bluuebunny/crossref_metadata_2025 huggingface dataset:
A prioriestimation of memory effects in reduced-order models of nonlinear systems using the Mori–Zwanzig formalism
Authors: Gouasmi Ayoub , Parish Eric J. , Duraisamy Karthik
Published: September 2017

Reduced models of nonlinear dynamical systems require closure, or the modelling of the unresolved modes. The Mori–Zwanzig procedure can be used to derive formally closed evolution equations for the resolved physics. In these equations, the unclosed terms are recast as a memory integral involving the time history of the resolved variables. While this procedure does not reduce the complexity of the original system, these equations can serve as a mathematically consistent basis to develop closures based on memory approximations. In this scenario, knowledge of the memory kernel is paramount in assessing the validity of a memory approximation. Unravelling the memory kernel requires solving the orthogonal dynamics, which is a high-dimensional partial differential equation that is intractable, in general. A method to estimate the memory kernela priori, using full-order solution snapshots, is proposed. The key idea is to solve a pseudo orthogonal dynamics equation, which has a convenient Liouville form, instead. This ersatz arises from the assumption that the semi-group of the orthogonal dynamics is a composition operator for one observable. The method is exact for linear systems. Numerical results on the Burgers and Kuramoto–Sivashinsky equations demonstrate that the proposed technique can provide valuable information about the memory kernel.
Helping in humans and other animals: a fruitful interdisciplinary dialogue
Authors: Bshary Redouan , Raihani Nichola J.
Published: September 2017

Humans are arguably unique in the extent and scale of cooperation with unrelated individuals. While pairwise interactions among non-relatives occur in some non-human species, there is scant evidence of the large-scale, often unconditional prosociality that characterizes human social behaviour. Consequently, one may ask whether research on cooperation in humans can offer general insights to researchers working on similar questions in non-human species, and whether research on humans should be published in biology journals. We contend that the answer to both of these questions is yes. Most importantly, social behaviour in humans and other species operates under the same evolutionary framework. Moreover, we highlight how an open dialogue between different fields can inspire studies on humans and non-human species, leading to novel approaches and insights. Biology journals should encourage these discussions rather than drawing artificial boundaries between disciplines. Shared current and future challenges are to study helping in ecologically relevant contexts in order to correctly interpret how payoff matrices translate into inclusive fitness, and to integrate mechanisms into the hitherto largely functional theory. We can and should study human cooperation within a comparative framework in order to gain a full understanding of the evolution of helping.
Offspring genes indirectly influence sibling and maternal behavioural strategies over resource share
Authors: Ashbrook David G. , Sharmin Naorin , Hager Reinmar
Published: September 2017

Family members show behavioural strategies predicted to maximize individual fitness. These behaviours depend directly on genes expressed in focal individuals but also indirectly on genes expressed in other family members. However, how sibling and parental behavioural strategies are modified by genes expressed in family members, and to what degree, remains unclear. To answer this question, we have used a split litter design in an experimental population of genetically variable mouse families, and identified loci that indirectly affected sibling and maternal behaviour simultaneously. These loci map to genomic regions that also show a direct effect on offspring behaviour. Directly and indirectly affected traits were significantly correlated at the phenotypic level, illustrating how indirect effects are caused. Genetic variants in offspring that influence solicitation also impacted their siblings' and maternal behaviour. However, in contrast to predictions from sibling competition, unrelated litter mates benefited from increased solicitation. Overall, such indirect genetic effects explained a large proportion of variation seen in behaviours, with candidate genes involved in metabolism to neuronal development. These results reveal that we need to view behavioural strategies as the result of conjoint selection on genetic variation in all interacting family members.
Male cooperation for breeding opportunities contributes to the evolution of multilevel societies
Authors: Qi Xiao-Guang , Huang Kang , Fang Gu , Grueter Cyril C. , Dunn Derek W. , Li Yu-Li , Ji Weihong , Wang Xiao-Yan , Wang Rong-Tao , Garber Paul A. , Li Bao-Guo
Published: September 2017

A small number of primate species including snub-nosed monkeys (colobines), geladas (papionins) and humans live in multilevel societies (MLSs), in which multiple one-male polygamous units (OMUs) coexist to form a band, and non-breeding males associate in bachelor groups. Phylogenetic reconstructions indicate that the papionin MLS appears to have evolved through internal fissioning of large mixed-sex groups, whereas the colobine MLS evolved through the aggregation of small, isolated OMUs. However, how agonistic males maintain tolerance under intensive competition over limited breeding opportunities remains unclear. Using a combination of behavioural analysis, satellite telemetry and genetic data, we quantified the social network of males in a bachelor group of golden snub-nosed monkeys. The results show a strong effect of kinship on social bonds among bachelors. Their interactions ranged from cooperation to agonism, and were regulated by access to mating partners. We suggest that an ‘arms race’ between breeding males' collective defence against usurpation attempts by bachelor males and bachelor males' aggregative offence to obtain reproductive opportunities has selected for larger group size on both sides. The results provide insight into the role that kin selection plays in shaping inter-male cohesion which facilities the evolution of multilevel societies. These findings have implications for understanding human social evolution, as male–male bonds are a hallmark of small- and large-scale human societies.
Quality change of sliced ginseng depending on different drying methods
Authors: Park Jongjin , Park Daehee , Lee Wonyoung
Published: September 2017

