fault detection strategies such as principal component analysis, independent component analysis, and fault diagnosis strategies such as empirical mode decomposition coupled with support vector machine. The proposed strategy is fully evaluated in a real self-validating multifunctional sensors experimental system, and the experimental results demonstrate that the proposed strategy provides an excellent solution to the FDID research topic of self-validating multifunctional sensors.
Vitamin A deficiency in Bos indicus heifers fed a wheat straw diet cannot be corrected with algae lick blocks or intramuscular injectable retinyl palmitate treatments
Authors: Parker A. J. , Goopy J. P. , Callaghan M. J. , Vermunt J. J. , de Nys R.
Published: June 2016

Serum and liver retinol concentrations and blood β-carotene concentrations were studied in 30 Bos indicus heifers rendered deficient of vitamin A over 180 days and then given treatments of access to algae-based lick blocks (n = 10), injectable retinyl palmitate and molasses-based lick blocks (n = 10), or a negative control given access to molasses-based lick blocks only (n = 10). All heifers became deficient in blood and liver vitamin A, as well as blood β-carotene by 180 days. There was no treatment effect on bodyweight (P = 0.347). However, a highly significant effect of time (P = 0.001) was detected where all heifers achieved an average daily gain of 0.74 kg/day throughout the depletion phase of the study but lost 0.150 kg/day during the repletion phase. The concentrations of serum and liver retinol and blood β-carotene were not different between treatment groups (P = 0.362, P = 0.535 and P = 0.839) during the depletion or repletion phases of the study. All heifers continued to be rendered deficient in the concentrations of serum and liver retinol and blood β-carotene throughout the experiment demonstrating a highly significant effect of time (P = 0.001). Injectable retinyl palmitate (818 100 IU retinol) or access to algal lick blocks (4180 IU retinol) did not elevate blood or liver retinol concentrations in heifers rendered deficient of vitamin A. It is speculated that the protein-deficient diet fed to the heifers had an adverse effect on the blood retinol transport proteins.
Fauna-rescue programs highlight unresolved scientific, ethical and animal welfare issues
Authors: Menkhorst Peter , Clemann Nick , Sumner Joanna
Published: June 2016

In response to a paper advocating large-scale, multi-species ‘fauna-rescue’ programs when habitat is being destroyed, we urge caution by highlighting the lack of evidence of success in such programs. We argue that any benefits are likely to be outweighed by ecological and animal welfare risks, and that any conservation gains are likely to be illusionary.
Dispersal-limited detritivores in fire-prone environments: persistence and population structure of terrestrial amphipods (Talitridae)
Authors: Menz L. , Gibb H. , Murphy N. P.
Published: June 2016

Invertebrate detritivores play a critical role in the decomposition of litter, an important component of wildfire fuel. Knowledge of invertebrate response to fire is often hampered by taxonomic resolution; however, genetic species identification can enable analysis of fine-scale assemblages and the interaction between dispersal and population recovery. In this study, we ask: do terrestrial amphipod assemblages differ following increasing fire severities and does population structure indicate in situ survival or recolonisation following severe fires? Using seven replicate sites over three fire severities, we measured amphipod abundance at the site of the catastrophic 2009 ‘Black Saturday’ fires in south-east Australia. Genetic analyses to distinguish species and population structure revealed 16 species. Populations of Arcitalitrus sylvaticus were highly structured, suggesting limited dispersal. Amphipod abundance and species richness were not affected by fire severity 3 years after fire. Localised population structure within A. sylvaticus suggests that in situ survival enabled amphipods to repopulate severely burnt sites. The genetic analyses used in this study enabled the detection of unrecognised diversity and population structure in these detritivores. With many detritivores showing similar life history strategies, studies that combine a genetic and ecological approach are essential for understanding the impact of fire on litter decomposition.
AgIn: measuring the landscape of CpG methylation of individual repetitive elements
Authors: Suzuki Yuta , Korlach Jonas , Turner Stephen W. , Tsukahara Tatsuya , Taniguchi Junko , Qu Wei , Ichikawa Kazuki , Yoshimura Jun , Yurino Hideaki , Takahashi Yuji , Mitsui Jun , Ishiura Hiroyuki , Tsuji Shoji , Takeda Hiroyuki , Morishita Shinichi
Published: June 2016

Motivation: Determining the methylation state of regions with high copy numbers is challenging for second-generation sequencing, because the read length is insufficient to map reads uniquely, especially when repetitive regions are long and nearly identical to each other. Single-molecule real-time (SMRT) sequencing is a promising method for observing such regions, because it is not vulnerable to GC bias, it produces long read lengths, and its kinetic information is sensitive to DNA modifications.

