bluuebunny/crossref_metadata_2025 huggingface dataset:
Noun-Modifying Clause Construction in Japanese
Authors: Matsumoto Yoshiko
Published: October 2017

The noun-modifying clause construction (NMCC) in Japanese is a complex noun phrase in which a prenominal clause is dependent on the head noun. Naturally occurring instances of the construction demonstrate that a single structure, schematized as [[… predicate (finite/adnominal)] Noun], represents a wide range of semantic relations between the head noun and the dependent clause, encompassing some that would be expressed by structurally distinct constructions such as relative clauses, noun complement clauses, and other types of complex noun phrases in other languages, such as English. In that way, the Japanese NMCC demonstrates a clear case of the general noun-modifying construction (GNMCC), that is, an NMCC that has structural uniformity across interpretations that extend beyond the range of relative clauses.

One of the notable properties of the Japanese NMCC is that the modifying clause may consist only of the predicate, reflecting the fact that referential density is moderate in Japanese—arguments of a predicate are not required to be overtly expressed either in the main clause or in the modifying clause. Another property of the Japanese NMCC is that there is no explicit marking in the construction that indicates the grammatical or semantic relation between the head noun and the modifying clause. The two major constituents are simply juxtaposed to each other.

Successful construal of the intended interpretations of instances of such a construction, in the absence of explicit markings, likely relies on an aggregate of structural, semantic, and pragmatic factors, including the semantic content of the linguistic elements, verb valence information, and the interpreter’s real-world knowledge, in addition to the basic structural information.

Researchers with different theoretical approaches have studied Japanese NMCCs or subsets thereof. Syntactic approaches, inspired by generative grammar, have focused mostly on relative clauses and aimed to identify universally recognized syntactic principles. Studies that take the descriptive approach have focused on detailed descriptions and the classification of a wide spectrum of naturally occurring instances of the construction in Japanese. The third and most recent group of studies has emphasized the importance of semantics and pragmatics in accounting for a wide variety of naturally occurring instances.

The examination of Japanese NMCCs provides information about the nature of clausal noun modification and affords insights into languages beyond Japanese, as similar phenomena have reportedly been observed crosslinguistically to varying degrees.
Polarity in the Semantics of Natural Language
Authors: Giannakidou Anastasia
Published: October 2017

This paper provides an overview of polarity phenomena in human languages. There are three prominent paradigms of polarity items: negative polarity items (NPIs), positive polarity items (PPIs), and free choice items (FCIs). What they all have in common is that they have limited distribution: they cannot occur just anywhere, but only inside the scope of licenser, which is negation and more broadly a nonveridical licenser, PPIs, conversely, must appear outside the scope of negation. The need to be in the scope of a licenser creates a semantic and syntactic dependency, as the polarity item must be c-commanded by the licenser at some syntactic level. Polarity, therefore, is a true interface phenomenon and raises the question of well-formedness that depends on both semantics and syntax.

Nonveridical polarity contexts can be negative, but also non-monotonic such as modal contexts, questions, other non-assertive contexts (imperatives, subjunctives), generic and habitual sentences, and disjunction. Some NPIs and FCIs appear freely in these contexts in many languages, and some NPIs prefer negative contexts. Within negative licensers, we make a distinction between classically and minimally negative contexts. There are no NPIs that appear only in minimally negative contexts.

The distributions of NPIs and FCIs crosslinguistically can be understood in terms of general patterns, and there are individual differences due largely to the lexical semantic content of the polarity item paradigms. Three general patterns can be identified as possible lexical sources of polarity. The first is the presence of a dependent variable in the polarity item—a property characterizing NPIs and FCIs in many languages, including Greek, Mandarin, and Korean. Secondly, the polarity item may be scalar: English any and FCIs can be scalar, but Greek, Korean, and Mandarin NPIs are not. Finally, it has been proposed that NPIs can be exhaustive, but exhaustivity is hard to precisely identify in a non-stipulative way, and does not characterize all NPIs. NPIs that are not exhaustive tend to be referentially vague, which means that the speaker uses them only if she is unable to identify a specific referent for them.
Introduction to Socio-Ecological Resilience
Authors: Bollettino Vincenzo , Alcayna Tilly , Dy Philip , Vinck Patrick
Published: October 2017

In recent years, the notion of resilience has grown into an important concept for both scholars and practitioners working on disasters. This evolution reflects a growing interest from diverse disciplines in a holistic understanding of complex systems, including how societies interact with their environment. This new lens offers an opportunity to focus on communities’ ability to prepare for and adapt to the challenges posed by natural hazards, and the mechanism they have developed to cope and adapt to threats. This is important because repeated stresses and shocks still cause serious damages to communities across the world, despite efforts to better prepare for disasters.