This study investigated quality change of ginseng depending on far-infrared (FIR) drying methods. The ginseng was cut into 2 mm slices and measured moisture content (MC), color, total polyphenol content (TPC), total flavonoid content (TFC) and DPPH radical scavenging activity (DPPH). The color values (L, a, and b) were decreased after far-infrared (FIR) drying. As increase in drying time, color was changed. Considering quality parameters including MC, TPC, TFC, and DPPH, the optimum condition for drying was set at 65℃ for 60 min. Furthermore, we compared color and functional compounds depending on drying process including FIR, freeze-, vacuum, and hot-air drying. The color values of ginseng were decreased when dried using vacuum and hot-air. While the color values of ginseng were increased after freeze drying. Comparison with another drying method, FIR drying presented the highest color difference. FIR and vacuum-dried ginseng indicate higher contents of TPC and TFC than freeze- and hot air-dried ginseng. And hot-air-dried ginseng present the highest DPPH when compared to another drying methods. On the other hand, freeze dried ginseng show the lowest TPC, TFC, and DPPH.
Comparison of volatile flavor compounds of yuzu, kumquat, lemon and lime
Authors: Hong Young Shin , Lee Ym Shik , Kim Kyong Su
Published: September 2017

This study was conducted to confirm the usefulness of essential oil components in yuzu and kumquat cultivated in Korea for comparison with those in lemon and lime. The volatile flavor compounds in citrus fruits (yuzu, kumquat, lemon and lime) were extracted for 3 h with 100 mL redistilled n-pentane/diethylether (1:1, v/v) mixture, using a simultaneous steam distillation and extraction apparatus (SDE). The volatile flavor compositions of the samples were analyzed by gas chromatography-mass spectrometry (GC-MS). The aroma compounds analyzed were 104 (3,713.02 mg/kg) in yuzu, 87 (621.71 mg/kg) in kumquat 103 (3,024.69 mg/kg) in lemon and 106 (2,209.16 mg/kg) in lime. Limonene was a major volatile flavor compound in four citrus fruits. The peak area of limonene was 35.03% in yuzu, 63.82% in kumquat, 40.35% in lemon, and 25.06% in lime. In addition to limonene, the major volatile flavor compounds were γ-terpinene, linalool, β-myrcene, (E)-β-farnesene, α-pinene and β-pinene in yuzu, and β-myrcene, α-pinene, (Z)-limonene oxide, (E)-limonene oxide, geranyl acetate and limonen-10-yl acetate in kumquat. Furthermore, γ-terpinene, β-pinene, β-myrcene, geranyl acetate, neryl acetate and (Z)-β-bisabolene in lemon and γ-terpinene, β-pinene, (Z)-β-bisabolene, neral, geranial and neryl acetate in lime were also detected. As a result, it was confirmed that the composition of volatile flavor compounds in four citrus fruits was different. Also, yuzu and kumquat are judged to be worthy of use alternatives for lemon and lime widely used in the fragrance industry.
Antioxidant and anti-inflammatory activity of extracts from red beet (Beta vulagaris) root
Authors: Yi Mi-Ran , Chang-Hee Kang , Bu Hee-Jung
Published: September 2017

This study was designed to examine the in vitro antioxidant and anti-inflammatory effects of red beet (Beta vulagaris) root. Red beet root was extracted using 70% ethanol and then fractionated sequentially with n-hexane, ethyl acetate and butanol. Antioxidative ability was evaluated by bioassays using total polyphenol contents and ABTS (2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid diammonium salt) radical scavenging activity. Ethyl acetate fraction of red beet root was best on total polyphenol contents (37.02±0.37 mg GAE/g) and ABTS radical scavenging effects (IC50 42.9±9.5 μg/mL). For the anti-inflammatory activity in RAW264.7 cells, the hexane fraction showed the highest inflammatory effect. Dose response studies were performed to determine the inhibitory effect of hexane fraction of red beet root on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The hexane fraction of red beet root inhibited the NO and PGE2 production and the protein level of iNOS and COX-2, and protein expression of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), in a dose-dependent manner. These results suggest that red beet root has considerable potential as a functional food ingredient with antioxidative and anti- inflammatory effects.
Antioxidative activity of roasted Pueraria lobata root extracts
Authors: Choi Goo-Hee , Kim Hyun Jung , Park In-Jae , Kim Bong-Gyun , Kim Hoi-Yeong , Jeong Jae-Hyun , Cho Ju-Hyun
Published: September 2017

