bluuebunny/crossref_metadata_2025 huggingface dataset:
Superdirectivity from arrays of strongly coupled meta-atoms
Authors: Radkovskaya A. , Kiriushechkina S. , Vakulenko A. , Petrov P. , Solymar L. , Li L. , Vallecchi A. , Stevens C. J. , Shamonina E.
Published: September 2018

We explore the possibility of achieving superdirectivity in metamaterial-inspired endfire antenna arrays relying on the good services of magnetoinductive waves. These are short-wavelength slow waves propagating by virtue of coupling between resonant meta-atoms. Magnetoinductive waves are capable of providing a rapidly varying current distribution on the scale of the free space wavelength. Using dimers and trimers of magnetically coupled split ring resonators with only one element driven by an external source, we introduce an analytical condition for realising superdirective current distributions. Although those current distributions have been known theoretically for a good 60 years, this is the first time that a recipe is given to realise them in practice. Our key parameters are the size of the array, the resonant frequency and quality factor of the elements, and their coupling constant. We compare our analytical results for coupled magnetic dipoles with numerical results from CST simulations for meta-atoms of various shapes. The calculated bandwidth of 5 MHz for a dimer operating at 150 MHz indicates that, contrary to popular belief, superdirective antennas exist not only in theory but may have practical applications.
Enhanced detection sensitivity of terahertz magnetic nearfield with cryogenically-cooled magnetooptical sampling in terbium-gallium-garnet
Authors: Kurihara Takayuki , Qiu Hongsong , Kato Kosaku , Watanabe Hiroshi , Nakajima Makoto
Published: September 2018

Due to its efficient coupling with electron spins, the application of terahertz magnetic nearfield in metallic microstructures has been attracting attention. While paramagnetic materials that exhibit magneto-optical effect have been known to enable visualization of the terahertz magnetic fields (magneto-optical sampling), the low field-detection sensitivity has been setting a practical limit to the broader application of such a method. Here we propose and experimentally demonstrate that the terahertz magnetic nearfield-detection sensitivity of magneto-optical sampling with terbium-gallium-garnet crystal can be drastically enhanced by cooling the crystal down to cryogenic temperatures in accordance with Curie's law. Our result paves the way for the efficient characterization of the terahertz magnetic nearfield in planer metamaterials.
Finite growth of InGaN/GaN triple-quantum-well microdisks on LiAlO2 substrate
Authors: Tsai Cheng-Da , Lo Ikai , Wang Ying-Chieh , Yang Chen-Chi , You Shuo-Ting , Yang Hong-Yi , Huang Hui-Chun , Chou Mitch M. C.
Published: September 2018

We have grown high-quality InxGa1-xN/GaN triple-quantum-well microdisks on LiAlO2 substrate by plasma-assisted molecular beam epitaxy. The InxGa1-xN/GaN microdisk with a hexagonal shape of oblique face 28o-angle off c-axis was achieved. The mechanism of the termination of awl-shaped growth and the growth rates of GaN-barrier and InxGa1-xN-well were evaluated and confirmed with the triple quantum wells. Based on the growth rates and 28o-angle geometric shape, one can control the finite size of InGaN/GaN microdisks by plasma-assisted molecular beam epitaxy.
Time dependent stability margin in multistable systems
Authors: Brzeski P. , Kurths J. , Perlikowski P.
Published: September 2018

We propose a novel technique to analyze multistable, non-linear dynamical systems. It enables one to characterize the evolution of a time-dependent stability margin along stable periodic orbits. By that, we are able to indicate the moments along the trajectory when the stability surplus is minimal, and even relatively small perturbation can lead to a tipping point. We explain the proposed approach using two paradigmatic dynamical systems, i.e., Rössler and Duffing oscillators. Then, the method is validated experimentally using the rig with a double pendulum excited parametrically. Both numerical and experimental results reveal significant fluctuations of sensitivity to perturbations along the considered periodic orbits. The proposed concept can be used in multiple applications including engineering, fluid dynamics, climate research, and photonics.
General theory of charge regulation and surface differential capacitance
Authors: Podgornik Rudolf
Published: September 2018

A generalization of the mean-field approach will be derived that will take into account the ion-ion as well as ion-surface non-electrostatic effects on an equal footing, being based on the bulk and surface equations of state in the absence of electrostatic interactions. This approach will be applied to the analysis of a single planar surface with dissociable sites with several models of the specific ion-surface non-electrostatic interactions, providing a general thermodynamic insight into the characteristics of the surface differential capacitance. The ion-surface interactions and ion-ion packing considerations at the surface will be shown to be more relevant than the bulk packing constraints for ions vicinal to the surface, as well as to set in prior to the conditions where the bulk packing constraints would become relevant.
Fostering healthcare innovation in public hospitals: the Queensland experience
Authors: Mundy Linda , Howard Sarah , McQueen Liam , Thomson Jacqui , Hewson Kaye
Published: September 2018

Faced with scarce resources and a demand for health care that exceeds supply, health policy makers at all levels of government need to adopt some form of rationing when deciding which health services should be funded in the public health system. With a relatively small investment, programs such as Queensland Health’s New Technology Funding Evaluation Program (NTFEP) fosters innovation by providing funding and pilot studies for new and innovative healthcare technologies. The NTFEP assists policy makers to make informed decisions regarding investments in new safe and effective technologies based on available evidence gathered from real-world settings relevant to Queensland patients and clinicians. In addition, the NTFEP allows appropriate patient access, especially in rural and remote locations, to potentially beneficial technologies and acts a gatekeeper, protecting them from technologies that may be detrimental or harmful.