Scholars from a variety of disciplines have developed resilience frameworks both to guide macro-level policy decisions about where to invest in preparedness and to measure which systems perform best in limiting losses from disasters and ensuring rapid recovery. Yet there are competing conceptions of what resilience encompasses and how best to measure it. While there is a significant amount of scholarship produced on resilience, the lack of a shared understanding of its conceptual boundaries and means of measurement make it difficult to demonstrate the results or impact of resilience programs.

If resilience is to emerge as a concept capable of aiding decision-makers in identifying socio-geographical areas of vulnerability and improving preparedness, then scholars and practitioners need to adopt a common lexicon on the different elements of the concept and harmonize understandings of the relationships amongst them and means of measuring them. This article reviews the origins and evolution of resilience as an interdisciplinary, conceptual umbrella term for efforts by different disciplines to tackle complex problems arising from more frequent natural disasters. It concludes that resilience is a useful concept for bridging different academic disciplines focused on this complex problem set, while acknowledging that specific measures of resilience will differ as different units and levels of analysis are employed to measure disparate research questions.
Risk and Resilience in the Management and Governance of Natural Hazards
Authors: Kuhlicke Christian
Published: October 2017

The management of natural hazards is undergoing considerable transformation, including the establishment of risk-based management approaches, the encouragement to govern natural hazards more inclusively, and the rising relevance of the concept of resilience. The benefits of this transformation are usually framed like this: Risk-based approaches are regarded as a rational way of balancing the costs associated with mitigating the consequences of hazards and the anticipated benefits; inclusive modes of governing risks help to increase the acceptance and quality of management processes as well as their outcomes; and the concept of resilience is connoted positively since it demands a greater openness to uncertainties and aims at increasing the capacities of various actors to cope with radical surprises.

However, the increasing consideration of both concepts in policy and decision-making processes is associated with a changing demarcation between public and private responsibilities and with an altering relationship between organizations involved in the management process and the wider public. To understand some of these dynamics, this contribution undertakes a change of perspective throughout its development: Instead of asking how the concepts of risk or resilience might be useful to improve the management and governance of natural hazards, one must understand how societies, particularly with regard to their handling of risks and hazards, are governed through the concepts of risk and resilience.

Following this perspective, risk-based management approaches have a defensive function in deflecting blame and rationalizing policy choices ex-ante by enabling managing organizations to more clearly define which risks they are responsible for (i.e., non-acceptable risks) and which are beyond their responsibility (i.e., acceptable risks). This demarcation also has profound distributional effects as acceptable risks usually need to be mitigated individually, raising the question of how to ensure the just sharing of the differently distributed benefits and burdens of risk-based approaches.

The concept of resilience in this context plays a paradoxical yet complementary role: In its more operational interpretation (e.g., adaptive management), resilience-based management approaches can be in conflict with risk-based approaches as they require those responsible for managing risks to follow antagonistic goals. While the idea of resilience puts an emphasis on openness and flexibility, risk-based approaches try to ensure proportionality by transforming uncertainties into calculable risks. At the same time, resilience-based governance approaches, with their emphasis on self-organization and learning, complement risk-based approaches in the sense that actors or communities that are exposed to “acceptable risks” are implicitly or explicitly made responsible for maintaining their own resilience, whereas the role of public authorities is usually restricted to an enabling one.
Causes of Soil Salinization, Sodification, and Alkalinization
Authors: Bui Elisabeth N.
Published: October 2017

Driving forces for natural soil salinity and alkalinity are climate, rock weathering, ion exchange, and mineral equilibria reactions that ultimately control the chemical composition of soil and water. The major weathering reactions that produce soluble ions are tabled. Where evapotranspiration is greater than precipitation, downward water movement is insufficient to leach solutes out of the soil profile and salts can precipitate. Microbes involved in organic matter mineralization and thus the carbon, nitrogen, and sulfur biogeochemical cycles are also implicated. Seasonal contrast and evaporative concentration during dry periods accelerate short-term oxidation-reduction reactions and local and regional accumulation of carbonate and sulfur minerals. The presence of salts and alkaline conditions, together with the occurrence of drought and seasonal waterlogging, creates some of the most extreme soil environments where only specially adapted organisms are able to survive. Sodic soils are alkaline, rich in sodium carbonates, with an exchange complex dominated by sodium ions. Such sodic soils, when low in other salts, exhibit dispersive behavior, and they are difficult to manage for cropping. Maintaining the productivity of sodic soils requires control of the flocculation-dispersion behavior of the soil. Poor land management can also lead to anthropogenically induced secondary salinity. New developments in physical chemistry are providing insights into ion exchange and how it controls flocculation-dispersion in soil. New water and solute transport models are enabling better options of remediation of saline and/or sodic soils.
The Impacts of Environmental Regulation on the U.S. Economy
Authors: Ferris Ann E. , Garbaccio Richard , Marten Alex , Wolverton Ann
Published: October 2017

Concern regarding the economic impacts of environmental regulations has been part of the public dialogue since the beginning of the U.S. EPA. Even as large improvements in environmental quality occurred, government and academia began to examine the potential consequences of regulation for economic growth and productivity. In general, early studies found measurable but not severe effects on the overall national economy. Although price increases due to regulatory requirements outweighed the stimulative effect of investments in pollution abatement, they nearly offset one another. However, these studies also highlighted potentially substantial effects on local labor markets due to the regional and industry concentration of plant closures.

