bluuebunny/crossref_metadata_2025 huggingface dataset:
Chloroplast structure and DNA methylation polymorphisms in an albino mutant of wheat (Triticum aestivum) cv. Xinong 1376
Authors: Song Yulong , Tang Huali , Ke Xiangsheng , Guo Jialin , Zhang Shuangxi , Wang Junwei , Niu Na , Ma Shoucai , Zhao Huiyan , Zhang Gaisheng
Published: April 2018

DNA methylation plays an important role in regulating plant development, including organ and tissue differentiation, which may determine variations in agronomic traits. However, no reports exist for the regulation of leaf colour in wheat. The present study investigated the chloroplast structure and epigenetic mechanisms regulating leaf colour in an albino mutant of wheat (Triticum aestivum L.) cv. Xinong 1376. Structural analysis was performed by scanning and transmission electron microscopy, and epigenetic modifications were detected by methylation-sensitive amplification polymorphism (MSAP) analysis. Mesophyll cells of green leaves showed a well-ordered arrangement and they were filled with chloroplasts with intact lamellar structures and thylakoid membranes. By contrast, mesophyll cells of red and white leaves were disorganised and contained only a few plastids or chloroplasts with no lamellar structures or thylakoid membranes. Comparison of MSAP profiles revealed that white or red leaves had higher levels of cytosine methylation and showed changes in polymorphic loci compared with green leaves (4.35% and 4.10%, respectively). We sequenced 150 DNA fragments that were differentially displayed in MSAP patterns of white or red and green leaves of the Xinong 1376 albino mutant. A further BLAST search of 77 cloned sequences located them in coding regions. Most of these sequences were found to be involved in processes such as signal transduction, transcription regulation, post-transcriptional processing, DNA modification and repair, transport, biosynthesis of cellulose, photosynthesis, protein ubiquitination, stress responses, and retroposition. Expression analysis demonstrated a decrease in the transcription of two methylated genes, psaA and psbD, which are involved in the photosystem. Although the DNA methylation changes and leaf colour changes were not directly associated, these results may indicate that methylation of specific genes is an active and rapid epigenetic response to variation of leaf colour in the Xinong 1376 albino mutant, further elucidating the mechanism of variation in leaf colour.
Deconstructing the myth of positively evaluative irony
Authors: Dynel Marta
Published: April 2018

Adopting a neo-Gricean perspective on the figure of irony, this chapter critically examines the species of irony that communicates positive evaluation in its implicated meaning. A critical overview of the existing scholarship on this type of irony is performed, with the focus being on the rationale for its intermittence and on the available examples. Further support is thus given to a view that irony must implicate negative evaluation. In the case of irony couched in overtly untruthful negatively evaluative expression of one referent, a negatively evaluated antecedent (another referent) is necessary. The speaker’s intention to convey the latter form of evaluative implicature lies at the heart of irony, whilst the positively evaluative implicature is just an optional concomitant.
Irony as counter positioning
Authors: Chovanec Jan
Published: April 2018

This chapter examines how ironic utterances in online news forums are used for the purpose of collective positioning of the commenting readers in opposition to other groups. Approaching irony as an act of echoic

interpretation, the analysis focuses on how readers echo both the representations made by the media texts and the beliefs and ideologies presumed to be held by other social actors. It is argued that through irony, readers express their oppositional attitudes, disaffiliating themselves from the ironized social actors and their real or assumed representations. Simultaneously, ironists enforce their own opinions and standpoints, which are not just personal but – as argued in the paper – representative of a larger group to which the commenter belongs. By tracing how irony is used in reader comments to delegitimize dissonant views and emphasize contrastive self-positioning, this paper seeks to extend the application of an interactional pragmatic approach to irony by adding a critical discourse analytical dimension to it.
Introduction
Authors: Ponsonnet Maïa , Vuillermet Marine
Published: April 2018

This volume presents nine chapters dealing with emotionally loaded morphology over four continents. The collection is the result of a workshop on “morphology and emotions” (MorphÉm) held by the first author at Dynamique du Langage (CNRS) in Lyon on 29–30 April 2015. In this introduction, we first discuss our definitions of the terms “emotions”, “morphology”, and the intersection between the two (Section 1). InSection 2, we contextualize the study of the morphological encoding of emotions within semantic typology and semantic ecology, and spell out some of the cross-linguistic generalizations that can be made about the morphological encoding of emotions on the basis of the contributions in this volume. InSection 3, we summarize the findings of the volume on the more specific topic of evaluative morphology, the most widespread type of emotionally loaded morphology. Finally,Section 4offers a chapter-by-chapter outline of the volume.
A preliminary typology of emotional connotations in morphological diminutives and augmentatives
Authors: Ponsonnet Maïa
Published: April 2018

This article presents a preliminary typology of emotional connotations in evaluative morphology, starting with diminutives and augmentatives. I inventory the emotional meanings and connotations found in a sample of nineteen languages for diminutives, and nine languages plus a few additional regional studies for augmentatives. Given the small size of the samples, this typology can only remain preliminary, but it does highlight a number of points. Across languages and continents, diminutives can express positive emotions such as compassion, love and admiration, as well as negative emotions such as contempt. The emotional connotations of augmentatives are more limited, but display a blend of positive and negative emotions including contempt and repulsion, admiration and respect, endearment and compassion. Diminutives and augmentatives do not contrast sharply with respect to emotional valence (positive or negative), but while diminutives are anchored in intimacy, the emotions conveyed by augmentatives more often relate to broader social contexts.
Diminutives and augmentatives in Beja (North-Cushitic)
Authors: Vanhove Martine , Hamid Ahmed Mohamed-Tahir
Published: April 2018

