bluuebunny/crossref_metadata_2025 huggingface dataset:
The Common European Framework of Reference (CEFR) in French immersion teacher education
Authors: Arnott Stephanie , Vignola Marie-Josée
Published: October 2018

Over 11% of Canadian students are currently enrolled in French immersion (FI) – a program where French is a subject of study and is
the language of instruction in at least two content areas. Research shows that stakeholders in FI initial teacher education (ITE)
programs identify French language proficiency development as an area of high priority; however, Canadian ITE programs do not
typically provide linguistic support. This article reports on an adaptation and implementation of the Common European
Framework of Reference (CEFR) (specifically, the European Language Portfolio [ELP]) as part of a
remedial 24-week French writing course in an FSL ITE program focused on developing French proficiency. Student-teachers
(n = 25) and the course instructor identified strengths and challenges associated with this initiative via
surveys and interviews. Findings show participant convergence and divergence on the portfolio experience, raising implications for
decision-making related to its use in ITE programs targeting FI teachers.
Becoming a “language-aware” content
teacher
Authors: He Peichang , Lin Angel M. Y.
Published: October 2018

Building on and extending the frameworks of Teacher Language Awareness (TLA) in
second/foreign language education and content-based/CLIL education (Andrews, 2007; Lindahl & Watkins, 2015; Andrews & Lin, 2017), this paper argues that
effective teaching of academic content in an L2 requires a special kind of
teacher knowledge that goes beyond simple addition of content knowledge and
Knowledge About Language (KAL). Through an ethnographic case study, the
researchers investigated the development of a science teacher’s TLA and teacher
identity through her participation in a school-university collaborative project.
Based on analysis of data from classroom observations, interviews, and lesson
video stimulated commentaries, the researchers have developed a model focusing
on CLIL teacher professional development as a collaborative, dynamic and
dialogic process, where both teachers and teacher educators (TEs) are
co-developing their knowledge and expertise in CLIL.
Teacher perceptions of immersion professional development experiences emphasizing language-focused content
instruction
Authors: Tedick Diane J. , Zilmer Caleb
Published: October 2018

The knowledge and pedagogies needed for immersion classrooms are unique and complex. Although there is a growing body of research
on immersion pedagogy, there is a dearth of research on professional development (PD) experiences that positively impact immersion
teacher practices. This paper focuses on exploring immersion teacher perceptions of PD experiences in the area of language-focused
content instruction that have a positive impact on their teaching. The theoretical framework guiding the study is “communities of
practice” (CoP) (Wenger, 1998), and survey and focus group data were analyzed in
relation to Wenger’s four realms of CoP (community, practice, meaning, and identity). Findings revealed specific features of high
impact assignments and PD experiences. The paper concludes with implications for designing meaningful and effective PD experiences
for immersion educators and others who teach in CBI settings.
From polarity focus to salient polarity
Authors: Matić Dejan , Nikolaeva Irina
Published: October 2018

The paper provides arguments against the denotational approach to polarity focus (also known as Verum), which treats it as a distinct denotation contributed by the dedicated grammatical structures. It shows that the purported category of polarity focus is routinely defined on the basis of faulty analytical procedures, reification of inferential interpretations and suppression of variation. As a result, this approach cannot account for the full range of usages of those grammatical structures that are standardly assumed to instantiate polarity focus. As an alternative to the denotational accounts, the paper proposes an interpretational approach that disposes of the idea of a discrete denotation defining a linguistic category. To emphasize the difference between these two understandings of linguistic meaning, the term salient polarity is introduced. Salient polarity is understood as an interpretive effect stemming from the speaker’s intention to draw the hearer’s attention to the truth value of the proposition. This interpretive effect comes about through different inferential mechanisms and for various communicative reasons, and can be derived from completely unrelated denotations. Thus, salient polarity is not a traditional linguistic category if the latter is defined based on the correspondence between a linguistic form and a denotation, but is rather to be conceived of as a fuzzy set of family resemblances unified by shared communicative intentions.
Biased declarative questions in Swedish and German
Authors: Seeliger Heiko , Repp Sophie
Published: October 2018

This paper investigates a class of biased questions with declarative syntax in Swedish and German that differ in their bias from the familiar class of declarative questions: rejecting questions (RQs), which may occur with or without negation. We provide a semantic-pragmatic analysis of RQs and show for negative RQs that the negation is non-propositional. We analyze the non-propositional negation as the speech-act modifying operator falsum (Repp 2009a, 2013). In both languages, falsum interacts with modal particles whose meanings relate to contrast and the epistemic state of the speaker. We propose that the illocutionary operator in RQs is rejectq, which is an operator that comes with presuppositions that are the source of the particular bias of RQs.
Denominal verbs with metaphorical meanings in British business media discourse
Authors: Smirnova Elizaveta , Shustova Svetlana
Published: October 2018