We evaluated the antioxidative activity of extracts of P. lobata root depending on roasting conditions. P. lobata roots were roasted at three different temperature at 150℃, 200℃, and 250℃ and three different time at 10 min, 20 min, and 30 min respectively. Roasted P. lobata root was extracted using water at 85℃ for 6 h and filtered using filter paper, followed by then evaporated (12±0.3 °Brix) and freeze-dried. The concentration of maker compound puerarin was determined using a high performance liquid chromatography system. 2 phenolic compounds, flavonoid contents, and antioxidant activities of the extract powder were evaluated. Puerarin contents, Phenolic compounds, and flavonoid contents of roasted P. lobata root were higher than those of unroasted P. lobata root. The results of DPPH and ABTS showed that roasted P. lobata root possessed higher antioxidant activity than unroasted P. lobata root. This study suggested that roasting process could be applied to P. lobata root in order to achieve its high quality and functionality.
The effect of superheated steam drying on physicochemical and microbial characteristics of Korean traditional actinidia (Actinidia arguta) leaves
Authors: Kim Ah-Na , Ko Hee-Suk , Lee Kyo-Yeon , Rahman M. Shafiur , Heo Ho Jin , Choi Sung-Gil
Published: September 2017

The purpose of this study was to evaluate the effect of superheated steam drying on physicochemical and microbial characteristics of Korean traditional actinidia (Actinidia arguta) leaves. Actinidia leaves were dried at steam temperature of 350℃ and oven temperature of 150℃ for 40-200 sec. Moisture content and water activity decreased with increasing the drying time, while color values including L, a, and b values and total color difference (ΔE) increased as drying time increased. The relationship between moisture content and water activity showed an exponential fit with high correlation vlaue (R2=0.9909). Total phenolics and flavonoids content and antioxidant activity such as DPPH radical scavenging activity, ABTS radical scavenging activity, and FRAP assay of dried actinidia leaves increased with increasing the drying time up to 160 sec, but dramatically decreased at drying of 200 sec. The numbers of total areobic bacteria of leaves was not detected at drying time over 120 sec and coliform of all the samples was not detected. As a results, the superheated steam was an very effective drying method of increase to the nutritional and sanitary quality of dried Korean traditional actinidia leaves.
Changes in pasting properties and free fatty acids of different brown rice cultivar during storage
Authors: Choi Induck , Kwak Jieun , Yoon Mi-Ra , Chun Areum , Choi Dong-Soo
Published: September 2017

Paddy rice is typically stored during postharvest until rice grain is processed into brown rice and milled rice by hulling and milling procedure, respectively. Recently, instead of storing paddy rice, storage of brown rice has been in the spotlight because it is more convenient and economically feasible. Different brown rice cultivars with varying amylose contents including waxy rice, medium-waxy rice, and non-glutinous rice were stored in room temperature storage for four months, and the changes in grain qualities of brown rice were evaluated. Amylose content significantly affected pasting properties in which rice cultivar with higher amylose content showed longer pasting time and higher peak viscosity. Storage also affected pasting viscosities, showing an increase in peak viscosity, but a decrease in breakdown viscosity. The changes in pasting viscosity during storage could be an important starch property for aged brown rice utilization. Waxy brown rice showed the weakest aging property in terms of free fatty acids (FFA) accumulation, whereas non-glutinous rice was more substantial grain quality against aging. The FFA values of two months storage were not significantly different from the initial FFA contents, suggesting that brown rice stored in room temperature for two months could be feasible for direct consumption of brown rice.
Ricinus communis extract inhibits the adipocyte differentiation through activating the Wnt/β-catenin signaling pathway
Authors: Kim Bora , Kim Hyun-Soo
Published: September 2017

Ricinus communis, belongs to the family Euphorbiaceae, has been known as medicinal plants for treatment of inflammation, tumors, antidiabetic, hepatoprotective and laxative. Compared to many pharmacological studies, the effect of R. communis extract on regulating adipogenesis as therapeutic drug for treating obesity has not been reported. R. communis extract (RCE) was investigated to determine its effects on the adipogenesis by monitoring the status of Wnt/β-catenin signaling and factors involving the differentiation of adipocytes. The differentiation of 3T3-L1 cells monitored by Oil Red O staining was inhibited in concentration dependent manner by RCE. The luciferase activity of HEK 293-TOP cells containing pTOPFlash with Tcf4 response element-luciferase gene was increased approximately 2-folds by the treatment of RCE at concentrations of 100 μg/mL compared to the control. Activation of the Wnt/β-catenin pathway by RCE was further confirmed by immunocytochemical analysis which shows an increment of nuclear localization of β-catenin. In addition, safety of RCE was verified through performing neural stem cell morphology assay. Among the identified flavonoids in RCE, isoquercitrin was the most abundant. Therefore, these results indicate that the adipocyte differentiation was significantly reduced by isoquercitrin in R. communis. In this study, RCE suppresses the adipogenesis of 3T3-L1 cells via the activation of Wnt/β-catenin signaling.
Internal Protein Motions in Molecular Dynamics Simulations of Bragg and Diffuse X-ray Scattering
Authors: Wall Michael E.
Published: September 2017

Synopsis

A molecular dynamics simulation of diffuse X-ray scattering from staphylococcal nuclease crystals is greatly improved when the unit cell model is expanded to a 2×2×2 layout of eight unit cells. The dynamics are dominated by internal protein motions rather than rigid packing interactions.