Results: We propose a novel linear-time algorithm that combines the kinetic information for neighboring CpG sites and increases the confidence in identifying the methylation states of those sites. Using a practical read coverage of ∼30-fold from an inbred strain medaka (Oryzias latipes), we observed that both the sensitivity and precision of our method on individual CpG sites were ∼93.7%. We also observed a high correlation coefficient (R = 0.884) between our method and bisulfite sequencing, and for 92.0% of CpG sites, methylation levels ranging over [0,1] were in concordance within an acceptable difference 0.25. Using this method, we characterized the landscape of the methylation status of repetitive elements, such as LINEs, in the human genome, thereby revealing the strong correlation between CpG density and hypomethylation and detecting hypomethylation hot spots of LTRs and LINEs. We uncovered the methylation states for nearly identical active transposons, two novel LINE insertions of identity ∼99% and length 6050 base pairs (bp) in the human genome, and 16 Tol2 elements of identity >99.8% and length 4682 bp in the medaka genome.

Availability and Implementation: AgIn (Aggregate on Intervals) is available at: https://github.com/hacone/AgIn

Contact:  ysuzuki@cb.k.u-tokyo.ac.jp or moris@cb.k.u-tokyo.ac.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
STRUM: structure-based prediction of protein stability changes upon single-point mutation
Authors: Quan Lijun , Lv Qiang , Zhang Yang
Published: June 2016

Motivation: Mutations in human genome are mainly through single nucleotide polymorphism, some of which can affect stability and function of proteins, causing human diseases. Several methods have been proposed to predict the effect of mutations on protein stability; but most require features from experimental structure. Given the fast progress in protein structure prediction, this work explores the possibility to improve the mutation-induced stability change prediction using low-resolution structure modeling.

Results: We developed a new method (STRUM) for predicting stability change caused by single-point mutations. Starting from wild-type sequences, 3D models are constructed by the iterative threading assembly refinement (I-TASSER) simulations, where physics- and knowledge-based energy functions are derived on the I-TASSER models and used to train STRUM models through gradient boosting regression. STRUM was assessed by 5-fold cross validation on 3421 experimentally determined mutations from 150 proteins. The Pearson correlation coefficient (PCC) between predicted and measured changes of Gibbs free-energy gap, ΔΔG, upon mutation reaches 0.79 with a root-mean-square error 1.2 kcal/mol in the mutation-based cross-validations. The PCC reduces if separating training and test mutations from non-homologous proteins, which reflects inherent correlations in the current mutation sample. Nevertheless, the results significantly outperform other state-of-the-art methods, including those built on experimental protein structures. Detailed analyses show that the most sensitive features in STRUM are the physics-based energy terms on I-TASSER models and the conservation scores from multiple-threading template alignments. However, the ΔΔG prediction accuracy has only a marginal dependence on the accuracy of protein structure models as long as the global fold is correct. These data demonstrate the feasibility to use low-resolution structure modeling for high-accuracy stability change prediction upon point mutations.

Availability and Implementation:  http://zhanglab.ccmb.med.umich.edu/STRUM/

Contact:  qiang@suda.edu.cn and zhng@umich.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
The structural effects of mutations can aid in differential phenotype prediction of beta-myosin heavy chain (Myosin-7) missense variants
Authors: Al-Numair Nouf S. , Lopes Luis , Syrris Petros , Monserrat Lorenzo , Elliott Perry , Martin Andrew C. R.
Published: June 2016

Motivation: High-throughput sequencing platforms are increasingly used to screen patients with genetic disease for pathogenic mutations, but prediction of the effects of mutations remains challenging. Previously we developed SAAPdap (Single Amino Acid Polymorphism Data Analysis Pipeline) and SAAPpred (Single Amino Acid Polymorphism Predictor) that use a combination of rule-based structural measures to predict whether a missense genetic variant is pathogenic. Here we investigate whether the same methodology can be used to develop a differential phenotype predictor, which, once a mutation has been predicted as pathogenic, is able to distinguish between phenotypes—in this case the two major clinical phenotypes (hypertrophic cardiomyopathy, HCM and dilated cardiomyopathy, DCM) associated with mutations in the beta-myosin heavy chain (MYH7) gene product (Myosin-7).