This study is a corpus-based examination of denominal verbs with figurative meanings in the British business broadsheet The “Financial Times”. Based on the study of word-formation as the source of metaphoricity (Brdar & Brdar-Szabó, 2013;Janda, 2011,2014;Steen et al., 2010) and propositional analysis (Pankrats, 1992;Steen, 2002), it presents the classification of such verbs, and discusses how and why denominal verbs with metaphorical meanings were used in the journalistic discourse about business. The empirical base of this study was a 621,000 word corpus of articles from The “Financial Times” from the years 2014–2015. The authors conclude that the frequency of denominal verbs is due to the conceptual and evaluative functions of metaphor. There is consideration of the implications of these findings for linguists, translators, ESP students and those interested in corpus research into metaphor.
‘From above’, ‘from below’, and regionally balanced
Authors: Niehaus Konstantin , Elspass Stephan
Published: October 2018

In this chapter, we report on an ongoing project on a corpus of German in the long nineteenth century. Similar to other
historical corpora of German (and unlike existing corpora for the nineteenth century), the Nineteenth-Century German Corpus will focus on regional variation. In addition, it will account for an
increasing demand for register variation, e.g. by considering formal as well as informal ‘oral’ texts. Thus, text
genres ‘from above’, such as regional newspaper texts, and ‘from below’, such as private letters, are incorporated.
Three case studies of variation in nineteenth-century grammar will demonstrate the benefits of such a corpus design
for the study of language continuity and language change.
“You can’t control a thing like that”
Authors: Haas Florian
Published: October 2018

While there is ample evidence showing that the impersonal use of second-person singular pronouns has increased in
several languages, the recent history of impersonal you in English has not yet received
much attention in the literature. The present investigation presents corpus evidence from Modern English indicating
that this strategy has indeed gained in frequency, independently of changes in the general frequency of second-person
pronouns and the evolution of genres. Tracing specific functions of impersonal you
diachronically reveals that you simulating the hearer’s membership in the set
generalized over and encoding hidden self-reference are relatively new uses, supporting the view that this impersonal
strategy has undergone semantic extensions comparable to developments found in other languages.
Genre influence on word formation (change)
Authors: Kempf Luise
Published: October 2018

Building on Kempf (2016), this paper analyzes genre influence on
adjectival derivation in the history of German. The approach is empirical, based on data from two corpora of
historical German (1350–1800 ). Quantitative measures of word-formation productivity reveal substantial differences
between sermons, narrative prose, scientific texts, and newspapers. A long-term diachronic comparison highlights
considerable changes in suffix distribution. Against this backdrop, the four genres are assessed as progressive or
conservative. An analysis of the syntactic use of derived adjectives reveals stronger or weaker tendencies to condense
information within noun phrases. This reflects differing affinities to oral or written language, as does the differing
use of endophoric vs. exophoric reference (obig ‘the above’ vs. gestrig ‘of yesterday’). Overall, genre greatly impacts word-formation and conversely, word-formation
contributes to genre variation.
A Color Inference Framework
Authors: Schloss Karen B.
Published: October 2018

As people interact with the world, they form associations between colors and concepts. These color-concept associations are dynamic: they continually update with new experiences, and they vary in relevance depending on contextual cues. In this chapter, I present the Color Inference Framework, a functional system, to describe how people form conceptual inferences from color information (color inferences) and how those inferences influence people’s judgements about the world. Within the Color Inference Framework, I define three kinds of cognitive operations – pooling, transmitting, and assigning – that act on the same mental representation (color-concept association network) to produce different kinds of evaluative and interpretive judgements. I also discuss empirical evidence in support of the Color Inference Framework.
Cross-modal associations involving colour and touch
Authors: Jraissati Yasmina , Wright Oliver
Published: October 2018

Cross-modal associations involve non-arbitrary correspondences between different perceptual modalities. Investigating such associations can provide insights into the mechanisms underlying multisensory integration. This chapter provides an overview of research investigating associations between colour and touch. Studies have shown that associations exist between most tactile/haptic sensations and colour. For sensations of weight, hardness and roughness associations with colour appear driven by lightness/brightness. Saturation also appears to play a role in associations involving some haptic/tactile sensations, though results are somewhat inconsistent across studies. Whilst hue is clearly associated with temperature, its role in associations involving other haptic/tactile sensations is less established. At the end of the chapter, suggestions are made regarding future research in the domain.
Is it all guesswork?
Authors: Biggam Carole P.
Published: October 2018

Addressed to non-semanticists, this article discusses the means by which colour semanticists strive to pursue their research with as much objectivity as possible. Three functions of colour terms are presented: descriptive, classificatory and connotative, showing that colour expressions operate differently in various semantic environments. In addition, lexical meanings can change over the years, as a result, for example, of semantic shift or contact with other languages, and this is likely to render inappropriate the application of modern colour-term definitions to their historical antecedents. Finally, a connotative case-study of hair-colour descriptors in English across the centuries reveals that words operating in restricted contexts can convey more than colour.
ColCat
Authors: Jameson Kimberly A.
Published: October 2018