The evaluative morphology of Beja consists of four devices: gender shift to feminine on nouns, and sound change (r>l) on nouns, verbs and adjectives form the diminutives. A suffix-loːjon adjectives, and-lon Manner converbs, form the augmentatives. The analysis focuses on the evaluative, emotional and other pragmatic values associated with these morphemes, size, endearment, praise, romantic love, contempt, politeness and eloquence. When relevant, the links to the general mechanism of semantic change,lambda-abstraction-specificationproposed byJurafsky (1996), is discussed. This paper also discusses productivity, cases where the evaluative device has scope over an adjacent noun instead of its host, the distribution of values across semantic domains and genres, and cases of lexicalization. The corpus analysis shows that the proportional frequency of pragmatic expressive connotations compared to the denotational meaning is higher for diminutives than for augmentatives. Further, with diminutives, positive emotional values are more frequent than negative ones, while with augmentatives attested pejorative values are very rare. The analysis is set within a typological framework.
The grammatical expression of emotions in Tacana and other Takanan languages
Authors: Guillaume Antoine
Published: April 2018

This paper studies four grammatical markers of emotions in Tacana, an Amazonian language from the Takanan family spoken in Northern Bolivia. Two markers express positive emotions,chidi‘affection’ andichenu‘compassion’. The other two express negative emotions:base‘depreciation 1’ andmadha‘depreciation 2’. The paper also provides a historical-comparative study of similar morphemes in the other Takanan languages (Araona, Cavineña, Ese Ejja and Reyesano). The Tacana affection morpheme is probably reconstructible to a diminutive marker in proto-Takanan. The compassion and two depreciation morphemes are not reconstructible but recent grammaticalizations of lexical items still used in the different Takanan languages. Interestingly, these lexemes do not display any synchronic or diachronic link with the expression of “diminutivization” or “augmentativization”. Therefore, this paper suggests that the morphological expression of emotions should be studied in its own right, and not necessarily as a subtype of the evaluative field of research.
The rise and fall of Mojeño diminutives through the centuries
Authors: Rose Françoise
Published: April 2018

This paper investigates the diachrony of diminutives in Mojeño across four centuries. First, it shows that the three Mojeño diminutives have two lexical sources: ‘child’ and ‘seed’. This constitutes a counterexample toJurafsky’s (1996)theory concerning the universal source of diminutives. Second, the paper investigates the grammaticalization process of diminutives and their further distributional and functional changes. It shows that the extension of the distribution onto verbs and grammatical parts of speech correlates with the gain of emotional connotations. It describes the evolution of emotional connotations of the diminutives and the pragmaticalization of their interactional functions until the eventual shift to purely expressive morphemes when diminutives lose their core meaning of ‘smallness’. Third, since each of the three language varieties has one ‘true’ diminutive only, two successive cycles of diminutive renewal are hypothesized, whereby an old diminutive is replaced by a new one.
The encoding of emotions in Kakataibo (Panoan)
Authors: Zariquiey Roberto
Published: April 2018

Kakataibo (a Panoan language spoken in Peru) encodes emotional meanings by means of various morphological and prosodic devices. Some of them may be related to pragmatic implications (like the expression of affection by the diminutive), but others constitute dedicated emotional markers (as is the case of the illocutionary suffixes, augmentative nominalizers and nasalized imperatives). The fact that almost all the emotional markers carry nasalization is interpreted here as a possible case of language-internal sound-symbolism between nasalization and (negative) emotional meanings. This paper also shows that in Kakataibo we find a systematic pattern according to which dedicated emotional markers express negative emotions and never positive ones. Both the phonological and the semantic systems described in this paper may reveal patterns relevant for the cross-linguistic research on the grammar of emotions.
Expressive values of reduplication in Barunga Kriol (northern Australia)
Authors: Ponsonnet Maïa
Published: April 2018

This article describes the semantic values of reduplication in Barunga Kriol – an English-based creole of northern Australia –, with a focus on its expressive functions. Barunga Kriol reduplication has two types of functions. Its most frequent meaning is aspectual atelicity. In addition, it has a number of expressive meanings and connotations: hypocoristic usages; descriptions of children’s games and imitations; and a softening role in imperatives and reprimands. Contrary to the aspectual value of reduplication which is iconically motivated, expressive values are motivated by the pragmatic association of reduplication with children.