Results: A random forest predictor trained on rule-based structural analyses together with structural clustering data gave a Matthews’ correlation coefficient (MCC) of 0.53 (accuracy, 75%). A post hoc removal of machine learning models that performed particularly badly, increased the performance (MCC = 0.61, Acc = 79%). This proof of concept suggests that methods used for pathogenicity prediction can be extended for use in differential phenotype prediction.

Availability and Implementation: Analyses were implemented in Perl and C and used the Java-based Weka machine learning environment. Please contact the authors for availability.

Contacts: andrew@bioinf.org.uk or andrew.martin@ucl.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
New KEGG pathway-based interpretable features for classifying ageing-related mouse proteins
Authors: Fabris Fabio , Freitas Alex A.
Published: June 2016

Motivation: The incidence of ageing-related diseases has been constantly increasing in the last decades, raising the need for creating effective methods to analyze ageing-related protein data. These methods should have high predictive accuracy and be easily interpretable by ageing experts. To enable this, one needs interpretable classification models (supervised machine learning) and features with rich biological meaning. In this paper we propose two interpretable feature types based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and compare them with traditional feature types in hierarchical classification (a more challenging classification task regarding predictive performance) and binary classification (a classification task producing easier to interpret classification models). As far as we know, this work is the first to: (i) explore the potential of the KEGG pathway data in the hierarchical classification setting, (i) use the graph structure of KEGG pathways to create a feature type that quantifies the influence of a current protein on another specific protein within a KEGG pathway graph and (iii) propose a method for interpreting the classification models induced using KEGG features.

Results: We performed tests measuring predictive accuracy considering hierarchical and binary class labels extracted from the Mouse Phenotype Ontology. One of the KEGG feature types leads to the highest predictive accuracy among five individual feature types across three hierarchical classification algorithms. Additionally, the combination of the two KEGG feature types proposed in this work results in one of the best predictive accuracies when using the binary class version of our datasets, at the same time enabling the extraction of knowledge from ageing-related data using quantitative influence information.

Availability and Implementation: The datasets created in this paper will be freely available after publication.

Contact:  ff79@kent.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Statistical modeling of isoform splicing dynamics from RNA-seq time series data
Authors: Huang Yuanhua , Sanguinetti Guido
Published: June 2016

Motivation: Isoform quantification is an important goal of RNA-seq experiments, yet it remains problematic for genes with low expression or several isoforms. These difficulties may in principle be ameliorated by exploiting correlated experimental designs, such as time series or dosage response experiments. Time series RNA-seq experiments, in particular, are becoming increasingly popular, yet there are no methods that explicitly leverage the experimental design to improve isoform quantification.

Results: Here, we present DICEseq, the first isoform quantification method tailored to correlated RNA-seq experiments. DICEseq explicitly models the correlations between different RNA-seq experiments to aid the quantification of isoforms across experiments. Numerical experiments on simulated datasets show that DICEseq yields more accurate results than state-of-the-art methods, an advantage that can become considerable at low coverage levels. On real datasets, our results show that DICEseq provides substantially more reproducible and robust quantifications, increasing the correlation of estimates from replicate datasets by up to 10% on genes with low or moderate expression levels (bottom third of all genes). Furthermore, DICEseq permits to quantify the trade-off between temporal sampling of RNA and depth of sequencing, frequently an important choice when planning experiments. Our results have strong implications for the design of RNA-seq experiments, and offer a novel tool for improved analysis of such datasets.

Availability and Implementation: Python code is freely available at http://diceseq.sf.net.

Contact:  G.Sanguinetti@ed.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
SELAM: simulation of epistasis and local adaptation during admixture with mate choice
Authors: Corbett-Detig Russell , Jones Matt
Published: June 2016

Summary: SELAM is a forward time population genetic simulation program that provides a flexible framework for simulating admixture between any number of ancestral populations. The program can be used to simulate complex demographic and selection models, including dioecious or monoecious populations, autosomal or sex chromosomes, local adaptation, dominance, epistasis, and mate choice.