The ColCat Wiki (http://colcat.calit2.uci.edu/) is a multidisciplinary research platform featuring a new corpus of color categorization survey data from a variety of languages and language dialects. The Wiki’s contents can be examined, searched, downloaded and extended through non-commercial scientific investigations of human color categorization behaviors across ethnolinguistic groups. Launched in 2016 to make available unpublished raw data from Robert E. MacLaury’s color categorization archive, the ColCat database and its Wiki interface continues to grow and evolve as a public-access teaching and research platform for collaborative scientific investigations on color categorization behaviors. The ultimate aim of the ColCat Wiki is to serve as a repository of color categorization data and a collaborative workspace. This article summarizes properties of the wiki and its data, including database features that permit novel empirical research in the domain of global color categorization.
A theory of visual stress and its application to the use of coloured filters for reading
Authors: Wilkins Arnold
Published: October 2018

Coloured filters have been used, controversially, to reduce the perceptual distortions and discomfort sometimes associated with difficulty reading. It has been claimed that the filters can improve reading fluency. A neurological theory of visual stress is offered that attempts to examine perceptual distortions of text and the discomfort it evokes in relation to the way in the visual system evolved to process natural images. There are many possible interactions between colour and spatial processing, some involving the temporal modulation of electric lighting, and others the close relationship between colour contrast and the cortical haemodynamic response. It is argued that coloured filters can sometimes reduce the effects of strong visual stimulation when the visual cortex is hyperexcitable.
Fit & Strong! Plus Trial Outcomes for Obese Older Adults with Osteoarthritis
Authors: Hughes Susan L , Tussing-Humphreys Lisa , Schiffer Linda , Smith-Ray Renae , Marquez David X , DeMott Andrew D , Berbaum Michael L , Fitzgibbon Marian L
Published: October 2018

Background and Objectives

We compared the effectiveness of standard Fit & Strong! (F&S!; targets physical activity [PA]) to Fit & Strong! Plus (F&S! Plus; targets PA and dietary weight loss) on weight, diet quality, and PA outcomes.

Research Design and Methods

We randomly assigned 413 overweight older adults with OA to the F&S! or F&S! Plus programs and assessed outcomes at 2 and 6 months.

Results

The F&S! Plus group lost −2.0 ± 0.2 kg (mean ± SE, 2% of starting weight) at 2 months that was maintained at 6 months. Two- and 6-month BMI and waist circumference improved significantly in the F&S! Plus group (p < .001). Diet quality at 2 months showed greater improvement in the F&S! Plus group: 4.6 ± 0.7 versus 2.0 ± 0.7, p = .006, with no significant difference between groups at 6 months. The F&S! Plus group differentially improved on PA engagement at 2 months and at 2 and 6 months in joint pain (6-month mean ± SE: −1.5 ± 0.3 vs −0.6 ± 0.3, p = .02), function (−4.7 ± 0.9 vs −1.5 ± 0.9, p = .01), and 6-min walk test (29.5 ± 5.1 m vs 14.1 ± 5.2 m, p = .04).

Discussion and Implications

Adding a dietary weight loss component to F&S! achieved weight and waist circumference benefits that were maintained at 6 months. Importantly, the weight loss was accompanied by clinically meaningful improvements in OA symptoms and mobility. Future work should investigate minimum thresholds for weight reduction that improve long-term function in this population.
An Effector, BxSapB1, Induces Cell Death and Contributes to Virulence in the Pine Wood Nematode Bursaphelenchus xylophilus
Authors: Hu Long-Jiao , Wu Xiao-Qin , Li Hai-Yang , Zhao Qun , Wang Yuan-Chao , Ye Jian-Ren
Published: October 2018

The pine wood nematode (PWN) Bursaphelenchus xylophilus has caused serious damage to pine forests in China. Effectors secreted by phytonematodes play a role in host infection. We identified and characterized an effector, BxSapB1, based on the B. xylophilus transcriptome at the early stages of infection and the transient expression of proteins in Nicotiana benthamiana. BxSapB1 triggered cell death in N. benthamiana when secreted into the apoplast, and this effect was independent of N. benthamiana brassinosteroid-insensitive 1–associated kinase 1 (NbBAK1) and suppressor of BIR1-1 (NbSOBIR1). The signal peptide of BxSapB1 was proven to be functional in yeast using the yeast signal sequence trap system and BxSapB1 was strongly expressed in the subventral gland cells of B. xylophilus, as revealed by in-situ hybridization. In addition, based on local BLAST analysis, the BxSapB1 showed 100% identity to BUX.s00139.62, which was identified from the B. xylophilus secretome during Pinus thunbergii infection. BxSapB1 was upregulated in a highly virulent strain and downregulated in a weakly virulent strain of PWN at the early stages of infection. RNA interference assays showed that silencing BxSapB1 resulted in decreased expression of pathogenesis-related genes (PtPR-1b, PtPR-3, and PtPR-5) as well as delayed onset of symptoms in P. thunbergii infected by B. xylophilus. The combined data suggest that BxSapB1 can trigger cell death in N. benthamiana and that it contributes to the virulence in B. xylophilus during parasitic interaction.
Tunneled Pleural Catheters for Patients With Chronic Pleural Infection and Nonexpandable Lung
Authors: Majid Adnan , de Lima Andres , Parikh Mihir , Chee Alex , Fernandez-Bussy Sebastian , Kheir Fayez
Published: October 2018