Expressive uses of reduplication in Borunge are rarer and less regular than the grammaticalized aspectual uses, which are very frequent. Aspectual reduplication is optional most of the time, so that explaining its actual distribution in discourse is a complicated matter. This article shows that this distribution can often be explained in the view of the expressive values of reduplication (some of them also conveyed by affixal evaluative morphology in the Australian languages that have been replaced by this creole). Thus, taking into account the expressive dimension of reduplication contributes significantly to the linguistic analysis of the grammaticalized aspectual function of reduplication.
Spontaneous single nucleotide polymorphism in porcine microRNA-378 seed region leads to functional alteration
Authors: chai Jie , Chen Lei , Luo Zonggang , Zhang Tinghuan , Chen Li , Lou Pengbo , Sun Wenyang , Long Xi , Lan Jing , Wang Jinyong , Pu Hongzhou , Qiu Jinjie , Shuai Surong , Guo Zongyi
Published: April 2018

Sequence variation in a microRNA (miRNA) seed region can influence its biogenesis and effects on target mRNAs; however, in mammals, few seed region mutations leading to functional alterations have been reported to date. Here, we report the identification of a single nucleotide polymorphism (SNP) with functional consequence located in the seed region of porcine miR-378. In vitro analysis of this rs331295049 A17G SNP showed significantly up-regulated expression of the mature miR-378 (miR-378/G). In silico target prediction indicated that the SNP would modulate secondary structure and result in functional loss affecting >85% of the known target genes of the wild-type miR-378 (miR-378/A), and functional gain affecting >700 new target genes, and dual-luciferase reporter assay verified this result. This report of a SNP in the seed region of miR-378 leads to functional alteration and indicates the potential for substantive functional consequences to the molecular physiology of a mammalian organism.
Novel assay system for acidic Peptide:N-glycanase (aPNGase) activity in crude plant extract
Authors: Uemura Ryota , Ogura Mikako , Matsumaru Chihiro , Akiyama Tsuyoshi , Maeda Megumi , Kimura Yoshinobu
Published: April 2018

Acidic peptide:N-glycanase (aPNGase) plays a pivotal role in plant glycoprotein turnover. For the construction of aPNGase-knockout or -overexpressing plants, a new method to detect the activity in crude plant extracts is required because endogenous peptidases present in the extract hamper enzyme assays using fluorescence-labeled N-glycopeptides as a substrate. In this study, we developed a new method for measuring aPNGase activity in crude extracts from plant materials.
Through the haze: a non-convex approach to blind gain calibration for linear random sensing models
Authors: Cambareri Valerio , Jacques Laurent
Published: April 2018

Computational sensing strategies often suffer from calibration errors in the physical implementation of their ideal sensing models. Such uncertainties are typically addressed by using multiple, accurately chosen training signals to recover the missing information on the sensing model, an approach that can be resource-consuming and cumbersome. Conversely, blind calibration does not employ any training signal, but corresponds to a bilinear inverse problem whose algorithmic solution is an open issue. We here address blind calibration as a non-convex problem for linear random sensing models, in which we aim to recover an unknown signal from its projections on sub-Gaussian random vectors, each subject to an unknown positive multiplicative factor (or gain). To solve this optimization problem we resort to projected gradient descent starting from a suitable, carefully chosen initialization point. An analysis of this algorithm allows us to show that it converges to the exact solution provided a sample complexity requirement is met, i.e., relating convergence to the amount of information collected during the sensing process. Interestingly, we show that this requirement grows linearly (up to log factors) in the number of unknowns of the problem. This sample complexity is found both in absence of prior information, as well as when subspace priors are available for both the signal and gains, allowing a further reduction of the number of observations required for our recovery guarantees to hold. Moreover, in the presence of noise we show how our descent algorithm yields a solution whose accuracy degrades gracefully with the amount of noise affecting the measurements. Finally, we present some numerical experiments in an imaging context, where our algorithm allows for a simple solution to blind calibration of the gains in a sensor array.
Off-diagonal Asymptotic Properties of Bergman Kernels Associated to Analytic Kähler Potentials
Authors: Hezari Hamid , Lu Zhiqin , Xu Hang
Published: April 2018

We prove a new off-diagonal asymptotic of the Bergman kernels associated to tensor powers of a positive line bundle on a compact Kähler manifold. We show that if the Kähler potential is real analytic, then the Bergman kernel accepts a complete asymptotic expansion in a neighborhood of the diagonal of shrinking size $k^{-\frac 14}$. These improve the earlier results in the subject for smooth potentials, where an expansion exists in a $k^{-\frac 12}$ neighborhood of the diagonal. We obtain our results by finding upper bounds of the form $C^m m!^{2}$ for the Bergman coefficients $b_m(x, \bar y)$, which is an interesting problem on its own. We find such upper bounds using the method of [3]. We also show that sharpening these upper bounds would improve the rate of shrinking neighborhoods of the diagonal x = y in our results. In the special case of metrics with local constant holomorphic sectional curvatures, we obtain off-diagonal asymptotic in a fixed (as $k \to \infty$) neighborhood of the diagonal, which recovers a result of Berman [2] (see Remark 3.5 of [2] for higher dimensions). In this case, we also find an explicit formula for the Bergman kernel mod $O(e^{-k \delta } )$.
Abundance of Bacteria, Fungi, and Sclerotinia homoeocarpa in the Thatch and Soil of Golf Courses
Authors: Allan-Perkins Elisha , Manter Daniel , Jung Geunhwa
Published: April 2018

