bluuebunny/crossref_metadata_2025 huggingface dataset:
Factual vs. evidential? The past tense forms of spoken Khalkha Mongolian
Authors: Brosig Benjamin
Published: July 2018

Past tense forms of spoken Khalkha Mongolian distinguish between established (‑sang) and non-established knowledge, which is then either based on direct (‑laa) or indirect (‑jee) evidence. Time of acquisition thus determines whether information source is marked, though vivid recollection (‑laa) and deferred realization (‑jee) overrule it. Conversely, attempted recollection in questions (‑l=uu) doesn’t presuppose sensory perception. A fourth suffix (‑v) is used if well-established events still surprise the speaker. These suffixes may also be used in a discontinuous fashion to refer to the future and then modally qualify predictions as inevitable (‑sang), apprehended [but preventable] (‑v), based on sensory evidence (‑laa) or inferred (‑jee). The distinction between unsourced ‑sang and sourced ‑laa/-jee is thus not about factual stance, but codes the extent to which information is consolidated in memory.
(Yo) creo que as a marker of evidentiality and epistemic modality
Authors: Mulder Gijs
Published: July 2018

This chapter surveys the use of the first person present of the cognitive verb creer ‘believe’ in contemporary Peninsular Spanish. It is based on data that were gathered from Twitter. The different functions of creo ‘I believe’ are closely related to a limited set of syntactic patterns. Creo with complementizer que proves to be a highly frequent and prolific marker of evidentiality, epistemic modality and related functions. After a detailed description of these functions, I focus on creo que with and without subject personal pronoun yo. While creo que fits all functions equally well, the use of yo creo que is more restricted to speaker-oriented, subjective functions.
Uralic perspectives on experimental evidence for evidentials
Authors: Tamm Anne , Argus Reili , Suurmäe Kadri
Published: July 2018

The chapter gives an overview on evidentiality in the Uralic languages. It then focuses on a behavioral experiment testing the processing of Estonian evidentials by four- and six-year-old children. The predominantly agglutinative Estonian, a Uralic language spoken in Europe, has an evidential morpheme on verbs (typical of various non-European languages), combining evidentiality and epistemic modality (typical in various European languages). We examine the effect of the Estonian evidential on preschoolers’ exploratory play, contrasting it with the effect of unmarked indicative sentences. Initially, the novel morpheme causes increased play, but the effect disappears as the acquisition of the indirect evidential meaning progresses. Novel grammar raises expectations of communicative intent in young children and makes them try out (or generalize over) statements.
Evidence for the development of ‘evidentiality’ as a grammatical category in the Tibetic languages
Authors: Zeisler Bettina
Published: July 2018

The coding of evidentiality and/or the speaker’s attitude grammaticalized in most Modern Tibetic languages, whereas Classical Tibetan lacks a fully developed evidential system. The source for marking sensory perception is the hedging use of the verb ḥdug. Its lexical meaning of limited stay was extended to the notion of limited truth: ‘it seems’. This was further applied to situations merely perceived. ḥdug spread first into West Tibetan as an inferential marker; later it was re-borrowed as an experiential maker. This scenario allows reconstructing the timeline and the semantic path, and explaining the flexible use of ‘evidential’ markers in Tibetic languages.
What do different methods of data collection reveal about evidentiality?
Authors: Kittilä Seppo , Jalava Lotta , Sandman Erika
Published: July 2018

In this chapter, different types of data used in evidentiality studies are discussed. We first discuss reference grammars, which are necessary for any cross-linguistic study of evidentials. This is followed by a discussion of (different types of) usage-based data, as well as natural language data and stimulus-based data collection used in linguistic fieldwork. We end our discussion by examining data collected by means of questionnaires and acceptability judgments. It is shown that all the types of data discussed are relevant for a full understanding of evidentiality, but they differ in their contribution and complement each other. For example, usage-based data is necessary for studying frequencies in languages, while reference grammars reveal what is common across languages.
Socioeconomic Pragmatic Variation
Authors: Staley Larssyn
Published: July 2018

On a regular basis people encounter unfamiliar uses of pragmatic features, such as offers or requests with differing levels of directness or terms of address showing differing amounts of solidarity or deference. Variational pragmatics is the study of such uses, according to region, gender, age, ethnicity and socioeconomic status, among national and sub-national varieties of pluricentric languages. Despite the wide focus just outlined, this volume provides the first study of pragmatic variation across different social classes, using naturally occurring, interactional data. The discourse analyzed here was collected in over twenty restaurant service encounters spanning three price points. The aim of this study is two-fold: to provide a potential framework for how pragmatic variables and their context can be defined, using the concept of a communicative activity, and to investigate socioeconomic variation in pragmatics by taking offers, thanks responses and address forms as examples. This study contributes, both on a methodological and empirical level, to the growing body of research in variational pragmatics, as well as speech acts, terms of address, relational work and sociolinguistics.
Sociocultural and linguistic constraints in address choice from Latin to Italian
Authors: Molinelli Piera
Published: July 2018

This chapter identifies the changes which led from the Early Latin address system, when address choice was unmarked as to the reverential dimension, to Late Latin, when such functions progressively emerged establishing the opposition between tu and Vos (2pl), and then to the Italian system. Speakers of Old Italian continued the differentiation in the address system, and, starting from the tu/Vos opposition, subsequent developments led to a tripartite system (tu/Voi/Lei).