Chronic pleural infection is characterized by thickened pleura and nonexpandable lung often requiring definitive surgical intervention, such as decortication and/or pleural obliteration procedures. Such procedures are associated with significant morbidity and require proper patient selection for a successful outcome. We report a cohort of 11 patients with pleural space infection and a nonexpandable lung treated with tunneled pleural catheters (TPCs). Following placement, hospital discharge and TPC removal occurred after a median of 5 and 36 days, respectively. Three patients presented with residual loculated effusion that resolved with instillation of intrapleural fibrinolytic therapy. One patient eventually required open window thoracostomy for ongoing pleural infection due to poor medical compliance with TPC care and drainage instructions. TPCs represent an alternative option for drainage of an infected pleural space in nonsurgical candidates with a nonexpandable lung. Their use, as a compliment to traditional treatment, may facilitate prompt hospital discharge and ambulatory management in patients with limited life expectancy.
The “Minimum Clinically Important Difference” in Frequently Reported Objective Physical Function Tests After a 12-Week Renal Rehabilitation Exercise Intervention in Nondialysis Chronic Kidney Disease
Authors: Wilkinson Thomas J. , Watson Emma L. , Xenophontos Soteris , Gould Douglas W. , Smith Alice C.
Published: October 2018

Objective

Chronic kidney disease patients are characterized by impaired physical function. The goal of exercise-based interventions is an improvement in functional performance. However, improvements are often determined by “statistically significant” changes. We investigated the “minimum clinically important difference,” “the smallest change that is important to the patient,” for commonly reported physical function tests.

Design

Nondialysis chronic kidney disease patients completed 12-wks of a combined aerobic (plus resistance training). The incremental shuttle walking test, sit-to-stand 5 and 60, estimated 1-repetition maximum for the knee extensors, and VO2peak were assessed. After the intervention, patients rated their perceived change in health. Both anchor- and distribution-based minimum clinically important difference approaches were calculated.

Results

The minimum clinically important difference was calculated as follows: incremental shuttle walking test, +45 m; sit-to-stand 5, −4.2 secs; VO2peak, +1.5 ml/kg per min. Because of comparable increases in “anchor” groups, no minimum clinically important difference was estimated for the sit-to-stand 60 or estimated 1-repetition maximum.

Conclusions

We have established the minimum clinically important difference in chronic kidney disease for common tests of physical function. These values represent the minimum change required for patients to perceive noticeable and beneficial change to their health. These scores will help interpret changes after exercise interventions where these tests are used. These minimum clinically important differences can be used to power future studies to detect clinically important changes.

To Claim CME Credits

Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME

CME Objectives

Upon completion of this article, the reader should be able to: (1) Define the “minimum clinically important difference”; (2) Distinguish between concepts of minimum clinically important difference, “minimal detectable change,”, and “statistically significant change”; and (3) Interpret other study findings and their own results in the context of the minimum clinically important difference rather than statistically significant changes.

Level

Advanced

Accreditation

The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Distinct mesoderm migration phenotypes in extra-embryonic and embryonic regions of the early mouse embryo
Authors: Saykali Bechara , Mathiah Navrita , Nahaboo Wallis , Racu Marie-Lucie , Defrance Matthieu , Migeotte Isabelle
Published: October 2018

In the gastrulating mouse embryo, epiblast cells delaminate at the primitive streak to form mesoderm and definitive endoderm, through an epithelial-mesenchymal transition.

Mosaic expression of a membrane reporter in nascent mesoderm enabled recording cell shape and trajectory through live imaging. Upon leaving the streak, cells changed shape and extended protrusions of distinct size and abundance depending on the neighboring germ layer, as well as the region of the embryo. Embryonic trajectories were meandrous but directional, while extra-embryonic mesoderm cells showed little net displacement.

Embryonic and extra-embryonic mesoderm transcriptomes highlighted distinct guidance, cytoskeleton, adhesion, and extracellular matrix signatures. Specifically, intermediate filaments were highly expressed in extra-embryonic mesoderm, while live imaging for F-actin showed abundance of actin filaments in embryonic mesoderm only. Accordingly,RhoAorRac1conditional deletion in mesoderm inhibited embryonic, but not extra-embryonic mesoderm migration.

Overall, this indicates separate cytoskeleton regulation coordinating the morphology and migration of mesoderm subpopulations.
Phylogenetic Clustering by Linear Integer Programming (PhyCLIP)
Authors: Han Alvin X. , Parker Edyth , Scholer Frits , Maurer-Stroh Sebastian , Russell Colin A.
Published: October 2018

Sub-species nomenclature systems of pathogens are increasingly based on sequence data. The use of phylogenetics to identify and differentiate between clusters of genetically similar pathogens is particularly prevalent in virology from the nomenclature of human papillomaviruses to highly pathogenic avian influenza (HPAI) H5Nx viruses. These nomenclature systems rely on absolute genetic distance thresholds to define the maximum genetic divergence tolerated between viruses designated as closely related. However, the phylogenetic clustering methods used in these nomenclature systems are limited by the arbitrariness of setting intra- and inter-cluster diversity thresholds. The lack of a consensus ground truth to define well-delineated, meaningful phylogenetic subpopulations amplifies the difficulties in identifying an informative distance threshold. Consequently, phylogenetic clustering often becomes an exploratory, ad-hoc exercise.