Thatch management in turfgrass has been recommended as part of integrated pest management; however, there is limited understanding of the microbial community in thatch. Previous studies on the turfgrass phytobiome mostly focused on the soil; however, culture-based studies have suggested that the thatch layer of golf courses contains higher bacterial and fungal abundances than the soil. In our study, quantitative PCR was used to investigate total abundance of bacteria, fungi, and the turfgrass pathogen, Sclerotinia homoeocarpa (causal agent of dollar spot) in the thatch and soil of three golf courses on two sampling dates. Additionally, we compared the abundance of these organisms among roughs, fairways, and putting greens, which are under different management intensities. Our results demonstrate bacterial abundance was higher in May than in September, but not consistently higher in the thatch or soil among the three golf courses or management areas. Fungi, and specifically S. homoeocarpa, are more abundant in the thatch than in the soil. These results show the necessity for future turfgrass phytobiome studies to analyze both thatch and soil to obtain a complete picture of bacterial and fungal microbial community structure and dynamics on golf courses. Despite the differences in fungicide usage and management inputs, there were no differences in S. homoeocarpa abundance among the three management areas in the soil. S. homoeocarpa abundance was higher in the thatch on the conventional golf course fairway in September. These results may have important practical implications for development of integrated disease management strategies and for understanding the epidemiology of S. homoeocarpa on golf courses.
Genetic Diversity and Population Structure of Pythium irregulare from Soybean and Corn Production Fields in Ohio
Authors: Huzar-Novakowiski J. , Dorrance A. E.
Published: April 2018

High levels of genetic diversity have been described within the Pythium irregulare complex from several host plants; however, little is known about the population structure in fields used for grain production. Therefore, the objective of this study was to evaluate the genetic diversity and population structure of 53 isolates baited from 28 soybean and corn production fields from 25 counties in Ohio. Genetic diversity was characterized based on sequence analysis of the internal transcribed spacer (ITS1-5.8S-ITS2) region and with 21 simple sequence repeat (SSR) markers. In addition, aggressiveness on soybean, optimum growth temperature, and sensitivity to metalaxyl fungicide were determined. ITS sequence analysis indicated that four isolates clustered with P. cryptoirregulare, whereas the remaining isolates clustered with P. irregulare that was subdivided into two groups (1 and 2). Cluster analysis of SSR data revealed a similar subdivision, which was also supported by structure analysis. The isolates from group 2 grew at a slower rate, but both groups of P. irregulare and P. cryptoirregulare recovered in this study had the same optimum growth at 27°C. Variability of aggressiveness and sensitivity toward metalaxyl fungicide was also observed among isolates within each group. The results from this study will help in the selection of isolates to be used in screening for resistance, assessment of fungicide efficacy, and disease management recommendations.
Functional Interactions Between Major Rice Blast Resistance Genes, Pi-ta and Pi-b, and Minor Blast Resistance Quantitative Trait Loci
Authors: Chen Xinglong , Jia Yulin , Jia Melissa H. , Pinson Shannon R. M. , Wang Xueyan , Wu B. M.
Published: April 2018

Major blast resistance (R) genes confer resistance in a gene-for-gene manner. However, little information is available on interactions between R genes. In this study, interactions between two rice blast R genes, Pi-ta and Pi-b, and other minor blast resistance quantitative trait loci (QTLs) were investigated in a recombinant inbred line (RIL) population comprising 243 RILs from a Cybonnet (CYBT) × Saber (SB) cross. CYBT has the R gene Pi-ta and SB has Pi-b. Ten differential isolates of four Magnaporthe oryzae races (IB-1, IB-17, IB-49, and IE-1K) were used to evaluate disease reactions of the 243 RILs under greenhouse conditions. Five resistance QTLs were mapped on chromosomes 2, 3, 8, 9, and 12 with a linkage map of 179 single nucleotide polymorphism markers. Among them, qBR12 (Q1), was mapped at the Pi-ta locus and accounted for 45.41% of phenotypic variation while qBR2 (Q2) was located at the Pi-b locus and accounted for 24.81% of disease reactions. The additive-by-additive epistatic interaction between Q1 (Pi-ta) and Q2 (Pi-b) was detected; they can enhance the disease resistance by an additive 0.93 using the 0 to 9 standard phenotyping method. These results suggest that Pi-ta interacts synergistically with Pi-b.
Development of mirror coatings for gravitational-wave detectors
Authors: Steinlechner J.
Published: April 2018

Gravitational waves are detected by measuring length changes between mirrors in the arms of kilometre-long Michelson interferometers. Brownian thermal noise arising from thermal vibrations of the mirrors can limit the sensitivity to distance changes between the mirrors, and, therefore, the ability to measure gravitational-wave signals. Thermal noise arising from the highly reflective mirror coatings will limit the sensitivity both of current detectors (when they reach design performance) and of planned future detectors. Therefore, the development of coatings with low thermal noise, which at the same time meet strict optical requirements, is of great importance. This article gives an overview of the current status of coatings and of the different approaches for coating improvement.

This article is part of a discussion meeting issue ‘The promises of gravitational-wave astronomy’.
Placental-expanded, mesenchymal cells improve muscle function following hip arthroplasty
Authors: Winkler Tobias , Perka Carsten , Roth Philipp von , Agres Alison N. , Plage Henning , Preininger Bernd , Pumberger Matthias , Geissler Sven , Hagai Esther Lukasiewicz , Ofir Racheli , Pinzur Lena , Eyal Eli , Stoltenburg-Didinger Gisela , Meisel Christian , Consentius Christine , Streitz Mathias , Reinke Petra , Duda Georg N. , Volk Hans-Dieter
Published: April 2018

Background

No regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite high frequency and associated functional deficits. We sought to address surgical trauma related muscle injuries using local intraoperative application of allogeneic placenta-derived, mesenchymal-like adherent cells (PLX-PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type.