More recently, a substantial body of work examined industry-specific effects of environmental regulation on the productivity of pollution-intensive firms most likely to face pollution control costs, as well as on plant location and employment decisions within firms. Most econometric-based studies found relatively small or no effect on sector-specific productivity and employment, though firms were less likely to open plants in locations subject to more stringent regulation compared to other U.S. locations. In contrast, studies that used economy-wide models to explicitly account for sectoral linkages and intertemporal effects found substantial sector-specific effects due to environmental regulation, including in sectors that were not directly regulated.

It is also possible to think about the overall impacts of environmental regulation on the economy through the lens of benefit-cost analysis. While this type of approach does not speak to how the costs of regulation are distributed across sectors, it has the advantage of explicitly weighing the benefits of environmental improvements against their costs. If benefits are greater than costs, then overall social welfare is improved. When conducting such exercises, it is important to anticipate the ways in which improvements in environmental quality may either directly improve the productivity of economic factors—such as through the increased productivity of outdoor workers—or change the composition of the economy as firms and households change their behavior. If individuals are healthier, for example, they may choose to reallocate their time between work and leisure. Although introducing a role for pollution in production and household behavior can be challenging, studies that have partially accounted for this interconnection have found substantial impacts of improvements in environmental quality on the overall economy.
Involving Parents in Schools
Authors: Joyce Hilary
Published: October 2017

Parent involvement is a broad, multidimensional term that refers to parental attitudes, expectations, and behaviors related to their child’s learning and healthy development. Parent involvement in schools is linked to numerous positive outcomes for youth, teachers, and schools and is critical to school improvement; however a number of barriers often prevent parents from becoming fully involved with schools. Several models exist that provide key strategies to enhance parent and family involvement. This article defines parent involvement, explores an expanded view of parent involvement, describes common barriers, and outlines key strategies to enhance parent involvement. Possible implications for social work practice are also provided.
ThreaDNA: predicting DNA mechanics’ contribution to sequence selectivity of proteins along whole genomes
Authors: Cevost Jasmin , Vaillant Cédric , Meyer Sam
Published: October 2017

Motivation

Many DNA-binding proteins recognize their target sequences indirectly, by sensing DNA’s response to mechanical distortion. ThreaDNA estimates this response based on high-resolution structures of the protein–DNA complex of interest. Implementing an efficient nanoscale modeling of DNA deformations involving essentially no adjustable parameters, it returns the profile of deformation energy along whole genomes, at base-pair resolution, within minutes on usual laptop/desktop computers. Our predictions can also be easily combined with estimations of direct selectivity through a generalized form of position-weight-matrices. The formalism of ThreaDNA is accessible to a wide audience.

Results

We demonstrate the importance of indirect readout for the nucleosome as well as the bacterial regulators Fis and CRP. Combined with the direct contribution provided by usual sequence motifs, it significantly improves the prediction of sequence selectivity, and allows quantifying the two distinct physical mechanisms underlying it.

Availability and implementation

Python software available at bioinfo.insa-lyon.fr, natively executable on Linux/MacOS systems with a user-friendly graphical interface. Galaxy webserver version available.

Supplementary information

Supplementary data are available at Bioinformatics online.
Squeakr: an exact and approximate k-mer counting system
Authors: Pandey Prashant , Bender Michael A , Johnson Rob , Patro Rob
Published: October 2017

Motivation

k-mer-based algorithms have become increasingly popular in the processing of high-throughput sequencing data. These algorithms span the gamut of the analysis pipeline from k-mer counting (e.g. for estimating assembly parameters), to error correction, genome and transcriptome assembly, and even transcript quantification. Yet, these tasks often use very different k-mer representations and data structures. In this article, we show how to build a k-mer-counting and multiset-representation system using the counting quotient filter, a feature-rich approximate membership query data structure. We introduce the k-mer-counting/querying system Squeakr (Simple Quotient filter-based Exact and Approximate Kmer Representation), which is based on the counting quotient filter. This off-the-shelf data structure turns out to be an efficient (approximate or exact) representation for sets or multisets of k-mers.

Results

Squeakr takes 2×–4.3× less time than the state-of-the-art to count and perform a random-point-query workload. Squeakr is memory-efficient, consuming 1.5×–4.3× less memory than the state-of-the-art. It offers competitive counting performance. In fact, it is faster for larger k-mers, and answers point queries (i.e. queries for the abundance of a particular k-mer) over an order-of-magnitude faster than other systems. The Squeakr representation of the k-mer multiset turns out to be immediately useful for downstream processing (e.g. de Bruijn graph traversal) because it supports fast queries and dynamic k-mer insertion, deletion, and modification.