Availability and Implementation: The SELAM package (C ++ source code, examples and manuals) is available via github at https://github.com/russcd/SELAM. This package is distributed under version 3 of the GNU general public license.

Contact:  russcd@gmail.com
NegGOA: negative GO annotations selection using ontology structure
Authors: Fu Guangyuan , Wang Jun , Yang Bo , Yu Guoxian
Published: June 2016

Motivation: Predicting the biological functions of proteins is one of the key challenges in the post-genomic era. Computational models have demonstrated the utility of applying machine learning methods to predict protein function. Most prediction methods explicitly require a set of negative examples—proteins that are known not carrying out a particular function. However, Gene Ontology (GO) almost always only provides the knowledge that proteins carry out a particular function, and functional annotations of proteins are incomplete. GO structurally organizes more than tens of thousands GO terms and a protein is annotated with several (or dozens) of these terms. For these reasons, the negative examples of a protein can greatly help distinguishing true positive examples of the protein from such a large candidate GO space.

Results: In this paper, we present a novel approach (called NegGOA) to select negative examples. Specifically, NegGOA takes advantage of the ontology structure, available annotations and potentiality of additional annotations of a protein to choose negative examples of the protein. We compare NegGOA with other negative examples selection algorithms and find that NegGOA produces much fewer false negatives than them. We incorporate the selected negative examples into an efficient function prediction model to predict the functions of proteins in Yeast, Human, Mouse and Fly. NegGOA also demonstrates improved accuracy than these comparing algorithms across various evaluation metrics. In addition, NegGOA is less suffered from incomplete annotations of proteins than these comparing methods.

Availability and Implementation: The Matlab and R codes are available at https://sites.google.com/site/guoxian85/neggoa.

Contact:  gxyu@swu.edu.cn

Supplementary information:  Supplementary data are available at Bioinformatics online.
TADtool: visual parameter identification for TAD-calling algorithms
Authors: Kruse Kai , Hug Clemens B. , Hernández-Rodríguez Benjamín , Vaquerizas Juan M.
Published: June 2016

Summary: Eukaryotic genomes are hierarchically organized into topologically associating domains (TADs). The computational identification of these domains and their associated properties critically depends on the choice of suitable parameters of TAD-calling algorithms. To reduce the element of trial-and-error in parameter selection, we have developed TADtool: an interactive plot to find robust TAD-calling parameters with immediate visual feedback. TADtool allows the direct export of TADs called with a chosen set of parameters for two of the most common TAD calling algorithms: directionality and insulation index. It can be used as an intuitive, standalone application or as a Python package for maximum flexibility.

Availability and implementation: TADtool is available as a Python package from GitHub (https://github.com/vaquerizaslab/tadtool) or can be installed directly via PyPI, the Python package index (tadtool).

Contact:  kai.kruse@mpi-muenster.mpg.de, jmv@mpi-muenster.mpg.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Assemblytics: a web analytics tool for the detection of variants from an assembly
Authors: Nattestad Maria , Schatz Michael C.
Published: June 2016

Summary: Assemblytics is a web app for detecting and analyzing variants from a de novo genome assembly aligned to a reference genome. It incorporates a unique anchor filtering approach to increase robustness to repetitive elements, and identifies six classes of variants based on their distinct alignment signatures. Assemblytics can be applied both to comparing aberrant genomes, such as human cancers, to a reference, or to identify differences between related species. Multiple interactive visualizations enable in-depth explorations of the genomic distributions of variants.

Availability and Implementation:  http://assemblytics.com, https://github.com/marianattestad/assemblytics

Contact:  mnattest@cshl.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Genome puzzle master (GPM): an integrated pipeline for building and editing pseudomolecules from fragmented sequences
Authors: Zhang Jianwei , Kudrna Dave , Mu Ting , Li Weiming , Copetti Dario , Yu Yeisoo , Goicoechea Jose Luis , Lei Yang , Wing Rod A.
Published: June 2016

Motivation: Next generation sequencing technologies have revolutionized our ability to rapidly and affordably generate vast quantities of sequence data. Once generated, raw sequences are assembled into contigs or scaffolds. However, these assemblies are mostly fragmented and inaccurate at the whole genome scale, largely due to the inability to integrate additional informative datasets (e.g. physical, optical and genetic maps). To address this problem, we developed a semi-automated software tool—Genome Puzzle Master (GPM)—that enables the integration of additional genomic signposts to edit and build ‘new-gen-assemblies’ that result in high-quality ‘annotation-ready’ pseudomolecules.