Phylogenetic Clustering by Linear Integer Programming (PhyCLIP) was developed to provide a statistically-principled phylogenetic clustering framework that negates the need for an arbitrarily-defined distance threshold. Using the pairwise patristic distance distributions of an input phylogeny, PhyCLIP parameterises the intra- and inter-cluster divergence limits as statistical bounds in an integer linear programming model which is subsequently optimised to cluster as many sequences as possible. When applied to the haemagglutinin phylogeny of HPAI H5Nx viruses, PhyCLIP was not only able to recapitulate the current WHO/OIE/FAO H5 nomenclature system but also further delineated informative higher resolution clusters that capture geographically-distinct subpopulations of viruses. PhyCLIP is pathogen-agnostic and can be generalised to a wide variety of research questions concerning the identification of biologically informative clusters in pathogen phylogenies. PhyCLIP is freely available at http://github.com/alvinxhan/PhyCLIP.
Enigma at the nanoscale: can the NPC act as an intrinsic reporter for isotropic expansion microscopy?
Authors: Pesce Luca , Cozzolino Marco , Lanzanò Luca , Diaspro Alberto , Bianchini Paolo
Published: October 2018

Expansion microscopy is a super-resolution method that allows expanding uniformly biological samples, by increasing the relative distances among fluorescent molecules labeling specific components. The main “enigma” regarding this approach is given by the isotropic behavior at the nanoscale. The present study aims to determine the robustness of such a technique, quantifying the expansion parameters i.e. scale factor, isotropy, uniformity. Our focus is on the nuclear pore complex (NPC), as well-known nanoscale component endowed of a preserved and symmetrical structure localized on the nuclear envelope. Here, we show that Nup153 is a good reporter to quantitatively address the isotropy of the expansion process. The quantitative analysis carried out on NPCs, at different spatial scales, allows concluding that expansion microscopy can be used at the nanoscale with a uniform accuracy in the range of 20 nm. In addition, it is an excellent method for structural studies of macromolecular complexes.
Fibrocyte accumulation in bronchi: a cellular hallmark of COPD
Authors: Dupin Isabelle , Thumerel Matthieu , Maurat Elise , Coste Florence , Begueret Hugues , Trian Thomas , Montaudon Michel , Marthan Roger , Girodet Pierre-Olivier , Berger Patrick
Published: October 2018

Background

The remodeling mechanism and cellular players causing persistent airflow limitation in chronic obstructive pulmonary disease (COPD) remain largely elusive. We have recently demonstrated that circulating fibrocytes, a rare population of fibroblast-like cells produced by the bone marrow stroma, are increased in COPD patients during an exacerbation. It remains, however, unclear, whether fibrocytes are present in bronchial tissue of COPD patients.

Objective

We aimed to quantify fibrocytes density in bronchial specimens from both control subjects and COPD patients, and to define associations with clinical, functional and computed tomography relevant parameters.

Methods

17 COPD patients and 25 control subjects with normal lung function testing and no chronic symptoms, all of them requiring thoracic surgery, were recruited. LFT and CT-scan were performed before surgery. Using co-immunostaining and image analysis, we identify CD45+ FSP1+ cells as tissue fibrocytes and quantify their density in distal and proximal bronchial specimens from the whole series.

Results

Here, we demonstrate that fibrocytes are increased in both distal and proximal tissue specimens of COPD patients, compared to those of controls. The density of fibrocytes is negatively correlated with lung function parameters, such as FEV1 and FEV1/FVC, and positively with bronchial wall thickness assessed by CT scan. High density of distal bronchial fibrocytes predicts presence of COPD with a sensitivity of 83% and a specificity of 70%.

Conclusions

Our results thus suggest that recruitment of fibrocytes in the bronchi may participate to lung function decline during COPD progression.

Clinical Implications

High density of tissue fibrocytes is associated with a deteriorated lung function and an increase in airway wall thickness. A low density tissue fibrocytes virtually eliminates the presence of COPD.

Capsule summary

Blood fibrocytes assessed during exacerbation is a predictor of mortality in COPD. This study shows an increase of bronchial fibrocytes, that is associated with lower lung function, increased bronchial thickness and air trapping in COPD.
Transcriptome analysis of the human tibial nerve identifies sexually dimorphic expression of genes involved in pain, inflammation and neuro-immunity
Authors: Ray Pradipta , Khan Jawad , Wangzhou Andi , Tavares-Ferreira Diana , Akopian Armen N. , Dussor Gregory , Price Theodore J.
Published: October 2018