The chapter traces the main pragmatic and structural steps in the development of address terms and the external and internal factors involved. Whereas the emergence of reverential forms in the history of Latin is mainly due to socio-cultural factors, the change from Voi to Lei can be attributed to both social (contact with Spanish) and linguistic factors, since the use of honorifics triggered anaphoric abstract reference to a third person, then morphologised as third singular pronouns (Lei).
Beyond the notion of periphery
Authors: Salameh Jiménez Shima , Estellés María , Pons Bordería Salvador
Published: July 2018

This paper offers an alternative analysis to the Subjectivity, Intersubjectivity and Peripheries Hypothesis or SIPH (Beeching, Degand, Detges, Traugott and Waltereit 2009; Traugott 2012; Beeching and Detges 2014; Higashizumi, Onodera and Sohn 2016). The SIPH focuses on the left and right peripheries of a single reference unit: sentence, utterance or turn. Against this unidimensional analysis, this paper argues in favour of a bidimensional analysis such as the one offered by the Val.Es.Co. model where eight different-scope units and four positions per unit offer a more flexible way to capture the evolution of discourse markers. The analysis of Sp. ¿no? (huh?), mira (look), oye (hey) and ¡vaya! (wow!) reveals that the subjective and intersubjective positioning of the speakers is better accounted for by taking the discourse unit and the meaning of the DM into account, rather than its structural position at the left or right periphery of an utterance.
Orthography as an identity marker
Authors: Guerini Federica
Published: July 2018

This chapter focuses on the introduction of road signs displaying both the Italian and the local Italo-Romance dialect (Bergamasco) version of place-names by some municipal authorities in the province of Bergamo (in Northern Italy). I will argue that the decision to consider the local Bergamasco dialect eligible for public display carries social and political meaning. Bilingual road signs will be shown to challenge the traditional distinction between ‘top-down’ and ‘bottom-up’ items of the linguistic landscape (Landry and Bourhis 1997: 25). Through the analysis of the graphic solutions adopted in order to write a language used almost exclusively up until now in the spoken form (i.e. the local Bergamasco dialect), I will offer a few observations on the significance of orthographic variation and on the symbolic, identity-related, value of spelling choices.
Positioning the self in talk about group
Authors: Höfler Concha Maria
Published: July 2018

This paper focuses on the discourse marker chestno govorya ‘honestly speaking’ as a device allowing speakers to create greater closeness between interlocutors and then drawing sharp social boundaries in positioning their own community in relation to others. The study is based on an ethnographically informed conversation analysis of 49 semi-structured interviews with members of Georgia’s Greek community and elucidates the links between the nano level of interaction and larger societal discourses ranging from the communal to the (post-) Soviet imaginary. It is shown how chestno serves firstly as a disclaimer of potentially difficult topics ahead, of risky self-disclosure which fosters intimacy, enabling speakers to establish the recurring boundary between ‘Christians’ and ‘Muslims’ or rehearse stereotypes, established as a child. Methodologically, a corpus search for veracity devices, such as chestno govorya, can help identify sections of discourse where problematic issues relating to the way speakers position themselves in their community are being discussed.
Givenness and the difference between wh-fronted and wh-in-situ questions in Spanish
Authors: Biezma María
Published: July 2018

In the last fifteen years, the literature on wh-questions has tried to understand speakers’ intuitions regarding the meaning differences between wh-in-situ (WIQs) and wh-fronted (WFQs) questions. The different proposals agree in that WIQs require givenness, but there is no consensus on what notion of givenness is at stake. In this paper I argue that in Castilian Spanish WIQs presuppose that the WIQ is embedded in a specific discourse: what is given then is the (hierarchical) discourse-structure in which the question is embedded. Spanish illustrates a possibility on the spectrum of variation, imposing very specific discourse-structural conditions to allow WIQs. From a broader theoretical perspective, the proposal made in this paper makes a contribution to the study of presupposition, since I argue that there are conventional linguistic devices that target discourse-structure.
On ben in Trentino regional Italian
Authors: Cognola Federica , Schifano Norma
Published: July 2018

The aim of the present article is to discuss the syntactic distribution and semantic/pragmatic interpretation of the discourse particle ben (lit. ‘well’) as used in the Trentino regional variety of Italian. Regarding its distribution, the results of our investigation with native speakers show that ben is admitted in any of the tested TAM contexts (save for non-root embedded clauses) and always sits between the lexical/auxiliary/restructuring verb and the non-finite form. As for its interpretation, it is shown that ben is used to negate an implicit or explicit negative presupposition, i.e. it is primarily connected with negation. These syntactic and interpretative properties are captured by claiming that ben sits in NegPresuppositionalP, where it is licensed by the (c)overt operator no located in ForceP.
Exploring sociolinguistic discontinuity in a minority variety of French
Authors: Kaminskaïa Svetlana
Published: July 2018

In a language spoken in a minority setting, sociolinguistic variation is often reduced. This paper examines rhythm in Ontario French and explores the presence and extent of such variation. Text readings and spontaneous samples from men and women of two age groups are compared, and the following rhythmic aspects are examined: articulation rate, syllabic structure and typology, length of a stress group, syllable and vowel duration ratios within a stress group, and phonetic rhythm (using nPVI-V, VarcoV, and %V metrics). The results suggest that style and social factors affect rate and rhythmicity but do not interact: all participants articulated more slowly when reading; also, women and older participants demonstrated a more French-like rhythm, while younger participants appeared converging to English.
Spanish estarse is not only agentive, but also
inchoative
Authors: Marín Rafael , Fábregas Antonio
Published: July 2018