What is known about the topic?
Jurisdictions have struggled to identify ways to manage the introduction of new and innovative health technologies into clinical practice. The 2009 review of health technology in Australia recommended better assessment and appraisal by ensuring real-life practices in hospitals and community settings were considered, with a consumer and patient focus.

What does this paper add?
Queensland Health’s NTFEP provides a robust and transparent mechanism to manage the introduction of innovative healthcare technologies into clinical practice, providing an opportunity to collect real-world data outside of formal clinical trials. These data can not only be used to inform clinical, but also purchasing, decision-making within the public health system. This model of investment and innovation has the potential to be implemented in other jurisdictions and provide opportunities to share learnings.

What are the implications for practitioners?
Programs such as the NTFEP provide reassurance to practitioners and patients alike that innovative healthcare technologies are adopted in public hospitals using an evidence-based approach after demonstrating that they are not only safe and clinically effective, but represent value for money and improved patient outcomes in a public health system.
Model of disharmonic succession of dystrophic lakes based on aquatic beetle fauna (Coleoptera)
Authors: Pakulnicka J. , Zawal A.
Published: September 2018

Directional changes in environmental conditions during individual stages of the succession of lakes should determine the character of the aquatic beetle fauna inhabiting them. Can changes in environmental conditions lead to degradation of fauna and to a deterioration of the ecological quality of lakes? We analysed this problem in 40 lakes. The fauna of the lakes proved to be rich and diverse in terms of species. Deterioration of species richness along successional stages was not observed, but distinct changes were noted in faunal composition. The eurytopic component proved stable, whereas changes in specialised components (i.e. lake and river species and tyrphophiles) were of key importance. The formation of beetle communities in the lakes was influenced to a greater extent by environmental factors, namely substrate, macrophyte structure and Sphagnum mat cover, than by the physical parameters of the water (pH, saturation or conductivity). The lakes proved to be of considerable ecological value. Regardless of the stage of succession, they are a habitat for numerous species, including rare and endangered ones. Hence, on the one hand humic lakes play an important role in local biodiversity, whereas on the other hand they may be perceived as refuges for species in environments that could be restored as a result of beneficial measures.
Superoxide dismutase activity confers (p)ppGpp-mediated antibiotic tolerance to stationary-phase
Pseudomonas aeruginosa
Authors: Martins Dorival , McKay Geoffrey , Sampathkumar Gowthami , Khakimova Malika , English Ann M. , Nguyen Dao
Published: September 2018

Significance

Antibiotic tolerance causes antibiotic treatment failure and promotes the emergence of genotypic resistance in chronic infections, such as those caused by the pathogen
Pseudomonas aeruginosa
. Laboratory stationary-phase bacteria exhibit a slow growing and metabolically quiescent state associated with high levels of multidrug tolerance likely analogous to the in vivo environment during chronic infection. We demonstrate that superoxide dismutases confer multidrug tolerance in stationary-phase bacteria, and identify a link between (p)ppGpp-mediated stress responses, superoxide metabolism, and membrane permeability to antibiotics. Inhibition of superoxide dismutase activity may overcome multidrug tolerance and potentiate current bactericidal antibiotics in the treatment of
P. aeruginosa
chronic infections.
Improving nanopore read accuracy with the R2C2 method enables the sequencing of highly multiplexed full-length single-cell cDNA
Authors: Volden Roger , Palmer Theron , Byrne Ashley , Cole Charles , Schmitz Robert J. , Green Richard E. , Vollmers Christopher
Published: September 2018

High-throughput short-read sequencing has revolutionized how transcriptomes are quantified and annotated. However, while Illumina short-read sequencers can be used to analyze entire transcriptomes down to the level of individual splicing events with great accuracy, they fall short of analyzing how these individual events are combined into complete RNA transcript isoforms. Because of this shortfall, long-distance information is required to complement short-read sequencing to analyze transcriptomes on the level of full-length RNA transcript isoforms. While long-read sequencing technology can provide this long-distance information, there are issues with both Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT) long-read sequencing technologies that prevent their widespread adoption. Briefly, PacBio sequencers produce low numbers of reads with high accuracy, while ONT sequencers produce higher numbers of reads with lower accuracy. Here, we introduce and validate a long-read ONT-based sequencing method. At the same cost, our Rolling Circle Amplification to Concatemeric Consensus (R2C2) method generates more accurate reads of full-length RNA transcript isoforms than any other available long-read sequencing method. These reads can then be used to generate isoform-level transcriptomes for both genome annotation and differential expression analysis in bulk or single-cell samples.
Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury
Authors: Xia Yuguo , Pu Hongjian , Leak Rehana K. , Shi Yejie , Mu Hongfeng , Hu Xiaoming , Lu Zhengyu , Foley Lesley M. , Hitchens T. Kevin , Dixon C. Edward , Bennett Michael V. L. , Chen Jun
Published: September 2018