Molecular dynamics (MD) simulations of Bragg and diffuse X-ray scattering provide a means of obtaining experimentally validated models of protein conformational ensembles. This paper shows that, compared to a single periodic unit cell model, the accuracy in simulating diffuse scattering is increased when the crystal is modeled as a periodic supercell, consisting of a 2×2×2 layout of eight unit cells. The MD simulations capture the general dependence of correlations on the separation of atoms. There is substantial agreement between the simulated Bragg reflections and the crystal structure; there are local deviations, however, indicating both the limitation of using a single structure to model disordered regions of the protein and local deviations of the average structure away from the crystal structure. Although it was anticipated that a longer duration simulation might be required to achieve convergence of the diffuse scattering calculation using the supercell model, only a microsecond is required, the same as for the unit cell. Rigid protein motions only account for a small fraction of the variation in atom positions from the simulation. The results indicate that protein crystal dynamics can be dominated by internal motions rather than packing interactions, and that MD simulations can be combined with Bragg and diffuse X-ray scattering to model the protein conformational ensemble.
Improved Prokaryotic Gene Prediction Yields Insights into Transcription and Translation Mechanisms on Whole Genome Scale
Authors: Lomsadze Alexandre , Gemayel Karl , Tang Shiyuyun , Borodovsky Mark
Published: September 2017

In a conventional view of the prokaryotic genome organization promoters precede operons and RBS sites with Shine-Dalgarno consensus precede genes. However, recent experimental research suggesting a more diverse view motivated us to develop an algorithm with improved gene-finding accuracy. We describe GeneMarkS-2, anab initioalgorithm that uses a model derived by self-training for finding species-specific (native) genes, along with an array of pre-computedheuristicmodels designed to identify harder-to-detect genes (likely horizontally transferred). Importantly, we designed GeneMarkS-2 to identify several types of distinct sequence patterns (signals) involved in gene expression control, among them the patterns characteristic for leaderless transcription as well as non-canonical RBS patterns. To assess the accuracy of GeneMarkS-2 we used genes validated by COG annotation, proteomics experiments, and N-terminal protein sequencing. We observed that GeneMarkS-2 performed better on average in all accuracy measures when compared with the current state-of-the-art gene prediction tools. Furthermore, the screening of ∼5,000 representative prokaryotic genomes made by GeneMarkS-2 predicted frequent leaderless transcription in both archaea and bacteria. We also observed that the RBS sites in some species with leadered transcription did not necessarily exhibit the Shine-Dalgarno consensus. The modeling of different types of sequence motifs regulating gene expression prompted a division of prokaryotic genomes into five categories with distinct sequence patterns around the gene starts.

[Supplemental material is available for this article].
The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology
Authors: Brikell Isabell , Larsson Henrik , Lu Yi , Pettersson Erik , Chen Qi , Kuja-Halkola Ralf , Karlsson Robert , Lahey Benjamin B , Lichtenstein Paul , Martin Joanna
Published: September 2017

Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder, with common genetic risk variants implicated in the clinical diagnosis and symptoms of ADHD. However, given evidence of comorbidity and genetic overlap across neurodevelopmental and externalizing conditions, it remains unclear whether these genetic risk variants are ADHD-specific. The aim of this study was to evaluate the associations between ADHD genetic risks and related neurodevelopmental and externalizing conditions, and to quantify the extent to which any such associations can be attributed to a general genetic liability towards psychopathology. We derived ADHD polygenic risk scores (PRS) for 13,460 children aged 9 and 12 years from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. Associations between ADHD PRS, a latent general psychopathology factor, and six latent neurodevelopmental and externalizing factors were estimated using structural equation modelling. ADHD PRS were statistically significantly associated with elevated levels of inattention, hyperactivity/impulsivity, autistic traits, learning difficulties, oppositional-defiant, and conduct problems (standardized regression coefficients=0.07-0.12). Only the association with specific hyperactivity/impulsivity remained significant after accounting for a general psychopathology factor, on which all symptoms loaded positively (standardized mean loading=0.61, range=0.32-0.91). ADHD PRS simultaneously explained 1% (p-value<0.001) of the variance in the general psychopathology factor and 0.50% (p-value<0.001) in the specific hyperactivity/impulsivity factor. Our results suggest that common genetic risk variants associated with ADHD have largely general pleiotropic effects on neurodevelopmental and externalizing traits in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.
Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer
Authors: Patten Darren K. , Corleone Giacomo , Győrffy Balázs , Erdős Edina , Saiakhova Alina , Goddard Kate , Vingiani Andrea , Shousha Sami , Pongor Lőrinc Sándor , Hadjiminas Dimitri J. , Schiavon Gaia , Barry Peter , Palmieri Carlo , Coombes Raul C. , Scacheri Peter , Pruneri Giancarlo , Magnani Luca
Published: September 2017