Sex differences in gene expression are important contributors to normal physiology and mechanisms of disease. This is increasingly apparent in understanding and potentially treating chronic pain where molecular mechanisms driving sex differences in neuronal plasticity are giving new insight into why certain chronic pain disorders preferentially affect women versus men. Large transcriptomic resources are increasingly available and can be used to mine for sex differences and molecular insight using donor cohorts. We analyzed more than 250 human tibial nerve (hTN) transcriptomes from the GTex Consortium project to gain insight into sex-dependent gene expression in the peripheral nervous system (PNS). We discover 149 genes with sex differential expression. Many of the genes upregulated in men are associated with inflammation, and appear to be primarily expressed by glia or immune cells. In women, we find the differentially upregulated transcription factor SP4 that drives a regulatory program, and may impact sex differences in PNS physiology. Many of these 149 DE genes have some previous association with chronic pain but few of them have been explored thoroughly. Additionally, using clinical data in the GTex database, we identify a subset of differentially expressed (DE) genes in diseases associated with chronic pain, arthritis and type II diabetes. Our work identifies sexually dimorphic gene expression in the human PNS with implications for discovery of sex-specific pain mechanisms.
Cyclical environments drive variation in life history strategies: a general theory of cyclical phenology
Authors: Park John S.
Published: October 2018

Cycles, such as seasons or tides, characterize many systems in nature. Overwhelming evidence shows that climate change-driven alterations to environmental cycles—such as longer seasons— are associated with phenological shifts around the world, suggesting a deep link between environmental cycles and life cycles. However, general mechanisms of life history evolution in cyclical environments are still not well understood. Here I build a demographic framework and ask how life history strategies optimize fitness when the environment perturbs a structured population cyclically, and how strategies should change as cyclicality changes. I show that cycle periodicity alters optimality predictions of classic life history theory because repeated cycles have rippling selective consequences over time and generations. Notably, fitness landscapes that relate environmental cyclicality and life history optimality vary dramatically depending on which trade-offs govern a given species. The model tuned with known life history trade-offs in a marine intertidal copepod T. californicus successfully predicted the shape of life history variation across natural populations spanning a gradient of tidal periodicities. This framework shows how environmental cycles can drive life history variation—without complex assumptions of individual responses to cues such as temperature—thus expanding the range of life history diversity explained by theory and providing a basis for adaptive phenology.
Pervasive and Dynamic Transcription Initiation inSaccharomyces cerevisiae
Authors: Lu Zhaolian , Lin Zhenguo
Published: October 2018

Transcription initiation is finely regulated to ensure the proper expression and function of these genes. The regulated transcription initiation in response to various environmental cues in the model organismSaccharomyces cerevisiaehas not been systematically investigated. In this study, we generated quantitative maps of transcription start site (TSS) at a single-nucleotide resolution forS. cerevisiaegrown in nine different conditions using no-amplification non-tagging Cap analysis of gene expression (nAnT-iCAGE) sequencing. Based on 337 million uniquely mapped CAGE tags, we mapped ~1 million well-supported TSSs, suggesting highly pervasive transcription initiation in the compact genome of yeast. The comprehensive TSS maps allowed us to identify core promoters for ~96% verified protein-coding genes and to revise the predicted translation start codon for 183 genes. We found that 56% of yeast genes have at least two core promoters and alternative usage of different core promoters in a gene is widespread in response to changing environments. More importantly, most core promoter shifts are coupled with differential gene expression, indicating that core promoter shift might play an important role in controlling transcriptional activity of yeast genes. Based on their dynamic activities, we divided yeast core promoters as constitutive core promoters (55%) and inducible core promoters (45%). The two classes of core promoters exhibit distinctive patterns in transcriptional abundance, chromatin structure, promoter shape, and sequence context. In summary, the quantitative TSS maps generated by this study improved the annotation of yeast genome, and revealed a highly pervasive and dynamic nature of transcription initiation in yeast.
Subthalamic nucleus mediates the modulation on cocaine self-administration induced by ultrasonic 3 vocalizations playback in rats
Authors: Christian Montanari , Elodie Giorla , Yann Pelloux , Christelle Baunez
Published: October 2018

Drug intake is known to be under the influence of social context. We have recently shown that presence of a peer influences drug intake in both rats and humans. Whether or not social acoustic communications between the peers play a role during cocaine or sucrose self-administration (SA) was investigated here, using playback of ultrasonic vocalizations (USV) at 50- and 22-kHz, conveying respectively positive and negative internal affective states in adult rats. To assess the neurobiological substrate of a potential USV influence on drug and food intake, we tested the effects of subthalamic nucleus (STN) lesions, given its role in emotional and motivational processes. In sham-control rats, playback of USV associated with positive affective states induced long-term decreased cocaine consumption, while USV associated with negative affective states induced short-term increase. Interestingly, no effect of USV playback was observed on sucrose intake, whatever the frequency. STN lesions abolished the influence of USV on cocaine intake, highlighting the influence of STN in emotional processes induced by USV emitted by a peer. These results show how acoustic social communication is important to regulate drug intake in rats and how STN modulation could interfere with addiction processes.
Choice between 1- and 2-furrow cytokinesis inCaenorhabditis elegansembryos with tripolar spindles
Authors: Kondo Tomo , Kimura Akatsuki
Published: October 2018