Significance

Tissue plasminogen activator (tPA) is employed in stroke patients to lyse blood clots, but its therapeutic potential in brain trauma victims is far from settled, partly due to fears of internal bleeding. The long-term effects of tPA upon the white matter of the brain and neurological outcomes after head trauma are also uncertain. To address these gaps, we performed electrophysiological, anatomical, and behavioral studies in genetically modified or wild-type mice subjected to traumatic brain injury and infused tPA through the nose. We found that natural or synthetic forms of tPA protect or repair white matter tracts without magnifying internal bleeding. Thus, tPA treatment after brain injury promotes communication across neuronal networks through nerve fiber tracts and improves long-term adaptive behavior.
Decoding and encoding the discourse meaning of punctuation
Authors: Wang Caiwen
Published: September 2018

This exploratory research examines translation students’ use of punctuation, by applying Newmark’s (1988) classical idea of punctuation as a discourse unit for meaning demarcation. Data were collected from a group of 25 Chinese students studying specialised translation at a British university. The research focuses on the use of two punctuation marks in English: comma and period or full stop. The aim is to investigate how students of translation analyse the meaning of a source text with punctuation marks and how they subsequently convert this meaning into the target language again using punctuation marks. It is found that students generally do not automatically copy the punctuation marks of the source text into the translation. They will customize or modify the original punctuation marks according to their meaning analysis of the text and their knowledge of punctuation in source and target languages. Finally, we will discuss the implications of the research for translation education.
Can serious games help to mitigate climate change? Exploring their influence on Spanish and American teenagers’ attitudes / ¿Pueden los serious games ayudar a mitigar el cambio climático? Una exploración de su influencia sobre las actitudes de los adolescentes españoles y estadounidenses
Authors: Ouariachi Tania , Gutiérrez-Pérez José , Olvera-Lobo María-Dolores
Published: September 2018

There is an urgent need to curb emissions and mitigate climate change, and this fight requires a change in teenagers’ attitudes. In search of new approaches targeting youth, online games are seen as a promising tool for communication and education. Using the serious game 2020 Energy as a case study, the main objective of this paper is to examine the influence of the game on Spanish and American teenagers’ attitudes ( N = 108), employing a pretest-posttest design with an experimental condition (playing the game) and a control condition (not playing the game). Results show that there have not been statistically significant differences after playing the game, although when looking closer at each factor, some positive consequences can be found.
Early Modern Play: Three Perspectives
Authors: Rothstein Bret
Published: September 2018

Let us Draw on the past as we look toward the future. Specifically, let us begin with the Propositiones ad acuendos juvenes, or “Problems to Sharpen the Young,” by Alcuin of York. Written sometime in the later eighth century, this text offers a number of logical and mathematical problems meant, as the title suggests, to refine one’s intellect. Some of the problems are fairly straightforward, as in the case of a question about how many sheep might fit in a field measuring 200 × 100 feet, with each sheep being allocated a space of 5 × 4 feet. Others, like de porcis, are somewhat trickier. This latter example is an impossible puzzle that asks how one might slaughter 300 pigs in three days by only slaughtering an odd number on each of the days.
Community sport and social cohesion: in search of the practical understandings of community sport practitioners in Flanders
Authors: Sabbe Shana , Bradt Lieve , Spaaij Ramón , Roose Rudi
Published: September 2018

Current literature suggests that community sport contributes to social cohesion. Yet, empirical research is still scant, and existing conceptualizations of social cohesion in the context of community sport are dominated by a social capital approach emphasizing the individual over the structural conditions that need to be addressed if social cohesion is to be achieved. This article aims to provide more insight into how social cohesion is operationalized in community sport practices. Qualitative research on the practical understandings of community sport practitioners was undertaken across three cities in Flanders, Belgium. The findings suggest that practitioners adopt both individual and structural understandings of social cohesion. Moreover, they experience that their efforts to develop a structural approach are pressured by a dominant individualized approach. These findings reveal a disjuncture between academic constructs of social cohesion and the practical understandings of community sport practitioners. The article proposes ways to address the need for the empirical and conceptual development of social cohesion in the context of community sport and the broader community development field.
Insight into the specificity and severity of pathogenic mechanisms associated with missense mutations through experimental and structural perturbation analyses
Authors: Medina-Carmona Encarnación , Betancor-Fernández Isabel , Santos Jaime , Mesa-Torres Noel , Grottelli Silvia , Batlle Cristina , Naganathan Athi N , Oppici Elisa , Cellini Barbara , Ventura Salvador , Salido Eduardo , Pey Angel L
Published: September 2018