Methods

Our pilot phase I/IIa study was prospective, randomized, double blind and placebo-controlled. Twenty patients undergoing hip arthroplasty via a direct lateral approach were injected with 3.0×108or 1.5×108PLX-PAD or a placebo into the gluteus medius muscle.

Results

We did not observe any relevant PLX-PAD-related adverse events at the 2-year follow-up. Improved gluteus medius strength was noted as early as week 6 in the treatment-groups. Surprisingly, until week 26 the low-dose outperformed the high-dose group and reached significantly improved strength compared to placebo, mirrored by an increase in muscle volume. Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that low-dose treatment reduced the surgery-related immunological stress reaction more than high-dose. Signs of late-onset immune reactivity after high-dose treatment corresponded to reduced functional improvement.

Conclusion

Allogeneic PLX-PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress-related immunological reactions.

Trial Registration

ClinicalTrials.gov(numberNCT01525667) and EudraCT (number 2011-003934-16)

Funding

The study was funded by the Sponsor, Pluristem Therapeutics, the Israeli innovation authority and the German Federal Ministry of Education and Research.

Conflict of interest

T. Winkler, C. Perka and G.N. Duda are members of a clinical advisory board of Pluristem Ltd for future indications. T. Winkler, C. Perka, G.N. Duda, P. von Roth filed a patent together with Pluristem Ltd. E. Lukasiewicz Hagai, R. Ofir, L. Pinzur and E. Eyal are current or former employees of Pluristem Ltd. T. Winkler, P. Reinke and H.-D. Volk received in the past consulting fees from Pluristem Ltd. but not for this project.
Mendelian randomisation analysis of the effect of educational attainment and cognitive ability on smoking behaviour
Authors: Sanderson Eleanor , Smith George Davey , Bowden Jack , Munafò Marcus R.
Published: April 2018

Recent analyses have shown educational attainment to be associated with a number of health outcomes. This association may, in part, be due to an effect of educational attainment on smoking behaviour. In this study we apply a multivariable Mendelian randomisation design to determine whether the effect of educational attainment on smoking behaviour could be due to educational attainment or general cognitive ability. We use individual data from the UK Biobank study (N = 120,050) and summary data from large GWAS studies of educational attainment, cognitive ability and smoking behaviour. Our results show that more years of education are associated with a reduced likelihood of smoking which is not due to an effect of general cognitive ability on smoking behaviour. Given the considerable physical harms associated with smoking, the effect of educational attainment on smoking is likely to contribute to the health inequalities associated with differences in educational attainment.
The effect of body mass index on smoking behaviour and nicotine metabolism: a Mendelian randomization study
Authors: Taylor Amy E. , Richmond Rebecca C. , Palviainen Teemu , Loukola Anu , Kaprio Jaakko , Relton Caroline , Smith George Davey , Munafò Marcus R.
Published: April 2018

Background

Given clear evidence that smoking lowers weight, it is possible that individuals with higher body mass index (BMI) smoke in order to lose or maintain their weight.

Methods and Findings

We undertook Mendelian randomization analyses using 97 genetic variants associated with BMI. We performed two sample Mendelian randomization analyses of the effects of BMI on smoking behaviour in UK Biobank (N=335,921) and the Tobacco and Genetics consortium genomewide association study (GWAS) (N≤74,035) respectively, and two sample Mendelian randomization analyses of the effects of BMI on cotinine levels (N≤4,548) and nicotine metabolite ratio (N≤1,518) in published GWAS, and smoking-related DNA methylation in the Avon Longitudinal Study of Parents and Children (N≤846).

In inverse variance weighted Mendelian randomization analysis, there was evidence that higher BMI was causally associated with smoking initiation (OR for ever vs never smoking per one SD increase in BMI: 1.19, 95% CI: 1.11 to 1.27) and smoking heaviness (1.45 additional cigarettes smoked per day per SD increase in BMI, 95% CI: 1.03 to 1.86), but little evidence for a causal effect with smoking cessation. Results were broadly similar using pleiotropy robust methods (MR-Egger, median and weighted mode regression). These results were supported by evidence for a causal effect of BMI on DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus. There was no strong evidence that BMI was causally associated with cotinine, but suggestive evidence for a causal negative association with the nicotine metabolite ratio.