Availability and implementation

https://github.com/splatlab/squeakr available under BSD 3-Clause License.

Supplementary information

Supplementary data are available at Bioinformatics online.
DIBS: a repository of disordered binding sites mediating interactions with ordered proteins
Authors: Schad Eva , Fichó Erzsébet , Pancsa Rita , Simon István , Dosztányi Zsuzsanna , Mészáros Bálint
Published: October 2017

Motivation

Intrinsically Disordered Proteins (IDPs) mediate crucial protein–protein interactions, most notably in signaling and regulation. As their importance is increasingly recognized, the detailed analyses of specific IDP interactions opened up new opportunities for therapeutic targeting. Yet, large scale information about IDP-mediated interactions in structural and functional details are lacking, hindering the understanding of the mechanisms underlying this distinct binding mode.

Results

Here, we present DIBS, the first comprehensive, curated collection of complexes between IDPs and ordered proteins. DIBS not only describes by far the highest number of cases, it also provides the dissociation constants of their interactions, as well as the description of potential post-translational modifications modulating the binding strength and linear motifs involved in the binding. Together with the wide range of structural and functional annotations, DIBS will provide the cornerstone for structural and functional studies of IDP complexes.

Availability and implementation

DIBS is freely accessible at http://dibs.enzim.ttk.mta.hu/. The DIBS application is hosted by Apache web server and was implemented in PHP. To enrich querying features and to enhance backend performance a MySQL database was also created.

Supplementary information

Supplementary data are available at Bioinformatics online.
Tropical Chow Hypersurfaces
Authors: Tripoli Paolo
Published: October 2017

Given a projective variety $X\subset\mathbb{P}^n$ of codimension $k+1$, the Chow hypersurface $Z_X$ is the hypersurface of the Grassmannian $\operatorname{Gr}(k, n)$ parametrizing projective linear spaces that intersect $X$. We introduce the tropical Chow hypersurface $\operatorname{Trop}(Z_X)$. This object only depends on the tropical variety $\operatorname{Trop}(X)$ and we provide an explicit way to obtain $\operatorname{Trop}(Z_X)$ from $\operatorname{Trop}(X)$. We also give a geometric description of $\operatorname{Trop}(Z_X)$. We conjecture that, as in the classical case, $\operatorname{Trop}(X)$ can be reconstructed from $\operatorname{Trop}(Z_X)$ and prove it for the case when $X$ is a curve in $\mathbb{P}^3$. This suggests that tropical Chow hypersurfaces could be the key to construct a tropical Chow variety.
Consumer and Object Experience in the Internet of Things: An Assemblage Theory Approach
Authors: Hoffman Donna L , Novak Thomas P
Published: October 2017

The consumer Internet of Things (IoT) has the potential to revolutionize consumer experience. Because consumers can actively interact with smart objects, the traditional, human-centric conceptualization of consumer experience as consumers’ internal subjective responses to branded objects may not be sufficient to conceptualize consumer experience in the IoT. Smart objects possess their own unique capacities and their own kinds of experiences in interaction with the consumer and each other. A conceptual framework based on assemblage theory and object-oriented ontology details how consumer experience and object experience emerge in the IoT. This conceptualization is anchored in the context of consumer-object assemblages, and defines consumer experience by its emergent properties, capacities, and agentic and communal roles expressed in interaction. Four specific consumer experience assemblages emerge: enabling experiences, comprising agentic self-extension and communal self-expansion, and constraining experiences, comprising agentic self-restriction and communal self-reduction. A parallel conceptualization of the construct of object experience argues that it can be accessed by consumers through object-oriented anthropomorphism, a nonhuman-centric approach to evaluating the expressive roles objects play in interaction. Directions for future research are derived, and consumer researchers are invited to join a dialogue about the important themes underlying our framework.
Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer
Authors: Panda Anshuman , Mehnert Janice M , Hirshfield Kim M , Riedlinger Greg , Damare Sherri , Saunders Tracie , Kane Michael , Sokol Levi , Stein Mark N , Poplin Elizabeth , Rodriguez-Rodriguez Lorna , Silk Ann W , Aisner Joseph , Chan Nancy , Malhotra Jyoti , Frankel Melissa , Kaufman Howard L , Ali Siraj , Ross Jeffrey S , White Eileen P , Bhanot Gyan , Ganesan Shridar
Published: October 2017

Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti–programmed death–ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P < 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10-4; log2 fold-change of CD8A = 1.85, P < 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low–mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.
A progenitor model of SN 1987A based on the slow-merger scenario
Authors: Urushibata Takaki , Takahashi Koh , Umeda Hideyuki , Yoshida Takashi
Published: October 2017