Most pathogenic missense mutations cause specific molecular phenotypes through protein destabilization. However, how protein destabilization is manifested as a given molecular phenotype is not well understood. We develop here a structural and energetic approach to describe mutational effects on specific traits such as function, regulation, stability, subcellular targeting or aggregation propensity. This approach is tested using large-scale experimental and structural perturbation analyses in over thirty mutations in three different proteins (cancer-associated NQO1, transthyretin related with amyloidosis and AGT linked to primary hyperoxaluria type I) and comprising five very common pathogenic mechanisms (loss-of-function and gain-of-toxic function aggregation, enzyme inactivation, protein mistargeting and accelerated degradation). Our results revealed that the magnitude of destabilizing effects and, particularly, their propagation through the structure to promote disease-associated conformational states largely determine the severity and molecular mechanisms of disease-associated missense mutations. Modulation of the structural perturbation at a mutated site is also shown to cause switches between different molecular phenotypes. When very common disease-associated missense mutations were investigated, we also found that they were not among the most deleterious possible missense mutations at those sites, and required additional contributions from codon bias and effects of CpG sites to explain their high frequency in patients. Our work sheds light on the molecular basis of pathogenic mechanisms and genotype–phenotype relationships, with implications for discriminating between pathogenic and neutral changes within human genome variability from whole genome sequencing studies.
Effect of fluconazole prophylaxis on Candida fluconazole susceptibility in premature infants
Authors: Autmizguine Julie , Smith P Brian , Prather Kristi , Bendel Catherine , Natarajan Girija , Bidegain Margarita , Kaufman David A , Burchfield David J , Ross Ashley S , Pandit Paresh , Schell Wiley A , Gao Jamie , Benjamin Daniel K ,   Fluconazole Prophylaxis Study Team, MacGilvray Scott , Wade Kelly , Bidegain Margarita , Toms Rune , Finer Neil , Burchfield David , Stewart Dan , Arrieta Antonio , Duara Shahnaz , Shankaran Seetha , Nedrelow Jonathan , White Robert , Kantak Anand , Shattuck Karen , Pammi Mohan , Kennedy Kathleen , Sanchez Pablo , Bendel Catherine , Dhanireddy Ramasubbareddy , Bloom Barry , Hudak Mark , Perenyi Agnes , Neu Natalie , Ezeanolue Echezona , Kim Roger , Hudak Mark , Ross Ashley , Mundakel Gratias , Pandit Paresh , Ross Ashley , Poindexter Brenda , Gordon Phillip
Published: September 2018

Objectives

Extremely premature infants are at high risk of developing invasive candidiasis; fluconazole prophylaxis is safe and effective for reducing invasive candidiasis in this population but further study is needed. We sought to better understand the effect of prophylactic fluconazole on a selection of fluconazole-resistant Candida species.

Methods

We evaluated the susceptibility to fluconazole of Candida isolates from premature infants (<750 g birth weight) enrolled in a multicentre, randomized, placebo-controlled trial of fluconazole prophylaxis. Candida species were isolated through surveillance cultures at baseline (study day 0–7), period 1 (study day 8–28) and period 2 (study day 29–49). Fluconazole MICs were determined for all Candida isolates.

Results

Three hundred and sixty-one infants received fluconazole (n = 188) or placebo (n = 173). After the baseline period, Candida colonization was significantly lower in the fluconazole group compared with placebo during periods 1 (5% versus 27%; P < 0.001) and 2 (3% versus 27%; P < 0.001). After the baseline period, two infants (1%) were colonized with at least one fluconazole-resistant Candida in each group. Median fluconazole MIC was similar in both treatment groups at baseline and period 1. However, in period 2, median MIC was higher in the fluconazole group compared with placebo (1.00 versus 0.50 mg/L, P = 0.01). There was no emergence of resistance observed and no patients developed invasive candidiasis with a resistant Candida isolate.

Conclusions

Fluconazole prophylaxis decreased Candida albicans and ‘non-albicans’ Candida colonization and was associated with a slightly higher fluconazole MIC for colonizing Candida isolates.
Impact of Case-Specific Education and Face-to-Face Feedback to Prescribers and Nurses in the Management of Hospitalized Patients With a Positive Clostridium difficile Test
Authors: Fabre Valeria , Markou Theodore , Sick-Samuels Anna , Rock Clare , Avdic Edina , Shulder Stephanie , Dzintars Kathryn , Saunders Heather , Andonian Jennifer , Cosgrove Sara E
Published: September 2018

Background

Approaches to changing providers’ behavior around Clostridium difficile (CD) management are needed. We hypothesized that case-specific teaching points and face-to-face discussions with prescribers and nurses would improve management of patients with a positive CD test.

Methods

Charts of patients age ≥18 years with positive CD tests hospitalized July 2016 to May 2017 were prospectively reviewed to assess CD practices and generate management recommendations. The study had 4 periods: baseline (pre-intervention), intervention #1, observation, and intervention #2. Both interventions consisted of an in-person, real-time, case-based discussion and education by a CD Action Team (CDAT). Assessment occurred within 24 hours of a positive CD test for all periods; during the intervention periods, management was also assessed within 48 hours after CDAT-delivered recommendations. Outcomes included proportion of patients receiving optimized treatment and incidence rate ratios of practice changes (both CDAT-prompted and CDAT-independent).

Results

Overall, the CDAT made recommendations to 84 of 96 CD cases during intervention periods, and providers accepted 43% of CDAT recommendations. The implementation of the CDAT led to significant improvement in bowel movement (BM) documentation, use of proton pump inhibitors, and antibiotic selection for non-CD infections. Selection of CD-specific therapy improved only in the first intervention period. Laxative use and treatment of CD colonization cases remained unchanged. Only BM documentation, a nurse-driven task, was sustained independent of CDAT prompting.