Conclusions

There is a causal bidirectional association between BMI and smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism. It may be useful to consider BMI
and smoking together when designing prevention strategies to minimise the effects of these risk factors on health outcomes.
Genomic and epidemiological monitoring of yellow fever virus transmission potential
Authors: N. R. Faria , M. U. G. Kraemer , S. C. Hill , J. Goes de Jesus , R. S. de Aguiar , F. C. M. Iani , J. Xavier , J. Quick , L. du Plessis , S. Dellicour , J. Thézé , R. D. O. Carvalho , G. Baele , C.-H. Wu , P. P. Silveira , M. B. Arruda , M. A. Pereira , G. C. Pereira , J. Lourenço , U. Obolski , L. Abade , T. I. Vasylyeva , M. Giovanetti , D. Yi , D.J. Weiss , G. R. W. Wint , F. M. Shearer , S. Funk , B. Nikolai , T. E. R. Adelino , M. A. A. Oliveira , M. V. F. Silva , L. Sacchetto , P. O. Figueiredo , I. M. Rezende , E. M. Mello , R. F. C. Said , D. A. Santos , M. L. Ferraz , M. G. Brito , L. F. Santana , M. T. Menezes , R. M. Brindeiro , A. Tanuri , F. C. P. dos Santos , M. S. Cunha , J. S. Nogueira , M. Rocco I. , A. C. da Costa , S. C. V. Komninakis , V. Azevedo , A. O. Chieppe , E. S. M. Araujo , M. C. L. Mendonça , C. C. dos Santos , C. D. dos Santos , A. M. Mares-Guia , R. M. R. Nogueira , P. C. Sequeira , R. G. Abreu , M. H. O. Garcia , R. V. Alves , A. L. Abreu , O. Okumoto , E. G. Kroon , C. F. C. de Albuquerque , K. Lewandowski , S. T. Pullan , M. Carroll , E. C. Sabino , R. P. Souza , M. A. Suchard , P. Lemey , G. S. Trindade , B. P. Drumond , A. M. B. Filippis , N. J. Loman , S. Cauchemez , L. C. J. Alcantara , O. G. Pybus
Published: April 2018

The yellow fever virus (YFV) epidemic that began in Dec 2016 in Brazil is the largest in decades. The recent discovery of YFV in BrazilianAedes sp.vectors highlights the urgent need to monitor the risk of re-establishment of domestic YFV transmission in the Americas. We use a suite of epidemiological, spatial and genomic approaches to characterize YFV transmission. We show that the age- and sex-distribution of human cases in Brazil is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally using a new protocol reveals an early phase of sylvatic YFV transmission restricted to Minas Gerais, followed in late 2016 by a rise in viral spillover to humans, and the southwards spatial expansion of the epidemic towards previously YFV-free areas. Our results establish a framework for monitoring YFV transmission in real-time, contributing to the global strategy of eliminating future yellow fever epidemics.
Identification of 12 genetic loci associated with human healthspan
Authors: Zenin Aleksandr , Tsepilov Yakov , Sharapov Sodbo , Getmantsev Evgeny , Menshikov L. I. , Fedichev Peter O. , Aulchenko Yurii
Published: April 2018

The mounting challenge of preserving the quality of life in an aging population directs the focus of longevity science to the regulatory pathways controlling healthspan. To understand the nature of the relationship between the healthspan and lifespan and uncover the genetic architecture of the two phenotypes, we studied the incidence of major age-related diseases in the UK Biobank (UKB) cohort. We observed that the incidence rates of major chronic diseases increase exponentially. The risk of disease acquisition doubled approximately every eight years, i.e., at a rate compatible with the doubling time of the Gompertz mortality law. Assuming that aging is the single underlying factor behind the morbidity rates dynamics, we built a proportional hazards model to predict the risks of the diseases and therefore the age corresponding to the end of healthspan of an individual depending on their age, gender, and the genetic background. We suggested a computationally efficient procedure for the determination of the effect size and statistical significance of individual gene variants associations with healthspan in a form suitable for a Genome-Wide Association Studies (GWAS). Using the UKB sub-population of 300,447 genetically Caucasian, British individuals as a discovery cohort, we identified 12 loci associated with healthspan and reaching the whole-genome level of significance. We observed strong (|ρg| > 0.3) genetic correlations between healthspan and the incidence of specific age-related disease present in our healthspan definition (with the notable exception of dementia). Other examples included all-cause mortality (as derived from parental survival, with ρg = −0.76), life-history traits (metrics of obesity, age at first birth), levels of different metabolites (lipids, amino acids, glycemic traits), and psychological traits (smoking behaviour, cognitive performance, depressive symptoms, insomnia). We conclude by noting that the healthspan phenotype, suggested and characterized here, offers a promising new way to investigate human longevity by exploiting the data from genetic and clinical data on living individuals.
Community origins and regional differences highlight risk of plasmid-mediated fluoroquinolone resistant Enterobacteriaceae infections in children
Authors: Logan Latania K. , Medernach Rachel L. , Rispens Jared R. , Marshall Steven H. , Hujer Andrea M. , Domitrovic T. Nicholas , Rudin Susan D. , Zheng Xiaotian , Qureshi Nadia K. , Konda Sreenivas , Hayden Mary K. , Weinstein Robert A. , Bonomo Robert A.
Published: April 2018

Background:

Fluoroquinolones (FQs) are uncommonly prescribed in children, yet pediatric multidrug-resistant (MDR)-Enterobacteriaceae (Ent) infections often reveal FQ resistance (FQR). We sought to define the molecular epidemiology of FQR and MDR-Ent in children.

Methods:

A case-control analysis of children with MDR-Ent infections at 3 Chicago hospitals was performed. Cases were children with third-generation-cephalosporin-resistant (3GCR) and/or carbapenem-resistant (CR)-Ent infections. PCR and DNA analysis assessed bla and plasmid-mediated FQR (PMFQR) genes. Controls were children with 3GC and carbapenem susceptible-Ent infections matched by age, source and hospital. We assessed clinical-epidemiologic predictors of PMFQR Ent infection.