Even after elaborate investigations spanning 30 years, it is still not understand how the progenitor of SN 1987A has evolved. In order to explain the unusual red-to-blue evolution, previous studies have suggested that in the red giant stage an increase either in the surface helium abundance or in the envelope mass was necessary. It is usually supposed that the helium enhancement is caused by rotational mixing, and that the mass increase is the result of a binary merger. We have thus investigated these scenarios thoroughly. We found that rotating single-star models do not satisfy all the observational constraints and that the enhancement of the envelope mass alone does not explain the observations. Here, we consider a slow-merger scenario in which both the helium abundance and the envelope mass enhancements are expected to occur. We show that most of the observational constraints, such as the red-to-blue evolution, lifetime, total mass and position in the Hertzsprung–Russell diagram at collapse, and the chemical anomalies are well reproduced by a merger model with 14 and 9 M⊙ stars. We also discuss the effects of the added envelope spin in the merger scenarios.
School Resource Officer Perceptions and Correlates of Work Roles
Authors: Rhodes Trisha
Published: October 2017

Officers assigned to schools are highly visible with many opportunities to communicate with citizens, though they are relatively isolated from other officers. School resource officers (SROs) are often expected to perform unconventional police roles, including counselling and teaching. Research is beginning to explore how SROs respond to different work settings and role expectations, which poses practical implications for how officers adapt and how they influence the lives of students, parents, and school staff. The present study first examined the work roles of SROs in a Midwestern region. Secondly, this study explored the relationships between SRO roles, individual characteristics, and school characteristics. SROs assigned to programmes in Nebraska, Kansas, Iowa, and Missouri were surveyed and a subset of 20 officers were interviewed and observed during their shifts. Findings showed SROs performed both conventional and non-conventional roles. Multivariate analyses revealed SROs in urban schools and high schools performed more conventional police tasks involving law enforcement and order maintenance, while SROs who supported community policing engaged in more service, mentoring, and teaching tasks. The results highlight areas to enhance community policing in schools, particularly through selection and training of SROs.
HIV Continuum of Care for Youth in the United States
Authors: Lally Michelle A. , van den Berg Jacob J. , Westfall Andrew O. , Rudy Bret J. , Hosek Sybil G. , Fortenberry J. Dennis , Monte Dina , Tanney Mary R. , McFarland Elizabeth J. , Xu Jiahong , Kapogiannis Bill G. , Wilson Craig M. ,   The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN)
Published: October 2017

Background:

Beneficial HIV treatment outcomes require success at multiple steps along the HIV Continuum of Care. Youth living with HIV are a key population, and sites in the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) are known for modeling optimum HIV adolescent care.

Methods:

A longitudinal cohort study conducted at 14 network sites across the United States assessed how the later steps of the Continuum of Care were achieved among the youth: engagement, treatment, and viral load (VL) suppression. Youth aged 13–24 who were behaviorally infected with HIV and linked to care at an ATN-affiliated site were eligible to participate.

Results:

A total of 467 youth were enrolled and had 1 year of available data. Most were aged 22–24 (57%), male (79%), and black/non-Hispanic (71%). Most used alcohol (81%) and marijuana (61%) in the 3 months before enrollment, and 40% had a history of incarceration. Among this cohort of youth, 86% met criteria for care engagement; among these, 98% were prescribed antiretroviral therapy and 89% achieved VL suppression. Sustained VL suppression at all measured time points was found among 59% with initial suppression. Site characteristics were notable for the prevalence of adherence counseling (100%), case management (100%), clinic-based mental health (93%), and substance use (64%) treatment.

Conclusions:

Youth living with HIV in the United States can be successfully treated at health care sites with experience, excellence, and important resources and services. Sustained VL suppression may be an important step to add to the Continuum of Care for youth.
Manipulation of both virus- and cell-specific factors is required for robust transient replication of a hepatitis C virus genotype 3a sub-genomic replicon
Authors: Kelly Lorna , Badhan Anjna , Roberts Grace C. , Mbisa Jean Lutamyo , Harris Mark
Published: October 2017

Hepatitis C virus (HCV) genotype (GT) 3 is the second most prevalent of the seven HCV genotypes and exhibits the greatest resistance to the highly potent, direct-acting antivirals (DAAs) that are currently in use. Previously a stable cell line harbouring the S52 GT3 sub-genomic replicon (SGR) was established, but this SGR was unable to robustly replicate transiently. As transient SGRs are a critical tool in the development of DAAs, and in the study of viral resistance, we sought to establish a transient SGR system based on S52. Next-generation sequencing was used to identify putative culture-adaptive substitutions that had arisen during long-term selection of the S52 SGR. A subset of these substitutions was built back into the S52 SGR in the context of a CpG/UpA-low luciferase reporter, with a single point mutation in NS4A conferring the greatest replication capability upon S52. Modification of the innate immune-sensing pathways of Huh7.5 hepatoma cells by expression of the parainfluenza virus type 5 V protein and SEC14L2 resulted in a further enhancement of S52 replication. Furthermore, this transiently replicating SGR showed genotype-specific differences in sensitivity to two clinically relevant NS5A DAAs. In conclusion, we report that a single substitution in NS4A, coupled with host cell modifications, enabled robust levels of transient replication by the GT3 S52 SGR. This system will have beneficial uses in both basic research into the unique aspects of GT3 biology and drug discovery.
Discriminability of numerosity-evoked fMRI activity patterns in human intra-parietal cortex reflects behavioral numerical acuity
Authors: Lasne G. , Piazza M. , Dehaene S. , Kleinschmidt A. , Eger E.
Published: October 2017