Results: With GPM, loaded datasets can be connected to each other via their logical relationships which accomplishes tasks to ‘group,’ ‘merge,’ ‘order and orient’ sequences in a draft assembly. Manual editing can also be performed with a user-friendly graphical interface. Final pseudomolecules reflect a user’s total data package and are available for long-term project management. GPM is a web-based pipeline and an important part of a Laboratory Information Management System (LIMS) which can be easily deployed on local servers for any genome research laboratory.

Availability and Implementation: The GPM (with LIMS) package is available at https://github.com/Jianwei-Zhang/LIMS

Contacts:  jzhang@mail.hzau.edu.cn or rwing@mail.arizona.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Pseudotime estimation: deconfounding single cell time series
Authors: Reid John E. , Wernisch Lorenz
Published: June 2016

Motivation: Repeated cross-sectional time series single cell data confound several sources of variation, with contributions from measurement noise, stochastic cell-to-cell variation and cell progression at different rates. Time series from single cell assays are particularly susceptible to confounding as the measurements are not averaged over populations of cells. When several genes are assayed in parallel these effects can be estimated and corrected for under certain smoothness assumptions on cell progression.

Results: We present a principled probabilistic model with a Bayesian inference scheme to analyse such data. We demonstrate our method’s utility on public microarray, nCounter and RNA-seq datasets from three organisms. Our method almost perfectly recovers withheld capture times in an Arabidopsis dataset, it accurately estimates cell cycle peak times in a human prostate cancer cell line and it correctly identifies two precocious cells in a study of paracrine signalling in mouse dendritic cells. Furthermore, our method compares favourably with Monocle, a state-of-the-art technique. We also show using held-out data that uncertainty in the temporal dimension is a common confounder and should be accounted for in analyses of repeated cross-sectional time series.

Availability and Implementation: Our method is available on CRAN in the DeLorean package.

Contact:  john.reid@mrc-bsu.cam.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
PhenoScanner: a database of human genotype–phenotype associations
Authors: Staley James R. , Blackshaw James , Kamat Mihir A. , Ellis Steve , Surendran Praveen , Sun Benjamin B. , Paul Dirk S. , Freitag Daniel , Burgess Stephen , Danesh John , Young Robin , Butterworth Adam S.
Published: June 2016

Summary: PhenoScanner is a curated database of publicly available results from large-scale genetic association studies. This tool aims to facilitate ‘phenome scans’, the cross-referencing of genetic variants with many phenotypes, to help aid understanding of disease pathways and biology. The database currently contains over 350 million association results and over 10 million unique genetic variants, mostly single nucleotide polymorphisms. It is accompanied by a web-based tool that queries the database for associations with user-specified variants, providing results according to the same effect and non-effect alleles for each input variant. The tool provides the option of searching for trait associations with proxies of the input variants, calculated using the European samples from 1000 Genomes and Hapmap.

Availability and Implementation: PhenoScanner is available at www.phenoscanner.medschl.cam.ac.uk.

Contact:  jrs95@medschl.cam.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Maternal Human Immunodeficiency Virus-Associated Hypergammaglobulinemia Reduces Transplacental Transfer of Immunoglobulin G to Plasmodium falciparum Antigens in Cameroonian Neonates
Authors: Babakhanyan Anna , Ekali Gabriel Loni , Dent Arlene , Kazura James , Nguasong John Tamo , Fodjo Barriere Airy Yetgang , Yuosembom Emile Keming , Esemu Livo Forgu , Taylor Diane Wallace , Leke Rose Gana Fomban
Published: June 2016

Background.  Human immunodeficiency virus (HIV) infection reduces placental transfer of antibodies from mother to the fetus for many antigens; however, conflicting data exist for transfer of immunoglobulin G (IgG) to malarial antigens. The mechanism(s) underlying reduced placental transfer is unknown.