The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs1,2. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers1,3,4. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ERα)-positive breast cancer specimens from clinical samples, and developed strategies to deduce phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Highly shared regions contain a unique set of regulatory information including the motif for the transcription factor YY1.In vitrowork shows that YY1 is essential for ERα transcriptional activity and defines the critical subset of functional ERα binding sites driving tumor growth in most luminal patients. YY1 also control the expression of genes that mediate resistance to endocrine treatment. Finally, we show that H3K27ac levels at active enhancer elements can be used as a surrogate of intra-tumor phenotypic heterogeneity, and to track expansion and contraction of phenotypic subpopulations throughout breast cancer progression. Tracking YY1 and SLC9A3R1 positive clones in primary and metastatic lesions, we show that endocrine therapies drive the expansion of phenotypic clones originally underrepresented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.
Non-canonical aberrant DNA hypermethylation in glioma
Authors: Fernandez Agustin F. , Bayón Gustavo F. , Sierra Marta I. , Urdinguio Rocio G. , Toraño Estela G. , García Maria , Carella Antonella , Lopez Virginia , Santamarina Pablo , Belmonte Thalia , Tejedor Juan Ramon , Cobo Isabel , Menendez Pablo , Mangas Cristina , Ferrero Cecilia , Rodrigo Luís , Astudillo Aurora , Ortea Ignacio , Cueto Díaz Sergio , Rodríguez-Gonzalez Pablo , García Alonso J. Ignacio , Mollejo Manuela , Meléndez Bárbara , Dominguez Gemma , Bonilla Felix , Fraga Mario F.
Published: September 2017

Aberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC in primary samples from 54 gliomas and 72 colorectal cancer patients. Levels of 5hmC in colorectal cancer were very low and no consistent changes were detected between control tissues and tumors. As expected, levels of 5hmC in non-tumoral brain samples were high and significantly reduced at the 49,601 CpG sites in gliomas. Strikingly, hypo-hydroxymethylation at 4,627 (9.3%) of these CpG sites was associated with aberrant DNA hypermethylation. The DNA regions containing these CpG sites were enriched in H3K4me2, and presented a different genuine chromatin signature to that characteristic of the genes classically aberrantly hypermethylated in cancer. We conclude that this data identifies a novel 5hmC-dependent non-canonical class of aberrant DNA hypermethylation in glioma.
A literature review at genome scale: improving clinical variant assessment
Authors: Cassa Christopher A. , Jordan Daniel M. , Adzhubei Ivan , Sunyaev Shamil
Published: September 2017

Introduction: Over 150,000 variants have been reported to cause Mendelian disease in the medical literature. It is still difficult to leverage this knowledge base in clinical practice as many reports lack strong statistical evidence or may include false associations. Clinical laboratories assess whether these variants (along with newly observed variants that are adjacent to these published ones) underlie clinical disorders.

Materials and Methods: We measured whether citation data—including journal impact factor and the number of cited variants (NCV) in each gene with published disease associations—can be used to improve variant assessment.

Results: Surprisingly, we find that impact factor is not predictive of pathogenicity, but the NCV score for each gene can provide statistical support of pathogenicity. When combining this gene-level citation metric with variant-level evolutionary conservation and structural features, classification accuracy reaches 89.5%. Further, variants identified in clinical exome sequencing cases have higher NCV scores than simulated rare variants from ExAC in matched genes and consequences (p<2.22x10-16).

Discussion: Aggregate citation data can complement existing variant-based predictive algorithms, and can boost their performance without accessing and reviewing large numbers of manuscripts. The NCV is a slow-growing metric of scientific knowledge about each gene’s association with disease.

Funding: This research was supported by NIH NHGRI grant HG007229 (C.C.) and NIGMS grant GM078598 (I.A., D.J., and S.S.).
Comprehensive, high-resolution binding energy landscapes reveal context dependencies of transcription factor binding
Authors: Le Daniel D. , Shimko Tyler C. , Aditham Arjun K. , Keys Allison M. , Orenstein Yaron , Fordyce Polly M.
Published: September 2017

Transcription factors (TFs) are primary regulators of gene expression in cells, where they bind specific genomic target sites to control transcription. Quantitative measurements of TF-DNA binding energies can improve the accuracy of predictions of TF occupancy and downstream gene expressionin vivoand further shed light on how transcriptional networks are rewired throughout evolution. Here, we present a novel sequencing-based TF binding assay and analysis pipeline capable of providing quantitative estimates of binding energies for more than one million DNA sequences in parallel at high energetic resolution. Using this platform, we measured the binding energies associated with all possible combinations of 10 nucleotides flanking the known consensus DNA target for two model yeast TFs, Pho4 and Cbf1. A large fraction of these flanking mutations change overall binding energies by an amount equal to or greater than consensus site mutations, suggesting that current definitions of TF binding sites may be too restrictive. By systematically comparing estimates of binding energies output by deep neural networks (NN) and biophysical models trained on these data, we establish that dinucleotide specificities are sufficient to explain essentially all variance in observed binding behavior, with Cbf1 binding exhibiting significantly more epistasis than Pho4. NN-derived binding energies agree with orthogonal biochemical measurements and reveal that dynamically occupied sitesin vivoare both energetically and mutationally distant from the highest-affinity sites.
DAFi: A Directed Recursive Filtering and Clustering Approach to Data-Driven Identification of Cell Populations from Polychromatic Flow Cytometry Data
Authors: Lee Alexandra J. , Chang Ivan , Burel Julie G. , Lindestam Arlehamn Cecilia S. , Weiskopf Daniela , Peters Bjoern , Sette Alessandro , Scheuermann Richard H. , Qian Yu
Published: September 2017