Areas of the primate intraparietal cortex have been identified as an important substrate of numerical cognition. In human fMRI studies, activity patterns in these and other areas have allowed researchers to read out the numerosity a subject is viewing, but the relation of such decodable information with behavioral numerical proficiency remains unknown.

Here, we estimated the precision of behavioral numerosity discrimination (internal Weber fraction) in twelve adult subjects based on psychophysical testing in a delayed numerosity comparison task outside the scanner. FMRI data were then recorded during a similar task, to obtain the accuracy with which the same sample numerosities could be read out from evoked brain activity patterns, as a measure of the precision of the neuronal representation. Sample numerosities were decodable in both early visual and intra-parietal cortex with approximately equal accuracy on average. In parietal cortex, smaller numerosities were better discriminated than larger numerosities of the same ratio, paralleling smaller behavioral Weber fractions for smaller numerosities. Furthermore, in parietal but not early visual cortex, fMRI decoding performance was correlated with behavioral number discrimination acuity across subjects (subjects with a more precise behavioral Weber fraction measured prior to scanning showed greater discriminability of fMRI activity patterns in intraparietal cortex, and more specifically, the right LIP region).

These results suggest a crucial role for intra-parietal cortex in supporting a numerical representation which is explicitly read out for numerical decisions and behavior.
Forward-reverse mutation cycles between stages of cancer development
Authors: Hu Taobo , Kumar Yogesh , Shazia Iram , Duan Shen-Jia , Li Yi , Chen Lei , Chen Jin-Fei , Yin Rong , Kwong Ava , Leung Gilberto Ka-Kit , Mat Wai-Kin , Wu Zhenggang , Long Xi , Chan Cheuk-Hin , Lee Peggy , Ng Siu-Kin , Ho Timothy Y. C. , Yang Jianfeng , Ding Xiaofan , Tsang Shui-Ying , Zhou Xuqing , Zhang Dan-Hua ,   International Cancer Genome Consortium, Zhou En-Xiang , Xu Lin , Poon Wai-Sang , Wang Hong-Yang , Xue Hong
Published: October 2017

Earlier, prominent occurrences of interstitial loss-of-heterozygosities (LOHs) were found in different cancers as a type of single-nucleotide-variations (SNVs), at rates far exceeding those of the commonly investigated gain-of-heterozygosities (GOHs) type of SNVs. Herein, such co-occurrences of LOHs and GOHs were confirmed in 102 cases of four cancer types analyzed with three different next-generation sequencing platforms, comparing non-tumor, paratumor, and tumor tissues with white-blood-cell controls; and in 246 pan-cancer cases of whole-genome tumor-control pairs. Unexpectedly, large numbers of SNVs enriched with CG>TG GOHs and copy-number-variations (CNVs) proximal to these GOHs were detected in the non-tumor tissues, which were extensively reversed in paratumors showing prominent TG>CG LOHs with proximal CNVs, and less so in tumors to form forward-reverse mutation cycles. Lineage effects in the reversions, likely resulting from directional selection, supported a sequential rather than parallel mode of evolution as described in a 'Stage Specific Populations' model of cancer development.
Modeling neuron–glia interactions with theBrian 2simulator
Authors: Stimberg Marcel , Goodman Dan F. M. , Brette Romain , De Pittà Maurizio
Published: October 2017

Despite compelling evidence that glial cells could crucially regulate neural network activity, the vast majority of available neural simulators ignores the possible contribution of glia to neuronal physiology. Here, we show how to model glial physiology and neuron-glia interactions in theBrian 2simulator.Brian 2offers facilities to explicitly describe any model in mathematical terms with limited and simple simulator-specific syntax, automatically generating high-performance code from the user-provided descriptions. The flexibility of this approach allows us to model not only networks of neurons, but also individual glial cells, electrical coupling of glial cells, and the interaction between glial cells and synapses. We therefore conclude thatBrian 2provides an ideal platform to efficiently simulate glial physiology, and specifically, the influence of astrocytes on neural activity.
Correlation structure of grid cells is preserved during sleep
Authors: Gardner Richard J. , Lu Li , Wernle Tanja , Moser May-Britt , Moser Edvard I.
Published: October 2017