This article explores the properties of constructions involving the stage
level copula estar with the pronominal form
se, which has been argued to encode an agentive
component lacking from the non se-marked form. While several previous
studies have argued that estarse constructions involve a
dynamic and telic component similar to an achievement, the goal of this
contribution is to show that estarse is essentially
stative, lacking all kinds of dynamicity and telicity, and should be
analysed as an inchoative state, that is, a state that encodes its onset,
but not the culmination of the transition preceding it. We show that this
analysis overcomes the problems of previous proposals with respect to the
temporal and aspectual behaviour of estarse
constructions.
From completely free to complete freedom
Authors: Masià Melania S.
Published: July 2018

Maximizers (completely, fully) are degree modifiers sensitive to the scale structure of the adjective they combine with. Spanish adjectives of completeness (completo ‘complete’, total ‘total’) show a distribution similar to that of their adverbial counterparts when modifying property concept [PC] nouns (libertad ‘freedom’, sabiduría ‘wisdom’). This paper argues that adjectives of completeness are degree modifiers in the nominal domain. It adopts a semantics of PC nouns according to which they denote substances, following Francez & Koontz-Garboden (2015). These substances can be bounded or unbounded, just like their related adjectives (libre ‘free’, etc.). By establishing a strict parallelism between adverbs and adjectives of completeness, this paper contributes to the understanding of completeness contributes to the understanding of scalarity across categories and the relation between degrees and measurements.
Romanian dependent numerals as ratios
Authors: Panaitescu Mara
Published: July 2018

The aim of the paper is to present an account of Romanian cardinal DPs containing the distributivity marker câte (Dependent Numerals – DNums henceforth), with a view to a possible extension to other DNums attested cross-linguistically. The proposal adopted here is expected to extend to dependency markers which do not enforce their own distributivity and which obligatorily apply to monotonic measures (câte 200 de grame, ‘CÂTE 200 grams’ vs. #câte 20 de grade Celsius, ‘CÂTE degrees Celsius’). Firstly, distributivity is satisfied by co-indexation with a plurality of events which is independently provided. The indirect relation between the DNum and the participant or runtime sortal key translates as a ratio. A sentence such as The boys read CÂTE two books verifies the condition that the ratio of read books (SHARE) per reading boy (KEY) is two. Secondly, the monotonicity constraint is claimed here to be an outcome of the following facts: câte ranges over event-object pairs; it induces event-related (ER) interpretations via the same mechanism as cumulative ER cardinals discussed in the literature, which accounts for the monotonicity constraint.1
For an overt movement analysis of comparison at a distance in French
Authors: Pasquereau Jérémy
Published: July 2018

This paper focuses on nominal comparative constructions in European French, specifically on constructions in which the comparative quantifier can appear separated from its nominal restrictor (hence the name Comparison At a Distance). One question is whether the nominal comparative construction in which the quantifier is separated from its restrictor is derivationally related to the corresponding construction in which the quantifier is adjacent to its restrictor (movement analysis) or whether those two constructions are not derivationally related (base-generation analysis). I show that there are arguments in favor of analyzing CAD as a case of overt quantifier movement (locality restrictions) and arguments against a base-generation analysis (reconstruction). Furthermore, I show that nominal comparative quantifiers that can be separated from their restrictor have the same locality restrictions as the quantifier tout ‘everything’, which has been argued to move (Kayne 1975), suggesting that tout and comparative quantifiers are amenable to the same movement rule.
Bueno-, pues-, and
bueno-pues-prefacing in Spanish
conversation
Authors: Raymond Chase Wesley
Published: July 2018

This chapter reports on two turn-initial particles in Spanish:
bueno and pues. While previous
research has equated both of these to
well-prefacing in English in that they project
“unexpectedness”, here the aim is to explicate the distinct
interactional work that each particle performs. Focusing on
responses to questions, I show that bueno-prefaced
responses do not overtly problematize the prior utterance, but
rather accept its terms before departing from them, and thereby
acquiesce to the prior turn’s design. Pues-prefaced
responses, by contrast, are directly addressed to the prior turn,
but they cast that prior turn’s action or design as problematic in
some way. I conclude by illustrating how these two uses are not
mutually exclusive by examining the compound preface
bueno-pues.
Diverging from ‘business as usual’
Authors: Mushin Ilana
Published: July 2018

This paper presents the first detailed attempt to analyse the
interactional functions of a turn-initial particle in an Australian
Aboriginal language. The Garrwa particle ngala has
grammatical properties of a clause connector that sets up a contrast
between two simultaneous but distinct events (similar to English
while). In this paper I show that
ngala is used in conversation turn-initially to
simultaneously connect the upcoming talk with the prior turn and to
project that the upcoming turn diverges in trajectory from the prior
talk or course of action. I also show how the clause connecting and
turn-initial functions of ngala are characterised
by distinct syntactic and prosodic shapes.
Contemporary capitalism, uneven development, and the arc of anti-capitalism
Authors: Latham Robert
Published: July 2018