Computational methods for identification of cell populations from high-dimensional flow cytometry data are changing the paradigm of cytometry bioinformatics. Data clustering is the most common computational approach to unsupervised identification of cell populations from multidimensional cytometry data. We found that combining recursive filtering and clustering with constraints converted from the user manual gating strategy can effectively identify overlapping and rare cell populations from smeared data that would have been difficult to resolve by either a single run of data clustering or manual segregation. We named this new method DAFi: Directed Automated Filtering and Identification of cell populations. Design of DAFi preserves the data-driven characteristics of unsupervised clustering for identifying novel cell-based biomarkers, but also makes the results interpretable to experimental scientists as in supervised classification through mapping and merging the high-dimensional data clusters into the user-defined 2D gating hierarchy. By recursive data filtering before clustering, DAFi can uncover small local clusters which are otherwise difficult to identify due to the statistical interference of the irrelevant major clusters. Quantitative assessment of cell type specific characteristics demonstrates that the population proportions calculated by DAFi, while being highly consistent with those by expert centralized manual gating, have smaller technical variance than those from individual manual gating analysis. Visual examination of the dot plots showed that the boundaries of the DAFi-identified cell populations followed the natural shapes of the data distributions. To further exemplify the utility of DAFi, we show that DAFi can incorporate the FLOCK clustering method to identify novel cell-based biomarkers. Implementation of DAFi supports options including clustering, bisecting, slope-based gating, and reversed filtering to meet various auto-gating needs from different scientific use cases.
Leveraging lung tissue transcriptome to uncover candidate causal genes in COPD genetic associations
Authors: Obeidat Ma’en , Lamontagne Maxime , Bérubé Jean-Christophe , Cho Michael H , Hobbs Brian D. , de Jong Kim , Boezen H. Marike ,   the International COPD Genetics Consortium, Nickle David , Hao Ke , Timens Wim , van den Berge Maarten , Joubert Philippe , Laviolette Michel , Sin Don D , Paré Peter D , Bossé Yohan
Published: September 2017

We collated 129 non-overlapping risk loci for chronic obstructive pulmonary disease (COPD) from the GWAS literature. Using recent and complementary integrative genomics approaches, combining GWAS and lung eQTL results, we identified 12 novel COPD loci and corresponding causal genes. In addition, we mapped candidate causal genes for 60 out of the 129 GWAS-nominated loci as well as for four sub-genome-wide significant COPD risk loci derived from the largest GWAS on COPD. Mapping causal genes in lung tissue represents an important contribution on the genetics of COPD, enriches our biological interpretation of GWAS findings, and brings us closer to clinical translation of genetic associations.
Impaired competence in flagellar mutants ofBacillus subtilisis connected to the regulatory network governed by DegU
Authors: Hölscher Theresa , Schiklang Tina , Dragoš Anna , Dietel Anne-Kathrin , Kost Christian , Kovács Ákos T.
Published: September 2017

The competent state is a developmentally distinct phase, in which bacteria are able to take up and integrate exogenous DNA into their genome.Bacillus subtilisis one of the naturally competent bacterial species and the domesticated laboratory strain 168 is easily transformable. In this study, we report a reduced transformation frequency ofB. subtilismutants lacking functional and structural flagellar components. This includeshag, the gene encoding the flagellin protein forming the filament of the flagellum. We confirm that the observed decrease of the transformation frequency is due to reduced expression of competence genes, particularly of the main competence regulatorcomK. The impaired competence is due to an increase in the phosphorylated form of the response regulator DegU, which is involved in regulation of both flagellar motility and competence. Altogether, our study identified a close link between motility and natural competence inB. subtilissuggesting that hindrance in motility has great impact on differentiation of this bacterium not restricted only to the transition towards sessile growth stage.

Originality-Significance statement

Understanding how versatile bacterial phenotypes influence each other is important for our basic understanding of microbial ecology. Our research highlights the novel intertwinement of bacterial differentiation and reveal how lack of single cell motility adjusts DNA exchange among bacterial strains.
Gauss-power mixing distributions comprehensively describe stochastic variations in RNA-seq data
Authors: Awazu Akinori , Tanabe Takahiro , Kamitani Mari , Tezuka Ayumi , Nagano Atsushi J.
Published: September 2017

Motivation

Gene expression levels exhibit stochastic variations among genetically identical organisms under the same environmental conditions. In many recent transcriptome analyses based on RNA sequencing (RNA-seq), variations in gene expression levels among replicates were assumed to follow a negative binomial distribution although the physiological basis of this assumption remain unclear.