The network of grid cells in the medial entorhinal cortex forms a fixed reference frame for mapping physical space. The mechanistic origin of the grid representation is unknown, but continuous attractor network (CAN) models explain multiple fundamental features of grid-cell activity. An untested prediction of CAN grid models is that the grid-cell network should exhibit an activity correlation structure that transcends behavioural or brain states. By recording from MEC cell ensembles during navigation and sleep, we found that spatial phase offsets of grid cells predict arousal-state-independent spike rate correlations. Similarly, state-invariant correlations between conjunctive grid-head-direction and pure head-direction cells were predicted by their head-direction tuning offsets. Spike rates of grid cells were only weakly correlated across modules, and module scale relationships disintegrated during slow-save sleep, suggesting that modules function as independent attractor networks. Collectively, our observations suggest that network states in MEC are expressed universally across brain and behaviour states.
Predicting microRNA targeting efficacy in Drosophila
Authors: Agarwal Vikram , Subtelny Alexander O. , Thiru Prathapan , Ulitsky Igor , Bartel David P.
Published: October 2017

Important for understanding the regulatory roles of miRNAs is the ability to predict the mRNA targets most responsive to each miRNA. Here, we acquired datasets needed for the quantitative study of microRNA targeting in Drosophila. Analyses of these data expanded the types of sites known to be effective in flies, expanded the mRNA regions with detectable targeting to include 5′ UTRs, and identified features of site context that correlate with targeting efficacy. Updated evolutionary analyses evaluated the probability of conserved targeting for each predicted site and indicated that more than a third of the Drosophila genes are preferentially conserved targets of miRNAs. Based on these results, a quantitative model was developed to predict targeting efficacy in insects. This model performed better than existing models and will drive the next version of TargetScanFly (v7.0; targetscan.org), thereby providing a valuable resource for placing miRNAs into gene-regulatory networks of this important experimental organism.
A natural variant and an engineered mutation in a GPCR promote DEET resistance in C. elegans
Authors: Dennis Emily J. , Dobosiewicz May , Jin Xin , Duvall Laura B. , Hartman Philip S. , Bargmann Cornelia I. , Vosshall Leslie B.
Published: October 2017

DEET (N,N-diethyl-meta-toluamide) is a synthetic chemical, identified by the United States Department of Agriculture in 1946 in a screen for repellents to protect soldiers from mosquito-borne diseases1,2. Since its discovery, DEET has become the world’s most widely used arthropod repellent3, and is effective against invertebrates separated by millions of years of evolution, including biting flies4, honeybees5, ticks6, and land leeches4,7. In insects, DEET acts on the olfactory system5,8–14 and requires the olfactory receptor co-receptor orco9,11–13, but its specific mechanism of action remains controversial. Here we show that the nematode Caenorhabditis elegans is sensitive to DEET, and use this genetically-tractable animal to study its mechanism of action. We found that DEET is not a volatile repellent, but interferes selectively with chemotaxis to a variety of attractant and repellent molecules. DEET increases pause lengths to disrupt chemotaxis to some odours but not others. In a forward genetic screen for DEET-resistant animals, we identified a single G protein-coupled receptor, str-217, which is expressed in a single pair of DEET-responsive chemosensory neurons, ADL. Misexpression of str-217 in another chemosensory neuron conferred strong responses to DEET. Both engineered str-217 mutants and a wild isolate of C. elegans carrying a deletion in str-217 are DEET-resistant. We found that DEET can interfere with behaviour by inducing an increase in average pause length during locomotion, and show that this increase in pausing requires both str-217 and ADL neurons. Finally, we demonstrated that ADL neurons are activated by DEET and that optogenetic activation of ADL increased average pause length. This is consistent with the “confusant” hypothesis, in which DEET is not a simple repellent but modulates multiple olfactory pathways to scramble behavioural responses12,13. Our results suggest a consistent motif for the effectiveness of DEET across widely divergent taxa: an effect on multiple chemosensory neurons to disrupt the pairing between odorant stimulus and behavioural response.
Symbiodiniumgenomes reveal adaptive evolution of functions related to symbiosis
Authors: Liu Huanle , Stephens Timothy G. , González-Pech Raúl A. , Beltran Victor H. , Lapeyre Bruno , Bongaerts Pim , Cooke Ira , Bourne David G. , Forêt Sylvain , Miller David J. , van Oppen Madeleine J. H. , Voolstra Christian R. , Ragan Mark A. , Chan Cheong Xin
Published: October 2017