Conclusions

A behavioral approach to changing the management of positive CD tests led to self-sustained practice changes among nurses but not physicians. Better understanding of prescribers’ decision-making is needed to devise enduring interventions.
Suzaku and NuSTAR X-ray spectroscopy of γ Cassiopeiae and HD 110432
Authors: Tsujimoto Masahiro , Morihana Kumiko , Hayashi Takayuki , Kitaguchi Takao
Published: September 2018

γ Cas and its dozen analogs comprise a small but distinct class of X-ray sources. They are early Be-type stars with an exceptionally hard thermal X-ray emission. The X-ray production mechanism has been under intense debate. Two competing ideas are (i) the magnetic activities in the Be star and its disk, and (ii) the mass accretion onto the unidentified white dwarf (WD). We adopt the latter as a working hypothesis and apply physical models developed to describe the X-ray spectra of classical WD binaries containing a late-type companion. Models of non-magnetic and magnetic accreting WDs were applied to γ Cas and its brightest analog HD 110432 using the Suzaku and NuSTAR data. The spectra were fitted by the two models, including the Fe fluorescence and the Compton reflection in a consistent geometry. The derived physical parameters are in a reasonable range in comparison to their classical WD binary counterparts. Additional pieces of evidence in the X-ray spectra—partial covering, Fe L lines, Fe i fluorescence—were not conclusive enough to classify these two sources into a subclass of accreting WD binaries. We discuss further observations, especially long-term temporal behaviors, which are important to elucidate the nature of these sources, if indeed they host accreting WDs.
Factors That Affect Length of Hospital Stay After Vestibular Schwannoma Surgery
Authors: Vorasubin Nopawan , Alexander Thomas H. , Mastrodimos Bill , Cueva Roberto A.
Published: September 2018

Objective:

To identify perioperative factors that influence hospital length of stay (LOS) after resection of vestibular schwannoma (VS).

Study Design:

Retrospective case review.

Setting:

Tertiary skull base referral center.

Patients:

Patients who underwent acoustic neuroma resection between January 1, 2007 and January 1, 2014.

Interventions:

Approaches used for VS resection included translabyrinthine and retrosigmoid.

Main Outcome Measures:

LOS and several perioperative factors that may delay hospital discharge were examined. Factors included were patient demographics (age and sex), tumor characteristics (size), surgical factors (operative time, approach, revision surgery, date of surgery), and immediate postoperative factors (presence of vertigo or immediate postoperative complications).

Results:

Two hundred eighty-eight patients underwent VS resection during the study period. Two hundred fifty-five patients had complete charts available for review. LOS ranged from 1 to 10 days with an average of 2.66 days and mode of 2 days. One hundred thirty-one patients were admitted for ≤2 days and 124 patients stayed longer. Of the perioperative factors examined with univariate analysis, female gender (p = 0.0266) and presence of postoperative vertigo (p < 0.0001) were statistically significant factors associated with LOS >2 days. On multivariate logistic regression analysis with odds ratios (OR), older patient age (OR = 1.028, p = 0.0177), female gender (OR = 1.810, p = 0.0314), longer operative time (OR = 1.424, p = 0.0007), and presence of postoperative vertigo (OR = 4.904, p < 0.0001) carried a statistically significant increased odds toward a LOS >2 days.

Conclusions:

VS surgery and postoperative care can be carried out efficiently with a minimal LOS. Identifying factors that may prolong LOS may help the operative team anticipate and address needs to optimize LOS.
What to Do When Cochlear Implant Users Plateau in Performance: a Pilot Study of Clinician-guided Aural Rehabilitation
Authors: Moberly Aaron C. , Vasil Kara , Baxter Jodi , Ray Christin
Published: September 2018

Hypothesis:

For experienced adult cochlear implant (CI) users who have reached a plateau in performance, a clinician-guided aural rehabilitation (CGAR) approach can improve speech recognition and hearing-related quality of life (QOL).

Background:

A substantial number of CI users do not reach optimal performance in terms of speech recognition ability and/or personal communication goals. Although self-guided computerized auditory training programs have grown in popularity, compliance and efficacy for these programs are poor. We propose that CGAR can improve speech recognition and hearing-related QOL in experienced CI users.

Methods:

Twelve adult CI users were enrolled in an 8-week CGAR program guided by a speech-language pathologist and audiologist. Nine patients completed the program along with pre-AR and immediate post-AR testing of speech recognition (AzBio sentences in quiet and in multitalker babble, Consonant-Nucleus-Consonant words in quiet), QOL (Nijmegen Cochlear Implant Questionnaire, Hearing Handicap Inventory for Adults/Elderly, and Speech, Spatial and Qualities of Hearing Scale), and neurocognitive functioning (working memory capacity, information-processing speed, inhibitory control, speed of lexical/phonological access, and nonverbal reasoning). Pilot data for these nine patients are presented.