Results:

Of 169 3GCR and/or CR Ent isolates from children (median age 4.8 years), 85 were FQR; 56 (66%) contained PMFQR genes. The predominant organism was E. coli and most common bla gene blaCTX-M-1 group. In FQR isolates, PMFQR gene mutations included aac6’1b-cr, oqxA/B, qepA, and qnrA/B/D/S in 83%, 15%, 13% and 11% of isolates, respectively. FQR E. coli was often associated with phylogroup B2, ST43/ST131. On multivariable analysis, PMFQR Ent infections occurred mostly in outpatients (OR 33.1) of non-black-white-Hispanic race (OR 6.5). Residents of Southwest Chicago were >5 times more likely to have PMFQR-Ent infections than those in the reference region, while residence in Central Chicago was associated with a 97% decreased risk. Other demographic, comorbidity, invasive-device, antibiotic use, or healthcare differences were not found.

Conclusions:

The strong association of infection with MDROs showing FQR with patient residence rather than with traditional risk factors suggests that the community environment is a major contributor to spread of these pathogens in children.
Tuning site-specific dynamics to drive allosteric activation in a pneumococcal zinc uptake regulator
Authors: Capdevila Daiana A. , Huerta Fidel , Edmonds Katherine A. , Le My T. , Wu Hongwei , Giedroc David P.
Published: April 2018

MarR (multiple antibiotic resistance repressor) family proteins are bacterial repressors that regulate transcription in response to a wide range of chemical signals. Although specific features of MarR family function have been described, the role of atomic motions in MarRs remains unexplored thus limiting insights into the evolution of allostery in this ubiquitous family of repressors. Here, we provide the first experimental evidence that internal dynamics play a crucial functional role in MarR proteins. Streptococcus pneumoniae AdcR (adhesin-competence repressor) regulates ZnIIhomeostasis and ZnIIfunctions as an allosteric activator of DNA binding. ZnIIcoordination triggers a transition from independent domains to a more compact structure. We identify residues that impact allosteric activation on the basis of ZnII-induced perturbations of atomic motions over a wide range of timescales. These findings reconcile the distinct allosteric mechanisms proposed for other MarRs and highlight the importance of conformational dynamics in biological regulation.
Charge fluctuation effects on the shape of flexible polyampholytes with applications to Intrinsically disordered proteins
Authors: Samanta Himadri S. , Chakraborty Debayan , Thirumalai D.
Published: April 2018

Random polyampholytes (PAs) contain positively and negatively charged monomers that are distributed randomly along the polymer chain. The interaction between charges is assumed to be given by the Debye-Huckel potential. We show that the size of the PA is determined by an interplay between electrostatic interactions, giving rise to the polyelectrolyte (PE) effect due to net charge per monomer (σ), and an effective attractive PA interaction due to charge fluctuations, δσ. The interplay between these terms gives rise to non-monotonic dependence of the radius of gyration, Rg on the inverse Debye length, κ when PA effects are important . In the opposite limit, Rg decreases monotonically with increasing κ. Simulations of PA chains, using a charged bead-spring model, further corroborates our theoretical predictions. The simulations unambiguously show that conformational heterogeneity manifests itself among sequences that have identical PA parameters. A clear implication is that the phases of PA sequences, and by inference IDPs, cannot be determined using only the bare PA parameters (σ and δσ).The theory is used to calculate the changes in Rg on N, the number of residues for a set of Intrinsically Disordered Proteins (IDPs). For a certain class of IDPs, with N between 24 to 441, the size grows as Rg ~ N0.6, which agrees with data from Small Angle X-ray Scattering (SAXS) experiments.
Routine Determination of Ice Thickness for Cryo-EM Grids
Authors: Rice William J. , Cheng Anchi , Noble Alex J. , Eng Edward T. , Kim Laura Y. , Carragher Bridget , Potter Clinton S.
Published: April 2018

Recent advances in instrumentation and automation have made cryo-EM a popular method for producing near-atomic resolution structures of a variety of proteins and complexes. Sample preparation is still a limiting factor in collecting high quality data. Thickness of the vitreous ice in which the particles are embedded is one of the many variables that need to be optimized for collection of the highest quality data. Here we present two methods, using either an energy filter or scattering outside the objective aperture, to measure ice thickness for potentially every image collected. Unlike geometrical or tomographic methods, these can be implemented directly in the single particle collection workflow without interrupting or significantly slowing down data collection. We describe the methods as implemented into the Leginon/Appion data collection workflow, along with some examples from test cases. Routine monitoring of ice thickness should prove helpful for optimizing sample preparation, data collection, and data processing.
The evolutionary traceability of proteins
Authors: Jain Arpit , von Haeseler Arndt , Ebersberger Ingo
Published: April 2018