Uneven and combined development remains crucial for understanding the continued widening and deepening of capitalism. However, the nature of the heterogeneous and uneven development of contemporary capitalism, especially since the 1970s, makes problematic the characterization of capitalist totality, as a coherent stage and as a singular, albeit uneven, combination. This complicates the successful pursuit of anti-capitalism, which now requires varied but interrelated responses at all scales and involving a range of approaches, from local community activism and non-capitalist alternatives to mass Leninist-inspired parties, and an international socialist movement. Thus, a far more uneven anticapitalism is appropriate; and a single, overarching anti-capitalist process, such as Permanent Revolution may not be the only or way forward. This is not an argument for a post-Marxist horizontal heterogeneity; but rather an exploration of the reasons and possibilities for a dialectical anti-capitalism, where beneficial encounters occur across the arc of anti-capitalism, within which proletariat mobilization remains a central component. Such confluence offers one starting point for contending with the perennial duality of reform and revolution, manifest today in the either/or of an anti-capitalism of total revolution and an agonistic, fractional post-Marxist politics working to reduce oppression and hardship within capitalism.
An actin shell delays oocyte chromosome capture by microtubules
Authors: Verlhac Marie-Hélène
Published: July 2018

The large nuclei and tiny spindles of oocytes create a challenge for chromosome capture at M-phase entry. A contractile F-actin mesh in starfish oocytes delivers chromosomes to the spindle and Burdyniuk et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201802080) show that F-actin delays the capture of chromosomes until they are within reach of microtubules.
Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I–driven CD8+ T cell response
Authors: Stockenhuber Krista , Hegazy Ahmed N. , West Nathaniel R. , Ilott Nicholas E. , Stockenhuber Alexander , Bullers Samuel J. , Thornton Emily E. , Arnold Isabelle C. , Tucci Andrea , Waldmann Herman , Ogg Graham S. , Powrie Fiona
Published: July 2018

Psoriasis is a complex inflammatory skin disease affecting ∼3% of the population worldwide. Although type I interferons (IFN-I) are thought to be involved in its pathogenesis, the details of this relationship remain elusive. Here we show that in a murine model of imiquimod-driven psoriatic skin inflammation, Foxp3+ regulatory T cells (T reg cells) control inflammation severity by restraining IFN-I. Depletion of T reg cells induces IFN-I and IFN-stimulated gene expression, and leads to accumulation of CD8+ T cells in lesional skin. Mononuclear phagocytes (MNPs) were the source of IFN-I, and their depletion reversed the effect of T reg cell depletion. Blockade of IFN-I signaling abolished CD8+ T cell infiltration and excess inflammation in the skin of T reg cell–depleted mice. Depletion of CD8+ T cells attenuated pathology, confirming their role as critical effector cells downstream of IFN-I. Our results describe an unexpected role for T reg cells in restraint of an MNP–IFN-I–driven CD8+ T cell response during psoriasiform skin inflammation. These findings highlight a pathway with potential relevance for the treatment of early-stage disease.
The N terminus of α-ENaC mediates ENaC cleavage and activation by furin
Authors: Kota Pradeep , Gentzsch Martina , Dang Yan L. , Boucher Richard C. , Stutts M. Jackson
Published: July 2018

Epithelial Na+ channels comprise three homologous subunits (α, β, and γ) that are regulated by alternative splicing and proteolytic cleavage. Here, we determine the basis of the reduced Na+ current (INa) that results from expression of a previously identified, naturally occurring splice variant of the α subunit (α-ENaC), in which residues 34–82 are deleted (αΔ34–82). αΔ34–82-ENaC expression with WT β and γ subunits in Xenopus oocytes produces reduced basal INa, which can largely be recovered by exogenous trypsin. With this αΔ34–82-containing ENaC, both α and γ subunits display decreased cleavage fragments, consistent with reduced processing by furin or furin-like convertases. Data using MTSET modification of a cysteine, introduced into the degenerin locus in β-ENaC, suggest that the reduced INa of αΔ34–82-ENaC arises from an increased population of uncleaved, near-silent ENaC, rather than from a reduced open probability spread uniformly across all channels. After treatment with brefeldin A to disrupt anterograde trafficking of channel subunits, INa in oocytes expressing αΔ34–82-ENaC is reestablished more slowly than that in oocytes expressing WT ENaC. Overnight or acute incubation of oocytes expressing WT ENaC in the pore blocker amiloride increases basal ENaC proteolytic stimulation, consistent with relief of Na+ feedback inhibition. These responses are reduced in oocytes expressing αΔ34–82-ENaC. We conclude that the α-ENaC N terminus mediates interactions that govern the delivery of cleaved and uncleaved ENaC populations to the oocyte membrane.
Minimal molecular determinants of isoform-specific differences in efficacy in the HCN channel family
Authors: Alvarez-Baron Claudia P. , Klenchin Vadim A. , Chanda Baron
Published: July 2018