Results:

From pre-CGAR to post-CGAR, group mean improvements in word recognition were found. Improvements were also demonstrated on some composite and subscale measures of QOL. Patients who demonstrated improvements in word recognition were those who performed most poorly at baseline.

Conclusions:

CGAR represents a potentially efficacious approach to improving speech recognition and QOL for experienced CI users. Limitations and considerations in implementing and studying aural rehabilitation approaches are discussed.
A Polymer-Based Extended Release System for Stable, Long-term Intracochlear Drug Delivery
Authors: Pierstorff Erik , Chen Shanshan , Chaparro Maria Paola , Cortez John M. , Chen Yen-Jung , Ryu Su Young , Tsai Sherry M. , Baum Marc M. , Yang Wan Wan , Kalinec Federico , Smith Thomas , Ludwig Stacey , Slattery William H.
Published: September 2018

Objective:

Investigate a new polymer-based drug coating suitability for safe intracochlear delivery and ability to maintain long-term physiologically active levels of the corticosteroid fluticasone propionate.

Study Design:

In vitro dissolution study to evaluate release profiles of polymer-coated drug particles and in vivo studies using a guinea pig model to measure perilymph drug concentrations at specific time points after implantation with polymer-coated drug particles and evaluate their effect on hearing function.

Methods:

Polymer-coated fluticasone propionate (FP) particles were surgically implanted in guinea pigs through the round window membrane into the cochlear scala tympani. In the pilot study, pre- and post-op hearing thresholds were conducted on days 7, 14, and 42. In a second study, post-op hearing thresholds were conducted on days 90, 120, and 180. Perilymph drug concentrations were measured on the same time points.

Results:

In 15 of 16 animals from day 7 through day 90, drug levels were within the targeted range, with no initial burst release detected. Drug was present in all animals on day 90 and was detected in some animals at 120 and 180 days. Hearing was tested and compared with non-implanted ears. Very good hearing preservation was observed in ears implanted with intracochlear particles when compared with contralateral ears.

Conclusions:

The polymer-based extended release system is effective in providing long-term, stable drug delivery for at least 90 days with good hearing outcomes. The results of this study support the potential for achieving long-term drug delivery with a single intracochlear administration.
Neuropeptides encoded bynlp-49modulate locomotion, arousal and egg-laying behaviours inCaenorhabditis elegansvia the receptor SEB-3
Authors: Chew Yee Lian , Grundy Laura J. , Brown André E. X. , Beets Isabel , Schafer William R.
Published: September 2018

Neuropeptide signalling has been implicated in a wide variety of biological processes in diverse organisms, from invertebrates to humans. TheCaenorhabditis elegansgenome has at least 154 neuropeptide precursor genes, encoding over 300 bioactive peptides. These neuromodulators are thought to largely signal beyond ‘wired’ chemical/electrical synapse connections, therefore creating a ‘wireless’ network for neuronal communication. Here, we investigated how behavioural states are affected by neuropeptide signalling through the G protein-coupled receptor SEB-3, which belongs to a bilaterian family of orphan secretin receptors. Using reverse pharmacology, we identified the neuropeptide NLP-49 as a ligand of this evolutionarily conserved neuropeptide receptor. Our findings demonstrate novel roles for NLP-49 and SEB-3 in locomotion, arousal and egg-laying. Specifically, high-content analysis of locomotor behaviour indicates thatseb-3andnlp-49deletion mutants cause remarkably similar abnormalities in movement dynamics, which are reversed by overexpression of wild-type transgenes. Overexpression of NLP-49 in AVK interneurons leads to heightened locomotor arousal, an effect that is dependent onseb-3.Finally,seb-3andnlp-49mutants also show constitutive egg-laying in liquid medium and alter the temporal pattern of egg-laying in similar ways. Together, these results providein vivoevidence that NLP-49 peptides act through SEB-3 to modulate behaviour, and highlight the importance of neuropeptide signalling in the control of behavioural states.

This article is part of a discussion meeting issue ‘Connectome to behaviour: modellingC. elegansat cellular resolution’.
Sensorimotor integration in
Caenorhabditis elegans
: a reappraisal towards dynamic and distributed computations
Authors: Kaplan Harris S. , Nichols Annika L.A. , Zimmer Manuel
Published: September 2018

The nematode
Caenorhabditis elegans
is a tractable model system to study locomotion, sensory navigation and decision-making. In its natural habitat, it is thought to navigate complex multisensory environments in order to find food and mating partners, while avoiding threats like predators or toxic environments. While research in past decades has shed much light on the functions and mechanisms of selected sensory neurons, we are just at the brink of understanding how sensory information is integrated by interneuron circuits for action selection in the worm. Recent technological advances have enabled whole-brain Ca
2+
imaging and Ca
2+
imaging of neuronal activity in freely moving worms. A common principle emerging across multiple studies is that most interneuron activities are tightly coupled to the worm's instantaneous behaviour; notably, these observations encompass neurons receiving direct sensory neuron inputs. The new findings suggest that in the
C. elegans
brain, sensory and motor representations are integrated already at the uppermost sensory processing layers. Moreover, these results challenge a perhaps more intuitive view of sequential feed-forward sensory pathways that converge onto premotor interneurons and motor neurons. We propose that sensorimotor integration occurs rather in a distributed dynamical fashion. In this perspective article, we will explore this view, discuss the challenges and implications of these discoveries on the interpretation and design of neural activity experiments, and discuss possible functions. Furthermore, we will discuss the broader context of similar findings in fruit flies and rodents, which suggest generalizable principles that can be learnt from this amenable nematode model organism.