Orthologs document the evolution of genes and metabolic capacities encoded in extant and ancient genomes. Orthologous genes that are detected across the full diversity of contemporary life allow reconstructing the gene set of LUCA, the last universal common ancestor. These genes presumably represent the functional repertoire common to – and necessary for – all living organisms. Design of artificial life has the potential to test this. Recently, a minimal gene (MG) set for a self-replicating cell was determined experimentally, and a surprisingly high number of genes have unknown functions and are not represented in LUCA. However, as similarity between orthologs decays with time, it becomes insufficient to infer common ancestry, leaving ancient gene set reconstructions incomplete and distorted to an unknown extent. Here we introduce theevolutionary traceability, together with the softwareprotTrace, that quantifies, for each protein, the evolutionary distance beyond which the sensitivity of the ortholog search becomes limiting. We show that the LUCA set comprises only high-traceable proteins most of which have catalytic functions. We further show that proteins in the MG set lacking orthologs outside bacteria mostly have low traceability, leaving open whether their eukaryotic orthologs have just been overlooked. On the example of REC8, a protein essential for chromosome cohesion, we demonstrate how a traceability-informed adjustment of the search sensitivity identifies hitherto missed orthologs in the fast-evolving microsporidia. Taken together, the evolutionary traceability helps to differentiate between true absence and non-detection of orthologs, and thus improves our understanding about the evolutionary conservation of functional protein networks.
Phenomic selection: a low-cost and high-throughput method based on indirect predictions. Proof of concept on wheat and poplar
Authors: Rincent Renaud , Charpentier Jean-Paul , Faivre-Rampant Patricia , Paux Etienne , Gouis Jacques Le , Bastien Catherine , Segura Vincent
Published: April 2018

Genomic selection - the prediction of breeding values using DNA polymorphisms - is a disruptive method that has widely been adopted by animal and plant breeders to increase productivity. It was recently shown that other sources of molecular variations such as those resulting from transcripts or metabolites could be used to accurately predict complex traits. These endophenotypes have the advantage of capturing the expressed genotypes and consequently the complex regulatory networks that occur in the different layers between the genome and the phenotype. However, obtaining such omics data at very large scales, such as those typically experienced in breeding, remains challenging. As an alternative, we proposed using near-infrared spectroscopy (NIRS) as a high-throughput, low cost and non-destructive tool to indirectly capture endophenotypic variants and compute relationship matrices for predicting complex traits and coined this new approach “phenomic selection” (PS). We tested PS on two species of economic interest (Triticum aestivum L. and Populus nigra L.) using NIRS on various tissues (grains, leaves, wood). We showed that one could reach predictions as accurate as with molecular markers, for developmental, tolerance and productivity traits, even in environments radically different from the one in which NIRS were collected. Our work constitutes a proof of concept and provides new perspectives for the breeding community, as PS is theoretically applicable to any organism at low cost and does not require any molecular information.

ARTICLE SUMMARY

Despite its widely adopted interest in breeding, genomic selection - the prediction of breeding values using DNA polymorphisms - remains difficult to implement for many species because of genotyping costs. As an alternative or complement depending on the context, we propose “phenomic selection” (PS) as the use of low-cost and high-throughput phenotypic records to reconstruct similarities between genotypes and predict their performances. As a proof of concept of PS, we made use of near infrared spectroscopy applied to different tissues in poplar and wheat to predict various key traits and showed that PS could reach predictions as accurate as with molecular markers.
DNA local structure decreases mutation rates
Authors: Duan Chaorui , Huan Qing , Chen Xiaoshu , Wu Shaohuan , Carey Lucas B. , He Xionglei , Qian Wenfeng
Published: April 2018

Background

Mutation rates vary across the genome. Whereas manytransfactors that influence mutation rates have been identified, as have specific sequence motifs at the 1-7 bp scale,ciselements remain poorly characterized. The lack of understanding why different sequences have different mutation rates hampers our ability to identify positive selection in evolution and to identify driver mutations in tumorigenesis.

Results

Here we show, using a combination of synthetic genes and sequencing of thousands of isolated yeast colonies, that intrinsic DNA curvature is the majorcisdeterminant of mutation rate. Mutation rate negatively correlates with DNA curvature within genes, and a 10% decrease in curvature results in a 70% increase in mutation rate. Consistently, both yeast cells and human tumors accumulate mutations in regions with small curvature. We further show that this effect is due to differences in the intrinsic mutation rate, likely due to differences in mutagen sensitivity, and not due to differences in the local activity of DNA repair.

Conclusions

Our study establishes a framework in understanding thecisproperties of DNA sequence in modulating the local mutation rate and identifies a novel causal source of non-uniform mutation rates across the genome.
Pupil responses as indicators of value-based decision-making
Authors: Van Slooten Joanne C. , Jahfari Sara , Knapen Tomas , Theeuwes Jan
Published: April 2018

Pupil responses have been used to track cognitive processes during decision-making. Studies have shown that in these cases the pupil reflects the joint activation of many cortical and subcortical brain regions, also those traditionally implicated in value-based learning. However, how the pupil tracks value-based decisions and reinforcement learning is unknown. We combined a reinforcement learning task with a computational model to study pupil responses during value-based decisions, and decision evaluations. We found that the pupil closely tracks reinforcement learning both across trials and participants. Prior to choice, the pupil dilated as a function of trial-by-trial fluctuations in value beliefs. After feedback, early dilation scaled with value uncertainty, whereas later constriction scaled with reward prediction errors. Our computational approach systematically implicates the pupil in value-based decisions, and the subsequent processing of violated value beliefs, ttese dissociable influences provide an exciting possibility to non-invasively study ongoing reinforcement learning in the pupil.