Hyperpolarization-activated, cyclic nucleotide–gated (HCN) channels generate rhythmic activity in the heart and brain. Isoform-specific functional differences reflect the specializations required for the various roles that they play. Despite a high sequence and structural similarity, HCN isoforms differ greatly in their response to cyclic nucleotides. Cyclic AMP (cAMP) enhances the activity of HCN2 and HCN4 isoforms by shifting the voltage dependence of activation to more depolarized potentials, whereas HCN1 and HCN3 isoforms are practically insensitive to this ligand. Here, to determine the molecular basis for increased cAMP efficacy in HCN2 channels, we progressively mutate residues in the C-linker and cyclic nucleotide–binding domain (CNBD) of the mouse HCN2 to their equivalents in HCN1. We identify two clusters of mutations that determine the differences in voltage-dependent activation between these two isoforms. One maps to the C-linker region, whereas the other is in proximity to the cAMP-binding site in the CNBD. A mutant channel containing just five mutations (M485I, G497D, S514T, V562A, and S563G) switches cAMP sensitivity of full-length HCN2 to that of HCN1 channels. These findings, combined with a detailed analysis of various allosteric models for voltage- and ligand-dependent gating, indicate that these residues alter the ability of the C-linker to transduce signals from the CNBD to the pore gates of the HCN channel.
A deep neural network approach for learning intrinsic protein-RNA binding preferences
Authors: Ben-Bassat Ilan , Chor Benny , Orenstein Yaron
Published: July 2018

Motivation

The complexes formed by binding of proteins to RNAs play key roles in many biological processes, such as splicing, gene expression regulation, translation and viral replication. Understanding protein-RNA binding may thus provide important insights to the functionality and dynamics of many cellular processes. This has sparked substantial interest in exploring protein-RNA binding experimentally, and predicting it computationally. The key computational challenge is to efficiently and accurately infer protein-RNA binding models that will enable prediction of novel protein-RNA interactions to additional transcripts of interest.

Results

We developed DLPRB (Deep Learning for Protein-RNA Binding), a new deep neural network (DNN) approach for learning intrinsic protein-RNA binding preferences and predicting novel interactions. We present two different network architectures: a convolutional neural network (CNN), and a recurrent neural network (RNN). The novelty of our network hinges upon two key aspects: (i) the joint analysis of both RNA sequence and structure, which is represented as a probability vector of different RNA structural contexts; (ii) novel features in the architecture of the networks, such as the application of RNNs to RNA-binding prediction, and the combination of hundreds of variable-length filters in the CNN. Our results in inferring accurate RNA-binding models from high-throughput in vitro data exhibit substantial improvements, compared to all previous approaches for protein-RNA binding prediction (both DNN and non-DNN based). A more modest, yet statistically significant, improvement is achieved for in vivo binding prediction. When incorporating experimentally-measured RNA structure, compared to predicted one, the improvement on in vivo data increases. By visualizing the binding specificities, we can gain biological insights underlying the mechanism of protein RNA-binding.

Availability and implementation

The source code is publicly available at https://github.com/ilanbb/dlprb.

Supplementary information

Supplementary data are available at Bioinformatics online.
Understanding the evolution of functional redundancy in metabolic networks
Authors: Sambamoorthy Gayathri , Raman Karthik
Published: July 2018

Motivation

Metabolic networks have evolved to reduce the disruption of key metabolic pathways by the establishment of redundant genes/reactions. Synthetic lethals in metabolic networks provide a window to study these functional redundancies. While synthetic lethals have been previously studied in different organisms, there has been no study on how the synthetic lethals are shaped during adaptation/evolution.

Results

To understand the adaptive functional redundancies that exist in metabolic networks, we here explore a vast space of ‘random’ metabolic networks evolved on a glucose environment. We examine essential and synthetic lethal reactions in these random metabolic networks, evaluating over 39 billion phenotypes using an efficient algorithm previously developed in our lab, Fast-SL. We establish that nature tends to harbour higher levels of functional redundancies compared with random networks. We then examined the propensity for different reactions to compensate for one another and show that certain key metabolic reactions that are necessary for growth in a particular growth medium show much higher redundancies, and can partner with hundreds of different reactions across the metabolic networks that we studied. We also observe that certain redundancies are unique to environments while some others are observed in all environments. Interestingly, we observe that even very diverse reactions, such as those belonging to distant pathways, show synthetic lethality, illustrating the distributed nature of robustness in metabolism. Our study paves the way for understanding the evolution of redundancy in metabolic networks, and sheds light on the varied compensation mechanisms that serve to enhance robustness.

Supplementary information

Supplementary data are available at Bioinformatics online.
Down‐regulation of acid sphingomyelinase and neutral sphingomyelinase‐2 inversely determines the cellular resistance to plasmalemmal injury by pore‐forming toxins
Authors: Schoenauer Roman , Larpin Yu , Babiychuk Eduard B. , Drücker Patrick , Babiychuk Viktoriia S. , Avota Elita , Schneider-Schaulies Sibylle , Schumacher Fabian , Kleuser Burkhard , Köffel René , Draeger Annette
Published: July 2018