Symbiosis between dinoflagellates of the genusSymbiodiniumand reef-building corals forms the trophic foundation of the world’s coral reef ecosystems. Here we present the first draft genome ofSymbiodinium goreaui(Clade C, type C1: 1.03 Gbp), one of the most ubiquitous endosymbionts associated with corals, and an improved draft genome ofSymbiodinium kawagutii(Clade F, strain CS-156: 1.05 Gbp), previously sequenced as strain CCMP2468, to further elucidate genomic signatures of this symbiosis. Comparative analysis of four availableSymbiodiniumgenomes against other dinoflagellate genomes led to the identification of 2460 nuclear gene families that show evidence of positive selection, including genes involved in photosynthesis, transmembrane ion transport, synthesis and modification of amino acids and glycoproteins, and stress response. Further, we identified extensive sets of genes for meiosis and response to light stress. These draft genomes provide a foundational resource for advancing our understandingSymbiodiniumbiology and the coral-algal symbiosis.
Auranofin inhibits virulence inPseudomonas aeruginosa
Authors: Wei Tan Leon Zhen , Hoong Yam Joey Kuok , Hong Ziyan , Santillan Salido May Margarette , Woo Bau Yi , Yau Li Sam Fong , Yang Liang , Givskov Michael , Chng Shu-Sin
Published: October 2017

Pseudomonas aeruginosais widely attributed as the leading cause of hospital-acquired infections. Due to intrinsic antibiotic resistance mechanisms and the ability to form biofilms,P. aeruginosainfections are challenging to treat.P. aeruginosaemploys multiple virulence mechanisms to establish infections, many of which are controlled by the global virulence regulator Vfr. An attractive strategy to combatP. aeruginosainfections is thus the use of anti-virulence compounds. Here, we report the discovery that FDA-approved drug auranofin attenuates virulence inP. aeruginosa. We demonstrate that auranofin acts by targeting Vfr, which in turn leads to inhibition of quorum sensing (QS) and Type IV pili (TFP). Consistent with inhibition of QS and TFP expression, we show that auranofin attenuates biofilm maturation, and when used in combination with colistin, displays strong synergy in eradicatingP. aeruginosabiofilms. Auranofin may have immediate applications as an anti-virulence drug againstP. aeruginosainfections.
Neural oscillations during conditional associative learning
Authors: Clarke Alex , Roberts Brooke M. , Ranganath Charan
Published: October 2017

Associative learning requires mapping between complex stimuli and behavioural responses. When multiple stimuli are involved, conditional associative learning is a gradual process with learning based on trial and error. It is established that a distributed network of regions track associative learning, however the role of neural oscillations in human learning remains less clear. Here we used scalp EEG to test how neural oscillations change during learning of arbitrary visuo-motor associations. Participants learned to associative 48 different abstract shapes to one of four button responses through trial and error over repetitions of the shapes. To quantify how well the associations were learned for each trial, we used a state-space computational model of learning that provided a probability of each trial being correct given past performance for that stimulus, that we take as a measure of the strength of the association. We used linear modelling to relate single-trial neural oscillations to single-trial measures of association strength. We found frontal midline theta oscillations during the delay period tracked learning, where theta activity was strongest during the early stages of learning and declined as the associations were formed. Further, posterior alpha and low-beta oscillations in the cue period showed strong desynchronised activity early in learning, while stronger alpha activity during the delay period were seen as associations became well learned. Moreover, the magnitude of these effects during early learning, before the associations were learned, related to improvements in memory seen on the next presentation of the stimulus. The current study provides clear evidence that frontal theta and posterior alpha/beta oscillations play a key role during associative memory formation.
Directed functional connectivity using dynamic graphical models
Authors: Schwab Simon , Harbord Ruth , Zerbi Valerio , Elliott Lloyd , Afyouni Soroosh , Smith Jim Q. , Woolrich Mark W. , Smith Stephen M. , Nichols Thomas E.
Published: October 2017

There are a growing number of neuroimaging methods that model spatio-temporal patterns of brain activity to allow more meaningful characterizations of brain networks. This paper proposes dynamic graphical models (DGMs) for dynamic, directed functional connectivity. DGMs are a multivariate graphical model with time-varying coefficients that describe instantaneous directed relationships between nodes. A further benefit of DGMs is that networks may contain loops and that large networks can be estimated. We use network simulations, human resting-state fMRI (N = 500) to investigate the validity and reliability of the estimated networks. We simulate systematic lags of the hemodynamic response at different brain regions to investigate how these lags potentially bias directionality estimates. In the presence of such lag confounds (0.4–0.8 seconds offset between connected nodes), our method has a sensitivity of 72%–77% to detect the true direction. Stronger lag confounds have reduced sensitivity, but do not increase false positives (i.e., directionality estimates of the opposite direction). In human resting-state fMRI, we find the DMN has consistent influence on the cerebellar, the limbic and the auditory/temporal network, as well a consistent reciprocal relationship between the visual medial and visual lateral network. Finally, we apply the method in a small mouse fMRI sample and discover a highly plausible relationship between areas in the hippocampus feeding into the cingulate cortex. We provide a computationally efficient implementation of DGM as a free software package for R.