This article is part of a discussion meeting issue ‘Connectome to behaviour: modelling
C. elegans
at cellular resolution’.
Caenorhabditis elegans
and the network control framework—FAQs
Authors: Towlson Emma K. , Vértes Petra E. , Yan Gang , Chew Yee Lian , Walker Denise S. , Schafer William R. , Barabási Albert-László
Published: September 2018

Control is essential to the functioning of any neural system. Indeed, under healthy conditions the brain must be able to continuously maintain a tight functional control between the system's inputs and outputs. One may therefore hypothesize that the brain's wiring is predetermined by the need to maintain control across multiple scales, maintaining the stability of key internal variables, and producing behaviour in response to environmental cues. Recent advances in network control have offered a powerful mathematical framework to explore the structure–function relationship in complex biological, social and technological networks, and are beginning to yield important and precise insights on neuronal systems. The network control paradigm promises a predictive, quantitative framework to unite the distinct datasets necessary to fully describe a nervous system, and provide mechanistic explanations for the observed structure and function relationships. Here, we provide a thorough review of the network control framework as applied to
Caenorhabditis elegans
(Yan
et al.
2017
Nature
550
, 519–523. (
doi:10.1038/nature24056
)), in the style of Frequently Asked Questions. We present the theoretical, computational and experimental aspects of network control, and discuss its current capabilities and limitations, together with the next likely advances and improvements. We further present the Python code to enable exploration of control principles in a manner specific to this prototypical organism.

This article is part of a discussion meeting issue ‘Connectome to behaviour: modelling
C. elegans
at cellular resolution’.
Three-dimensional simulation of the
Caenorhabditis elegans
body and muscle cells in liquid and gel environments for behavioural analysis
Authors: Palyanov Andrey , Khayrulin Sergey , Larson Stephen D.
Published: September 2018

To better understand how a nervous system controls the movements of an organism, we have created a three-dimensional computational biomechanical model of the
Caenorhabditis elegans
body based on real anatomical structure. The body model is created with a particle system–based simulation engine known as Sibernetic, which implements the smoothed particle–hydrodynamics algorithm. The model includes an elastic body-wall cuticle subject to hydrostatic pressure. This cuticle is then driven by body-wall muscle cells that contract and relax, whose positions and shape are mapped from
C. elegans
anatomy, and determined from light microscopy and electron micrograph data. We show that by using different muscle activation patterns, this model is capable of producing
C. elegans
-like behaviours, including crawling and swimming locomotion in environments with different viscosities, while fitting multiple additional known biomechanical properties of the animal.

 This article is part of a discussion meeting issue ‘Connectome to behaviour: modelling
C. elegans
at cellular resolution’.
Geppetto: a reusable modular open platform for exploring neuroscience data and models
Authors: Cantarelli Matteo , Marin Boris , Quintana Adrian , Earnshaw Matt , Court Robert , Gleeson Padraig , Dura-Bernal Salvador , Silver R. Angus , Idili Giovanni
Published: September 2018

Geppetto is an open-source platform that provides generic middleware infrastructure for building both online and desktop tools for visualizing neuroscience models and data and managing simulations. Geppetto underpins a number of neuroscience applications, including Open Source Brain (OSB), Virtual Fly Brain (VFB), NEURON-UI and NetPyNE-UI. OSB is used by researchers to create and visualize computational neuroscience models described in NeuroML and simulate them through the browser. VFB is the reference hub for
Drosophila melanogaster
neural anatomy and imaging data including neuropil, segmented neurons, microscopy stacks and gene expression pattern data. Geppetto is also being used to build a new user interface for NEURON, a widely used neuronal simulation environment, and for NetPyNE, a Python package for network modelling using NEURON. Geppetto defines domain agnostic abstractions used by all these applications to represent their models and data and offers a set of modules and components to integrate, visualize and control simulations in a highly accessible way. The platform comprises a backend which can connect to external data sources, model repositories and simulators together with a highly customizable frontend.

This article is part of a discussion meeting issue ‘Connectome to behaviour: modelling
C. elegans
at cellular resolution’.
OpenWorm: overview and recent advances in integrative biological simulation of
Caenorhabditis elegans
Authors: Sarma Gopal P. , Lee Chee Wai , Portegys Tom , Ghayoomie Vahid , Jacobs Travis , Alicea Bradly , Cantarelli Matteo , Currie Michael , Gerkin Richard C. , Gingell Shane , Gleeson Padraig , Gordon Richard , Hasani Ramin M. , Idili Giovanni , Khayrulin Sergey , Lung David , Palyanov Andrey , Watts Mark , Larson Stephen D.
Published: September 2018

The adoption of powerful software tools and computational methods from the software industry by the scientific research community has resulted in a renewed interest in integrative, large-scale biological simulations. These typically involve the development of computational platforms to combine diverse, process-specific models into a coherent whole. The OpenWorm Foundation is an independent research organization working towards an integrative simulation of the nematode
Caenorhabditis elegans
, with the aim of providing a powerful new tool to understand how the organism's behaviour arises from its fundamental biology. In this perspective, we give an overview of the history and philosophy of OpenWorm, descriptions of the constituent sub-projects and corresponding open-science management practices, and discuss current achievements of the project and future directions.