Bacterial pore‐forming toxins compromise plasmalemmal integrity, leading to Ca2+ influx, leakage of the cytoplasm, and cell death. Such lesions can be repaired by microvesicular shedding or by the endocytic uptake of the injured membrane sites. Cells have at their disposal an entire toolbox of repair proteins for the identification and elimination of membrane lesions. Sphingomyelinases catalyze the breakdown of sphingomyelin into ceramide and phosphocholine. Sphingomyelin is predominantly localized in the outer leaflet, where it is hydrolyzed by acid sphingomyelinase (ASM) after lysosomal fusion with the plasma membrane. The magnesium‐dependent neutral sphingomyelinase (NSM)‐2 is found at the inner leaflet of the plasmalemma. Because either sphingomyelinase has been ascribed a role in the cellular stress response, we investigated their role in plasma membrane repair and cellular survival after treatment with the pore‐forming toxins listeriolysin O (LLO) or pneumolysin (PLY). Jurkat T cells, in which ASM or NSM‐2 was down‐regulated [ASM knockdown (KD) or NSM‐2 KD cells], showed inverse reactions to toxin‐induced membrane damage: ASM KD cells displayed reduced toxin resistance, decreased viability, and defects in membrane repair. In contrast, the down‐regulation of NSM‐2 led to an increase in viability and enhanced plasmalemmal repair. Yet, in addition to the increased plasmalemmal repair, the enhanced toxin resistance of NSM‐2 KD cells also appeared to be dependent on the activation of p38/MAPK, which was constitutively activated, whereas in ASM KD cells, the p38/MAPK activation was constitutively blunted.—Schoenauer, R., Larpin, Y., Babiychuk, E. B., Drücker, P., Babiychuk, V. S., Avota, E., Schneider‐Schaulies, S., Schumacher, F., Kleuser, B., Köffel, R., Draeger, A. Down‐regulation of acid sphingomyelinase and neutral sphingomyelinase‐2 inversely determines the cellular resistance to plasmalemmal injury by pore‐forming toxins. FASEB J. 33, 275–285 (2019). www.fasebj.org
STAU1 binds to IBDV genomic double‐stranded RNA and promotes viral replication via attenuation of MDA5‐dependent β interferon induction
Authors: Ye Chengjin , Yu Zhaoli , Xiong Yiwei , Wang Yu , Ruan Yina , Guo Yueping , Chen Mianmian , Luan Shilu , Zhang Enli , Liu Hebin
Published: July 2018

Infectious bursal disease virus (IBDV) infection triggers the induction of type IIFN, which is mediated by melanoma differentiation‐associated protein 5 recognition of the viral genomic double‐stranded RNA (dsRNA). However, the mechanism of IBDV overcoming the type I IFN antiviral response remains poorly characterized. Here, we show that IBDV genomic dsRNA selectively binds to the host cellular RNA binding protein Staufen1 (STAU1) in vitro and in vivo. The viral dsRNA binding region was mapped to the N‐terminal moiety of STAU1 (residues 1–468). Down‐regulation of STAU1 impaired IBDV replication and enhanced IFN‐β transcription in response to IBDV infection, while having little effect on the viral attachment to the host cells and cellular entry. Conversely, over‐expression of STAU1 but not the IBDV dsRNA–binding deficient STAU1 mutant (469–702) led to a suppression of IBDV dsRNA–induced IFN‐β promoter activity. Moreover, we found that the binding of STAU1 to IBDV dsRNA decreased the association of melanoma differentiation‐associated protein 5 but not VP3 with the IBDV dsRNA in vitro. Finally, we showed that STAU1 and VP3 suppressed IFN‐β gene transcription in response to IBDV infection in an additive manner. Collectively, these findings provide a novel insight into the evasive strategies used by IBDV to escape the host IFN antiviral response.—Ye, C., Yu, Z., Xiong, Y., Wang, Y., Ruan, Y., Guo, Y., Chen, M., Luan, S., Zhang, E., Liu, H. STAU1 binds to IBDV genomic double‐stranded RNA and promotes viral replication via attenuation of MDA5‐dependent β interferon induction. FASEB J. 33, 286–300 (2019). www.fasebj.org
SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1‐WNT10B‐FZD7 axis
Authors: Wang Liang‐Jie , Lo Hsiao‐Fan , Lin Cheng‐Fu , Ng Pui‐Sze , Wu Yi‐Hung , Lee Yun‐Shien , Cheong Mei‐Leng , Chen Hungwen
Published: July 2018

Migration of placental extravillous trophoblast (EVT) cells into uterine decidua facilitates the establishment of blood circulation between mother and fetus and is modulated by EVT‐decidual cell interaction. Poor or excessive EVT migration is associated with pregnancy complications such as preeclampsia or placenta accreta. Glial cells missing 1 (GCM1) transcription factor is essential for placental development, and decreased GCM1 activity is detected in preeclampsia. To study whether GCM1 regulates trophoblast cell migration, here we showed that GCM1 promotes BeWo and JAR trophoblast cell migration through a novel target gene, WNT10B. Moreover, WNT10B signaling stimulated cytoskeletal remodeling via Rac1 and frizzled 7 (FZD7) was identified as the cognate receptor for WNT10B to up‐regulate cell migration. We further showed that secreted frizzled‐related protein 3 (SFRP3) is expressed in uterine decidual cells by immunohistochemistry and that SFRP3 expression in telomerase‐transformed human endometrial stromal cells (T‐HESCs) is elevated under decidualization stimuli and further enhanced by bone morphogenetic protein 2 via SMAD1. SFRP3 blocked the interaction between FZD7 and WNT10B to decrease BeWo cell migration, which corroborated the elevated BeWo cell migration when cocultured with decidualized and SFRP3‐knockdown T‐HESC monolayer. Our results suggest that GCM1 up‐regulates EVT cell migration through WNT10B and FZD7, which is negatively modulated by decidual SFRP3.—Wang, L.‐J., Lo, H.‐F., Lin, C.‐F., Ng, P.‐S., Wu, Y.‐H., Lee, Y.‐S., Cheong, M.‐L., Chen, H. SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1‐WNT10B‐FZD7 axis. FASEB J. 33, 314–326 (2019). www.fasebj.org
α‐Galactosidase A‐deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease
Authors: Miller James J. , Aoki Kazuhiro , Mascari Carly A. , Beltrame Angela K. , Sokumbi Olayemi , North Paula E. , Tiemeyer Michael , Kriegel Alison J. , Dahms Nancy M.
Published: July 2018