Results

In this study, RNA-seq data were obtained fromArabidopsis thalianaunder eight conditions (21–27 replicates), and the characteristics of gene-dependent distribution profiles of gene expression levels were analyzed. ForA. thaliana and Saccharomyces cerevisiae,the distribution profiles could be described by a Gauss-power mixing distribution derived from a simple model of a stochastic transcriptional network containing a feedback loop. The distribution profiles of gene expression levels were roughly classified as Gaussian, power law-like containing a long tail, and mixed. The fitting function predicted that gene expression levels with long-tailed distributions would be strongly influenced by feedback regulation. Thus, the features of gene expression levels are correlated with their functions, with the levels of essential genes tending to follow a Gaussian distribution and those of genes encoding nucleic acid-binding proteins and transcription factors exhibiting long-tailed distributions.

Availability

Fastq files of RNA-seq experiments were deposited into the DNA Data Bank of Japan Sequence Read Archive as accession no. DRA005887. Quantified expression data are available in supplementary information.

Contact

awa@hiroshima-u.ac.jp

Supplementary information

Supplementary data are available atBioinformaticsonline.
Name Conditioning in Event-Related Brain Potentials
Authors: Kotchoubey Boris , Pavlov Yuri G.
Published: September 2017

Four experiments are reported in which two harmonic tones (CS+ and CS-) were paired with a participant’s own name (SON) and different names (DN), respectively. A third tone was not paired with any other stimulus and served as a standard (frequent stimulus) in a three-stimuli oddball paradigm. The larger posterior positivity (P3) to SON than DN, found in previous studies, was replicated in all experiments. Conditioning of the P3 response was albeit observed in two similar experiments (1 and 3), but the obtained effects were weak and not identical in the two experiments. Only Experiment 4, where the number of CS/UCS pairings and the Stimulus-Onset Asynchrony between CS and UCS were increased, showed clear CS+/CS- differences both in time and time-frequency domains. Surprisingly, differential responses to CS+ and CS- were also obtained in Experiment 2, although SON and DN in that experiment were masked and never consciously recognized as meaning words (recognition rate 0/63 participants). The results are discussed in the context of other ERP conditioning experiments and, particularly, the studies of non-conscious effect on ERP. Several further experiments are suggested to replicate and extend the present findings and to remove the remaining methodological limitations.
The mechano-chemistry of a monomeric reverse transcriptase
Authors: Malik Omri , Khamis Hadeel , Rudnizky Sergei , Kaplan Ariel
Published: September 2017

Retroviral reverse transcriptase catalyses the synthesis of an integration-competent dsDNA molecule, using as a substrate the viral RNA. Using optical tweezers, we follow the Murine Leukemia Virus reverse transcriptase as it performs strand-displacement polymerization on a template under mechanical force. Our results indicate that reverse transcriptase functions as a Brownian ratchet, with dNTP binding as the rectifying reaction of the ratchet. We also found that reverse transcriptase is a relatively passive enzyme, able to polymerize on structured templates by exploiting their thermal breathing. Finally, our results indicate that the enzyme enters the recently characterized backtracking state from the pre-translocation complex.
Cell-type heterogeneity in the zebrafish olfactory placode is generated from progenitors within preplacodal ectoderm
Authors: Aguillon Raphaël , Batut Julie , Subramanian Arul , Madelaine Romain , Dufourcq Pascale , Schilling Thomas F. , Blader Patrick
Published: September 2017

Vertebrate olfactory placodes consists of a variety of neuronal populations, which are thought to have distinct embryonic origins. In the zebrafish, while ciliated sensory neurons arise from preplacodal ectoderm (PPE), previous lineage tracing studies suggest that both Gonadotropin releasing hormone 3 (Gnrh3) and microvillous sensory neurons derive from cranial neural crest (CNC). We find that the expression of Islet1/2 is restricted to Gnrh3 neurons associated with the olfactory placode. Unexpectedly, however, we find no change in Islet1/2+ cell numbers insox10mutant embryos, calling into question their CNC origin. Lineage reconstruction based on backtracking in time-lapse confocal datasets, and confirmed by photoconversion experiments, reveals that Gnrh3 neurons derive from the anterior/medial PPE. Similarly, all of the microvillous sensory neurons we have traced arise from preplacodal progenitors. Our results suggest that rather than originating from separate ectodermal populations, cell-type heterogeneity is generated from overlapping pools of progenitors within the preplacodal ectoderm.
Genetic Adaptation ofC. elegansto Environment Changes I: Multigenerational Analysis of the Transcriptome
Authors: Çelen İrem , Doh Jung H. , Sabanayagam Chandran R.
Published: September 2017