This article is part of a discussion meeting issue ‘Connectome to behaviour: modelling
C. elegans
at cellular resolution’.
Signatures of proprioceptive control inCaenorhabditis eleganslocomotion
Authors: Denham Jack E. , Ranner Thomas , Cohen Netta
Published: September 2018

Animal neuromechanics describes the coordinated self-propelled movement of a body, subject to the combined effects of internal neural control and mechanical forces. Here we use a computational model to identify effects of neural and mechanical modulation on undulatory forward locomotion ofCaenorhabditis elegans, with a focus on proprioceptively driven neural control. We reveal a fundamental relationship between body elasticity and environmental drag in determining the dynamics of the body and demonstrate the manifestation of this relationship in the context of proprioceptively driven control. By considering characteristics unique to proprioceptive neurons, we predict the signatures of internal gait modulation that contrast with the known signatures of externally or biomechanically modulated gait. We further show that proprioceptive feedback can suppress neuromechanical phase lags during undulatory locomotion, contrasting with well studied advancing phase lags that have long been a signature of centrally generated, feed-forward control.

This article is part of a discussion meeting issue ‘Connectome to behaviour: modellingC. elegansat cellular resolution’.
In vivo, regulated reconstitution of spindle checkpoint arrest and silencing through chemical-induced dimerisation
Authors: Amin Priya , Ní Chafraidh Sadhbh Soper , Leontiou Ioanna , Hardwick Kevin G.
Published: September 2018

Chemical-induced dimerisation (CID) uses small molecules to control specific protein-protein interactions. Here, we employ CID dependent on the plant hormone abscisic acid (ABA) to reconstitute spindle checkpoint signalling in fission yeast. The spindle checkpoint signal usually originates at unattached or inappropriately attached kinetochores. These are complex, multi-protein structures with several important functions. To bypass kinetochore complexity, we take a reductionist approach to study checkpoint signalling. We generate a synthetic checkpoint arrest ectopically by inducing hetero-dimerisation of the checkpoint proteins Mph1Mps1and Spc7KNL1. These proteins are engineered such that they can’t localise to kinetochores, and only form a complex in the presence of ABA. Using this novel assay we are able to checkpoint arrest a synchronous population of cells within 30 minutes of ABA addition. This assay allows for detailed genetic dissection of checkpoint activation and importantly it also provides a valuable tool for studying checkpoint silencing. To analyse silencing of the checkpoint and the ensuing mitotic exit, we simply wash-out the ABA from arrested cells. We show here that silencing is critically-dependent on PP1Dis2recruitment to Mph1Mps1-Spc7KNL1signalling platforms.
Context-dependent architecture of brain state dynamics is explained by white matter connectivity and theories of network control
Authors: Cornblath Eli J. , Ashourvan Arian , Kim Jason Z. , Betzel Richard F. , Ciric Rastko , Baum Graham L. , He Xiaosong , Ruparel Kosha , Moore Tyler M. , Gur Ruben C. , Gur Raquel E. , Shinohara Russell T. , Roalf David R. , Satterthwaite Theodore D. , Bassett Danielle S.
Published: September 2018

A diverse white matter network and finely tuned neuronal membrane properties allow the brain to transition seamlessly between cognitive states. However, it remains unclear how static structural connections guide the temporal progression of large-scale brain activity patterns in different cognitive states. Here, we deploy an unsupervised machine learning algorithm to define brain states as time point level activity patterns from functional magnetic resonance imaging data acquired during passive visual fixation (rest) and an n-back working memory task. We find that brain states are composed of interdigitated functional networks and exhibit context-dependent dynamics. Using diffusion-weighted imaging acquired from the same subjects, we show that structural connectivity constrains the temporal progression of brain states. We also combine tools from network control theory with geometrically conservative null models to demonstrate that brains are wired to support states of high activity in default mode areas, while requiring relatively low energy. Finally, we show that brain state dynamics change throughout development and explain working memory performance. Overall, these results elucidate the structural underpinnings of cognitively and developmentally relevant spatiotemporal brain dynamics.
Scalable tagging of endogenous genes by homology-independent intron targeting
Authors: Serebrenik Yevgeniy V , Sansbury Stephanie E , Kumar Saranya Santhosh , Henao-Mejia Jorge , Shalem Ophir
Published: September 2018

Genome editing tools have simplified the generation of knock-in gene fusions, yet the requirement for gene-specific homology directed repair (HDR) templates still hinders the scalability of most approaches. Here, we combine intron-based protein trapping with homology independent repair-based editing and demonstrate precise and efficient gene tagging that can be easily scaled due to use of a generic donor. As editing is done in introns, this approach tolerates mutations in the unedited allele, disruptive indels, and allows for flexible donor and sgRNA design.