Fabry disease is an X‐linked lysosomal storage disease caused by α‐galactosidase A (α‐Gal A) deficiency. Kidney and heart failure are frequent complications in adulthood and greatly contribute to patient morbidity and mortality. Because α‐Gal A‐deficient mouse models do not recapitulate cardiorenal findings observed in patients, a nonmouse model may be beneficial to our understanding of disease pathogenesis. In this study, we evaluated disease processes in a recently generated Fabry rat model. We found that male Fabry rats weighed significantly less than wild‐type (WT) males, whereas female Fabry rats weighed significantly more than WT females. Whereas no difference in female survival was detected, we observed that male Fabry rats had a decreased lifespan. Skin histology revealed that inflammation and lipoatrophy may be chief disease mediators in patients. With respect to the kidney and heart, we found that both organs accumulate α‐Gal A substrates, including the established biomarkers, globotriaosylceramide and globotriaosylsphingosine. Longitudinal serum and urine chemistry panels demonstrated pronounced renal tubule dysfunction, which was confirmed histologically. Mitral valve thickening was observed in Fabry rats using echocardiography. We conclude that Fabry rats recapitulate important kidney and heart phenotypes experienced by patients and can be further used to study disease mechanisms and test therapies.—Miller, J. J., Aoki, K., Mascari, C. A., Beltrame, A. K., Sokumbi, O., North, P. E., Tiemeyer, M., Kriegel, A. J., Dahms, N. M., α‐Galactosidase A‐deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease. FASEB J. 33, 418–429 (2019). www.fasebj.org
Microbial subnetworks related to short-term diel O2fluxes within geochemically distinct freshwater wetlands
Authors: Horton Dean J. , Cooper Matthew J. , Wing Anthony J. , Kourtev Peter S. , Uzarski Donald G. , Learman Deric R.
Published: July 2018

O2concentrations often fluctuate over diel timescales within wetlands, driven by temperature, sunlight, photosynthesis, and respiration. These daily fluxes have been shown to impact biogeochemical transformations (e.g. denitrification), which are mediated by the residing microbial community. However, little is known about how resident microbial communities respond to diel dramatic physical and chemical fluxes in freshwater wetland ecosystems. In this study, total microbial (bacterial and archaeal) community structure was significantly related to diel time points in just one out of four distinct freshwater wetlands sampled. This suggests that daily environmental shifts may influence wetlands differentially based upon the resident microbial community and specific physical and chemical conditions of a freshwater wetland. However, when exploring at finer resolutions of the microbial communities within each wetland, subcommunities within two wetlands were found to correspond to fluctuating O2levels. Microbial taxa that were found to be susceptible to fluctuating O2levels within these subnetworks may have intimate ties to metabolism and/or diel redox cycles. This study highlights that freshwater wetland microbial communities are often stable in community structure when confronted with short-term O2fluxes, however, specialist taxa may be sensitive to these same fluxes.
Phenotypic Age: a novel signature of mortality and morbidity risk
Authors: Liu Zuyun , Kuo Pei-Lun , Horvath Steve , Crimmins Eileen , Ferrucci Luigi , Levine Morgan
Published: July 2018

Background:

A person’s rate of aging has important implications for his/her risk of death and disease, thus, quantifying aging using observable characteristics has important applications for clinical, basic, and observational research. We aimed to validate a novel aging measure, “Phenotypic Age”, constructed based on routine clinical chemistry measures, by assessing its applicability for differentiating risk for morbidity and mortality in both healthy and unhealthy populations of various ages.

Methods:

A nationally representative US sample, NHANES III, was used to derive “Phenotypic Age” based on a linear combination of chronological age and nine multi-system clinical chemistry measures, selected via cox proportional elastic net. Mortality predictions were validated using an independent sample (NHANES IV), consisting of 11,432 participants, for whom we observed a total of 871 deaths, ascertained over 12.6 year of follow-up. Proportional hazard models and ROC curves were used to evaluate predictions.

Results:

Phenotypic Age was significantly associated with all-cause mortality and cause-specific mortality. These results were robust to age and sex stratification, and remained even when excluding short-term mortality. Similarly, Phenotypic Age was associated with mortality among seemingly “healthy” participants—defined as those who were disease-free and had normal BMI at baseline—as well as the oldest-old (aged 85+)—a group with high disease burden.