Excess numbers of centrosomes often lead to multipolar spindles, and thus probably to multipolar mitosis and aneuploidy. InCaenorhabditis elegans, approximately 70% of the paternalemb-27APC6mutant embryonic cells contained more than 2 centrosomes and formed multipolar spindles. However, only 30% of the cells with tripolar spindles formed 2 cytokinetic furrows. The rest formed 1 furrow, like normal cells. To investigate the mechanism how the cells avoided to form 2 cytokinetic furrows even with a tripolar spindle, we conducted live-cell imaging inemb-27APC6mutant cells. We found that the chromatids were aligned only on 2 of the 3 sides of the tripolar spindle, and the angle of the tripolar spindle relative to the long axis of the cell correlated with the number of cytokinetic furrow. Our numerical modeling showed that the combination of cell shape, cortical pulling forces, and heterogeneity of centrosome size determines whether cells with tripolar spindle form 1 or 2 cytokinetic furrows.
ddcP, pstB, and excess D-lactate impact synergism between vancomycin and chlorhexidine against Enterococcus faecium 1,231,410
Authors: Bhardwaj Pooja , Islam Moutusee Z. , Kim Christi , Nguyen Uyen Thy , Palmer Kelli L.
Published: October 2018

Vancomycin-resistant enterococci (VRE) are important nosocomial pathogens that cause life-threatening infections. To control hospital-associated infections, skin antisepsis and bathing utilizing chlorhexidine is recommended for VRE patients in acute care hospitals. Previously, we reported that exposure to inhibitory chlorhexidine levels induced the expression of vancomycin resistance genes in VanA-type Enterococcus faecium. However, vancomycin susceptibility actually increased for VanA-type E. faecium in the presence of chlorhexidine. Hence, a synergistic effect of the two antimicrobials was observed. In this study, we used multiple approaches to investigate the mechanism of synergism between chlorhexidine and vancomycin in the VanA-type VRE strain E. faecium 1,231,410. We generated clean deletions of 7 of 11 pbp, transpeptidase, and carboxypeptidase genes in this strain (ponA, pbpF, pbpZ, pbpA, ddcP, ldtfm, and vanY). Deletion of ddcP, encoding a membrane-bound carboxypeptidase, altered the synergism phenotype. Furthermore, using in vitro evolution, we isolated a spontaneous synergy escaper mutant and utilized whole genome sequencing to determine that a mutation in pstB, encoding an ATPase of phosphate-specific transporters, also altered synergism. Finally, addition of excess D-lactate, but not D-alanine, enhanced synergism. Overall, our work identified factors that alter chlorhexidine-induced vancomycin resensitization in a model VanA-type VRE strain.
Werner helicase control of human papillomavirus 16 E1-E2 DNA replication is regulated by SIRT1 deacetylation
Authors: Das Dipon , Bristol Molly L , Smith Nathan W , Wang Xu , Pichierri Pietro , Morgan Iain M
Published: October 2018

Human papillomaviruses (HPV) are double stranded DNA viruses causative in a host of human diseases including several cancers. Following infection two viral proteins, E1 and E2, activate viral replication in association with cellular factors, and stimulate the DNA damage response (DDR) during the replication process. E1-E2 uses homologous replication (HR) to facilitate DNA replication, but an understanding of host factors involved in this process remains incomplete. Previously we demonstrated that the class III deacetylase SIRT1, which can regulate HR, is recruited to E1-E2 replicating DNA and regulates the level of replication. Here we demonstrate that SIRT1 promotes the fidelity of E1-E2 replication and that the absence of SIRT1 results in reduced recruitment of the DNA repair protein Werner helicase (WRN) to E1-E2 replicating DNA. CRISPR/Cas9 editing demonstrates that WRN, like SIRT1, regulates the quantity and fidelity of E1-E2 replication. This is the first report of WRN regulation of E1-E2 DNA replication, or a role for WRN in the HPV life cycle. In the absence of SIRT1 there is an increased acetylation and stability of WRN, but a reduced ability to interact with E1-E2 replicating DNA. We present a model in which E1-E2 replication turns on the DDR stimulating SIRT1 deacetylation of WRN. This deacetylation promotes WRN interaction with E1-E2 replicating DNA to control the quantity and fidelity of replication. As well as offering a crucial insight into HPV replication control, this system offers a unique model for investigating the link between SIRT1 and WRN in controlling replication in mammalian cells.

Importance

HPV16 is the major viral human carcinogen, responsible for between 3 and 4% of all cancers worldwide. Following infection this virus activates the DNA damage response (DDR) to promote its life cycle, and recruits DDR proteins to its replicating DNA in order to facilitate homologous recombination during replication. This promotes the production of viable viral progeny. Our understanding of how HPV16 replication interacts with the DDR remains incomplete. Here we demonstrate that the cellular deacetylase SIRT1, which is a part of the E1-E2 replication complex, regulates recruitment of the DNA repair protein WRN to the replicating DNA. We demonstrate that WRN regulates the level and fidelity of E1-E2 replication. Overall the results suggest a mechanism where SIRT1 deacetylation of WRN promotes its interaction with E1-E2 replicating DNA to control the levels and fidelity of that replication.
Latent developmental potential to form limb-like skeletal structures in zebrafish
Authors: Hawkins M. Brent , Henke Katrin , Harris Matthew P.
Published: October 2018