Abrupt environment changes can elicit an array of genetic effects. However, many of these effects can be overlooked by functional genomic studies conducted in static laboratory conditions. We studied the transcriptomic responses ofCaenorhabditis elegansunder single generation exposures to drastically different culturing conditions. In our experimental scheme, P0worms were maintained on terrestrial environments (agar plates), F1in aquatic cultures, and F2back to terrestrial environments. The laboratory N2 strain and the wild isolate AB1 strain were utilized to examine how the genotype contributes to the transcriptome dynamics. Significant variations were found in the gene expressions between the “domesticated” laboratory strain and the wild isolate in the different environments. The results showed that 20% - 27% of the transcriptional responses to the environment changes were transmitted to the subsequent generation. In aquatic conditions, the domesticated strain showed differential gene expression particularly for the genes functioning in the reproductive system and the cuticle development. In accordance with the transcriptomic responses, phenotypic abnormalities were detected in the germline and cuticle of the domesticated strain. Further studies showed that distinct groups of genes are exclusively expressed under specific environmental conditions, and many of these genes previously lacked supporting biochemical evidence.
Conformational dynamics of the essential sensor histidine kinase WalK
Authors: Cai Yongfei , Su Mingyang , Ahmad Ashfaq , Hu Xiaojie , Sang Jiayan , Kong Lingyuan , Chen Xingqiang , Wang Chen , Shuai Jianwei , Han Aidong
Published: September 2017

Two-component systems (TCSs) are key elements in bacterial signal transduction in response to environmental stresses. TCSs generally consist of sensor histidine kinases (SKs) and their cognate response regulators (RRs). Many SKs exhibit autokinase, phosphoryltransferase and phosphatase activities, which regulate RR activity through a phosphorylation and dephosphorylation cycle. However, how SKs perform different enzymatic activities is poorly understood. Here, several crystal structures of the minimal catalytic region of WalK, an essential SK fromLactobacillus plantarumthat shares 60% sequence identity with its homologue VicK fromStreptococcus mutans, are presented. WalK adopts an asymmetrical closed structure in the presence of ATP or ADP, in which one of the CA domains is positioned close to the DHp domain, thus leading both the β- and γ-phosphates of ATP/ADP to form hydrogen bonds to the ∊- but not the δ-nitrogen of the phosphorylatable histidine in the DHp domain. In addition, the DHp domain in the ATP/ADP-bound state has a 25.7° asymmetrical helical bending coordinated with the repositioning of the CA domain; these processes are mutually exclusive and alternate in response to helicity changes that are possibly regulated by upstream signals. In the absence of ATP or ADP, however, WalK adopts a completely symmetric open structure with its DHp domain centred between two outward-reaching CA domains. In summary, these structures of WalK reveal the intrinsic dynamic properties of an SK structure as a molecular basis for multifunctionality.
Social impacts of a short-distance relocation process and new ways of working
Authors: Christersson Matti , Heywood Christopher , Rothe Peggie
Published: September 2017

Purpose

The purpose of this paper is to investigate the social impacts of short-distance office relocation that also involved a new way of working, as perceived by employees during a relocation process. Relocation is any process of moving business premises and can consist of (often) significant change in locality, building change, workplace change and ways of working. This case study was not influenced by the effect of locality change making it hence a short-distance relocation.

Design/methodology/approach

The social impacts are analysed based on the perceptions of approximately 15 per cent (nine employees) of the case organization across the relocation process – two months before, one week before and four months after the move. The qualitative data collection is conducted by semi-structured interviews, supplemented by diaries and participatory action research.

Findings

Before the relocation, the subject organization’s old premises were considered inadequate. Still, employees had concerns during the process about the new open office environment including the adoption of new ways of working. Some employees did experience resistance towards the change, although the amount of engagement possibilities was deemed sufficient and engagement recognized as an important part of the process. After the relocation, adaptation was considered easier than originally anticipated and experiences of improved inter-team collaboration were reported by most while others experienced just the opposite, pointing out to emerging individual differences.

Research limitations/implications

The limitations of this study arise mainly from the ability to statistically generalize on the basis of a single case study which this paper represents. Furthermore, since the last interviews were made four months after the move, all post-occupancy implications were possibly not yet fully experienced.

Originality/value

The paper provides information on the social impacts of organizational relocation process, as it identifies individual employee perceptions during a relocation process where locality change is minimal. Moreover, the threefold research approach across the relocation process enables the appearance of possible time-dependent development of adaptation to change in employee perceptions and these perceptions to be analysed in more detail.
FCA discussion paper on open-ended funds and illiquidity
Authors: Katsambas Panos , Ng Chu Ting
Published: September 2017

Purpose

To explore the issues and questions put forward for consideration by stakeholders by the UK Financial Conduct Authority (FCA) in its discussion paper dated February 2017 – the purpose of which was to gather stakeholders’ views on illiquid assets and open-ended investment funds and seek to provide a basis for debate by setting out several policies for FCA intervention.

Design/methodology/approach

Explains and discusses the potential consequences of each issue and question put forward by the FCA, including definitions of illiquid assets, liquidity management tools, treatment of professional and retail investors, portfolio restrictions and liquidity buffers, valuation of illiquid assets, direct intervention by the FCA, enhanced disclosure, and secondary markets for illiquid assets.

Findings

What was found in the course of the work? The decision to suspend redemptions by these large property funds has brought to the forefront the key question of whether real estate or other illiquid assets are appropriate for open-ended funds. Many questions and considerations remain as to what impact the FCA’s proposed changes could have on the industry. The FCA consultation closed on 8 May 2017 and the results could determine new and adapted rules.

Originality/value

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