Conclusions:

Phenotypic Age is a reliable predictor of all-cause and cause-specific mortality in multiple subgroups of the population. Risk stratification by this composite measure is far superior to that of the individual measures that go into it, as well as traditional measures of health. It is able to differentiate individuals who appear healthy, who may have otherwise been missed using traditional health assessments. Further, it can differentiate risk among persons with shared disease burden. Overall, this easily measured metric may be useful in the clinical setting and facilitate secondary and tertiary prevention strategies.
First heterobimetallic AgI–CoIII coordination compound with both bridging and terminal –NO2 coordination modes: synthesis, characterization, structural and computational studies of (PPh3)2AgI–(μ-κ2
O,O′:κN-NO2)–CoIII(DMGH)2(κN-NO2)
Authors: Kia Reza , Batmanghelich Shiva , Raithby Paul R.
Published: July 2018

An unusual heterobimetallic bis(triphenylphosphane)(NO2)AgI–CoIII(dimethylglyoximate)(NO2) coordination compound with both bridging and terminal –NO2 (nitro) coordination modes has been isolated and characterized from the reaction of [CoCl(DMGH)2(PPh3)] (DMGH2 is dimethylglyoxime or N,N′-dihydroxybutane-2,3-diimine) with excess AgNO2. In the title compound, namely bis(dimethylglyoximato-1κ2
O,O′)(μ-nitro-1κN:2κ2
O,O′)(nitro-1κN)bis(triphenylphosphane-2κP)cobalt(III)silver(I), [AgCo(C4H7N2O2)2(NO2)2(C18H15P)2], one of the ambidentate –NO2 ligands, in a bridging mode, chelates the AgI atom in an isobidentate κ2
O,O′-manner and its N atom is coordinated to the CoIII atom. The other –NO2 ligand is terminally κN-coordinated to the CoIII atom. The structure has been fully characterized by X-ray crystallography and spectroscopic methods. Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) have been used to study the ground-state electronic structure and elucidate the origin of the electronic transitions, respectively.
Semisynthesis and absolute configuration of a novel rearranged 19,20-δ-lactone (9βH)-pimarane diterpene
Authors: Brito Maria V. , Marques Ricardo A. , Mattos Marcos C. , Alvarenga Meiry E. , Valdo Ana Karoline S. M. , Oliveira Maria C. F. , Martins Felipe T.
Published: July 2018

Annonalide (3β,20-epoxy-3α,16-dihydroxy-15-oxo-7-pimaren-19,6β-olide, C20H26O6, 1) is the major (9βH)-pimarane diterpene isolated from tubers of Cassimirella ampla, and it exhibits cytotoxic properties upon interaction with ctDNA. We have prepared new derivatives of 1 by modification of the (9βH)-pimarane backbone and report here the semisynthesis and absolute configuration of a novel rearranged 19,20-δ-lactone (9βH)-pimarane. Our approach was the reduction of the carbonyl groups of 1 with sodium borohydride, at positions C15 (no stereoselectivity) and C3 (stereoselective reduction), followed by rearrangement of the 6,19-γ-lactone ring into the six-membered 19,20-δ-lactone ring in 4a (3β,6β,16-trihydroxy-7-pimaren-19,20β-olide monohydrate, C20H30O6·H2O). The absolute structure of the new compound, 4a, was determined unambiguously with a Flack parameter x of −0.01 (11), supporting the stereochemistry assignment of 1 redetermined here. Besides the changes in the pattern of covalent bonds caused by reduction and lactone rearrangement, the conformation of one of the three fused cyclohexane rings is profoundly different in 4a, adopting a chair conformation instead of the boat shape found in 1. Furthermore, the intramolecular hydrogen bond present in 1 is lost in new compound 4a, due to hydrogen bonding between the 3-OH group and the solvent water molecule.
(2R,3R)-1,4-Dioxaspiro[4.4]nonane-2,3-dicarboxylic and (2R,3R)-1,4-dioxaspiro[4.5]decane-2,3-dicarboxylic acids
Authors: Minyaev Mikhail E. , Roitershtein Dmitrii M. , Vinogradov Alexey A. , Ananyev Ivan V. , Nifant'ev Ilya E.
Published: July 2018

The title compounds, C9H12O6 and C10H14O6, were formed by careful hydrolysis of the corresponding diethyl esters. Their single crystals were grown from an ethyl acetate/hexane mixture. Crystals of both compounds have monoclinic (P21) symmetry with a single molecule in the asymmetric unit. Both crystal structures are very similar and display four –CO—OH...O=C(OH)– hydrogen bonds, forming a two-dimensional double-layered framework.
4,4-Diphenyl-1-propyl-2-propylsulfanyl-4,5-dihydro-1H-imidazol-5-one
Authors: Akrad Rachida , Guerrab Walid , Lazrak Fatima , Ansar Mhammed , Taoufik Jamal , Mague Joel T. , Ramli Youssef
Published: July 2018

In the title molecule, C21H24N2OS, the five-membered ring is planar with an r.m.s. deviation of 0.0142 Å. The phenyl rings are inclined to the plane of the dihydroimidazolone ring by 60.81 (6) and 79.23 (6)°. In the crystal, inversion dimers are formed by a C—H...O hydrogen bond and a C—H...π(ring) interaction. Additional C—H...O hydrogen bonds and C—H...π(ring) interactions connect these dimers into chains along the c-axis direction.
2-Methyl-4-(pyridin-2-yl)-3H-1,5-benzodiazepine
Authors: El Ghayati Lhoussaine , Ramli Youssef , Moussaif Ahmed , Koubachi Jamal , Taha Mohamed Labd , Essassi El Mokhtar , Mague Joel T.
Published: July 2018

In the title compound, C15H13N3, the seven-membered ring adopts a boat conformation. In the crystal, inversion-related C—H...N hydrogen bonds form dimers, which pack in an alternating fashion.