Methods.  Levels of maternal and cord total IgG, IgG subclasses, and cord-to-mother ratios (CMRs) were measured in 107 mother-cord pairs to 3 malarial antigens: circumsporozoite protein (CSP), apical membrane antigen 1 (AMA-1), merozoite surface protein 1 (MSP-1), and tetanus toxoid C-fragment (TTc).

Results.  Immunoglobulin G levels to CSP and TTc were lower in HIV+ mothers, and cord IgG to CSP, MSP-1, and TTc were significantly lower in neonates born to HIV+ mothers (all P values <.05). The prevalence of mothers with hypergammaglobulinemia was significantly higher among HIV+ women (68%) compared with HIV− mothers (8%) (P < .0001). Maternal hypergammaglobulinemia was associated with reduction in transplacental transfer of antibodies to CSP (P = .03), MSP-1 (P = .004), and TTc (P = .012), and CMRs <1 were found for MSP-1 (odds ratio [OR] = 6.5), TTc (OR = 4.95), and IgG1 to CSP (OR = 3.75, P = .025) in statistical models adjusted for maternal IgG.

Conclusions.  Data confirmed that HIV infections are associated with lower cord antibody levels to malarial antigens and that hypergammaglobulinemia may contribute to reduced antibody transfer.
RSQ: a statistical method for quantification of isoform-specific structurome using transcriptome-wide structural profiling data
Authors: Wang Yunfei , Zhu Xiaopeng , Sun Ming , Chen Yong , Chen Yiwen , Tu Shikui , Bai Boyang , Chen Min , Dai Qi , Wang Haozhe , Zhang Michael Q. , Xuan Zhenyu
Published: June 2016

The structure of RNA, which is considered to be a second layer of information alongside the genetic code, provides fundamental insights into the cellular function of both coding and non-coding RNAs. Several high-throughput technologies have been developed to profile transcriptome-wide RNA structures, i.e., the structurome. However, it is challenging to interpret the profiling data because the observed data represent an average over different RNA conformations and isoforms with different abundance. To address this challenge, we developed an RNA structurome quantification method (RSQ) to statistically model the distribution of reads over both isoforms and RNA conformations, and thus provide accurate quantification of the isoform-specific structurome. The quantified RNA structurome enables the comparison of isoform-specific conformations between different conditions, the exploration of RNA conformation variation affected by single nucleotide polymorphism (SNP),and the measurement of RNA accessibility for binding of either small RNAs in RNAi-based assays or RNA binding protein in transcriptional regulation. The model used in our method sheds new light on the potential impact of the RNA structurome on gene regulation.
Higher stress and immunity responses are associated with higher mortality in reef-building coral exposed to a bacterial challenge
Authors: Wright Rachel M. , Kenkel Carly D. , Dunn Carly E. , Shilling Erin N. , Bay Line K. , Matz Mikhail V.
Published: June 2016

Understanding the drivers of intraspecific variation in susceptibility is essential to manage increasingly frequent coral disease outbreaks. We challenged replicate fragments of eight Acropora millepora genotypes with Vibrio spp. to quantify variation in lesion development and to identify host and coral-associated microbial community properties associated with resistance. While Vibrio spp. remained relatively rare in the microbiome of challenged corals, other stress-associated microbial taxa significantly increased in abundance. Contrary to expectations, higher constitutive immunity and more active immune responses did not confer higher resistance to bacterial challenge. Furthermore, more pronounced gene expression responses to bacterial challenge were associated with higher rather than lower mortality. A newly developed gene expression assay based on two genes related to inflammation and immune responses, deleted in malignant brain tumors 1 and a matrix metalloproteinase, predicted mortality under Vibrio treatment both in the initial experiment and in a validation experiment involving another 20 A. millepora genotypes. Instead of mounting more robust responses, resistant corals were largely unaffected by the bacterial challenge and maintained gene expression signatures of healthier condition, including elevated fluorescent proteins and ribosomal biosynthesis along with diminished ubiquitination. Overall, our results support the view that coral disease and mortality is commonly due to opportunistic pathogens exploiting physiologically compromised hosts rather than specific infections, and show, contrary to the prevailing wisdom, that greater immune responses do not necessarily translate into greater disease resistance.