The evolution of fins into limbs was a key transition in vertebrate history. A hallmark of this transition is the addition of multiple long bones to the proximal-distal axis of paired appendages. Whereas limb skeletons are often elaborate and diverse, teleost pectoral fins retain a simple endoskeleton. Fins and limbs share many core developmental processes, but how these programs were reshaped to produce limbs from fins during evolution remains enigmatic. Here we identify zebrafish mutants that form supernumerary long bones along the proximal-distal axis of pectoral fins with limb-like patterning. These new skeletal elements are integrated into the fin, as they are connected to the musculature, form joints, and articulate with neighboring bones. This phenotype is caused by activating mutations in previously unrecognized regulators of appendage development,vav2andwaslb, which we show function in a common pathway. We find that this pathway functions in appendage development across vertebrates, and loss ofWaslin developing limbs results in patterning defects identical to those seen inHoxallknockout mice. Concordantly, formation of supernumerary fin long bones requires the function ofhoxallparalogs, indicating developmental homology with the forearm and the existence of a latent functional Hox code patterning the fin endoskeleton. Our findings reveal an inherent limb-like patterning ability in fins that can be activated by simple genetic perturbation, resulting in the elaboration of the endoskeleton.
Cellular polarity asymmetrically functionalizes pathogen recognition receptor-mediated intrinsic immune response in human intestinal epithelium cells
Authors: Stanifer Megan L. , Muenchau Stephanie , Mukenhirn Markus , Pervolaraki Kalliopi , Kanaya Takashi , Albrecht Dorothee , Odendall Charlotte , Hielscher Thomas , Haucke Volker , Kagan Jonathan , Bartfeld Sina , Ohno Hiroshi , Boulant Steeve
Published: October 2018

Intestinal epithelial cells (IECs) act as a physical barrier separating the commensal-containing intestinal tract from the sterile interior. These cells have found a complex balance allowing them to be prepared for pathogen attacks while still tolerating the presence of bacteria/viral stimuli present in the lumen of the gut. Using primary human IECs, we probed the mechanisms, which allow for such a tolerance. We discovered that viral infection emanating from the basolateral side of IECs elicited a stronger intrinsic immune response as compared to lumenal apical infection. We determined that this asymmetric immune response was driven by the clathrin-sorting adapter AP-1B which mediates the polarized sorting of Toll-like receptor 3 (TLR3) toward the basolateral side of IECs. Mice and human IECs lacking AP-1B showed an exacerbated immune response following apical stimulation. Together these results suggest a model where the cellular polarity program plays an integral role in the ability of IECs to partially tolerate apical commensals while remaining fully responsive against invasive basolateral pathogens.
Re-purposing Ac/Ds transgenic system for CRISPR/dCas9 modulation of enhancers and non-coding RNAs in zebrafish
Authors: Chong-Morrison Vanessa , Simões Filipa C. , Senanayake Upeka , Carroll Dervla S. , Riley Paul R. , Sauka-Spengler Tatjana
Published: October 2018

Due to its genetic amenability coupled with recent advances in genome editing, the zebrafish serves as an excellent model to examine the function of both coding and non-coding elements. Recently, the non-coding genome has gained prominence due to its critical role in development and disease. Here, we have re-purposed the Ac/Ds maize transposition system to reliably screen and efficiently characterise zebrafish enhancers, with or without germline propagation. We further utilised the system to stably express guide RNAs in microinjected embryos enabling tissue-specific CRISPR/dCas9-interference (CRISPRi) knockdown of lncRNA and enhancer activity without disrupting the underlying genetic sequence. Our study highlights the utility of Ac/Ds transposition for transient epigenome modulation of non-coding elements in zebrafish.

Summary statement

We adapted the Ac/Ds transposition system, which enables continuous expression of guide RNAs for CRISPR/dCas9 perturbation, to examine the function of non-coding RNAs and enhancer elements in zebrafish.
Transgenic Mice and Pluripotent Stem Cells Express EGFP under the Control of miR-302 Promoter
Authors: Rahimi Karim , Parsa Sara , Nikzaban Mehrnoush , Mowla Seyed Javad , Fathi Fardin
Published: October 2018

MicroRNAs are a group of short non-coding RNAs that undertake various roles in different cell signaling pathways and developmental stages. They regulate gene expression levels at the post-transcriptional stage, which results in cleavage of mRNAs or repression of their translation. Some miRNAs, including the miR-302 cluster, are critical regulators for the stemness state of embryonic stem cells and cell fate patterning. The miR-302 cluster is located in the intron of a non-coding gene that has no other reported function, other than hosting miR-302, and grant a complex expression regulation through upstream its regulatory sequences. To date, analysis of the miR-302 expression pattern in a transgenic mouse model has not been reported. In this study, we generated transgenic mice that expressed EGFP driven by miR-302 upstream regulatory sequences that harbored the core promoter of its host gene. We examined the activity of the miR-302 promotor in somatic tissues of transgenic mice, transgenic blastocysts, and embryonic stem cells derived from transgenic blastocysts. Our results showed that miR-302 highly expressed in both blastocysts and the first passages of transgenic embryonic stem cells, and has low expression in the somatic tissues of transgenic mice. It could be concluded that different temporal and spatial gene expression patterns occur during the embryonic and adult stages in mice.