bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational model of chimeric antigen receptors explains site-specific phosphorylation kinetics
Authors: Rohrs Jennifer A. , Zheng Dongqing , Graham Nicholas A. , Wang Pin , Finley Stacey D.
Published: February 2018

Chimeric antigen receptors (CARs) have recently been approved for the treatment of hematological malignancies, but our lack of understanding of the basic mechanisms that activate these proteins has made it difficult to optimize and control CAR-based therapies. In this study, we use phospho-proteomic mass spectrometry and mechanistic computational modeling to quantify thein vitrokinetics of individual tyrosine phosphorylation on a variety of CARs. We show that each of the ten tyrosine sites on the CD28-CD3ζ CAR is phosphorylated by LCK with distinct kinetics. The addition of CD28 at the N-terminal of CD3ζ increases the overall rate of CD3ζ phosphorylation. Our computational model identifies that LCK phosphorylates CD3ζ through a mechanism of competitive inhibition. This model agrees with previously published data in the literature and predicts that phosphatases in this system interact with CD3ζ through a similar mechanism of competitive inhibition. This quantitative modeling framework can be used to better understand CAR signaling and T cell activation.
A normalized drug response metric improves accuracy and consistency of anticancer drug sensitivity quantification in cell-based screening
Authors: Gupta Abhishekh , Gautam Prson , Wennerberg Krister , Aittokallio Tero
Published: February 2018

Accurate quantification of drug effects is crucial for identifying pharmaceutically actionable cancer vulnerabilities. Current cell viability-based measurements often lead to biased response estimates due to varying growth rates and experimental artifacts that explain part of the inconsistency in high-throughput screening results. We developed an improved drug scoring model, normalized drug response (NDR), which makes use of both positive and negative control conditions to account for differences in cell growth rates and experimental noise to better characterize drug-induced effects. We demonstrate an improved consistency and accuracy of NDR compared to existing metrics in assessing drug responses of cancer cells in various culture models and experimental setups. Notably, NDR reliably captures both toxicity and viability responses, and differentiates a wider spectrum of drug behavior, including lethal, growth-inhibitory and growth-stimulatory modes, based on a single viability readout. The method will therefore substantially reduce the time and resources required in cell-based drug sensitivity screening.
Neural Signatures of Reward and Sensory Prediction Error in Motor Learning
Authors: Palidis Dimitrios J. , Cashaback Joshua G.A. , Gribble Paul L.
Published: February 2018

At least two distinct processes have been identified by which motor commands are adapted according to movement-related feedback: reward based learning and sensory error based learning. In sensory error based learning, mappings between sensory targets and motor commands are recalibrated according to sensory error feedback. In reward based learning, motor commands are associated with subjective value, such that successful actions are reinforced. We designed two tasks to isolate reward and sensory error based motor adaptation, and recorded electroencephalography (EEG) from humans to identify and dissociate the neural correlates of reward and sensory error processing. We designed a visuomotor rotation task to isolate sensory error based learning which was induced by altered visual feedback of hand position. In a reward learning task, we isolated reward based learning induced by binary reward feedback that was decoupled from the visual target. We found that a fronto-central event related potential called the feedback related negativity (FRN) was elicited specifically by reward feedback but not sensory error feedback. A more posterior component called the P300 was evoked by feedback in both tasks. In the visuomotor rotation task, P300 amplitude was increased by sensory error induced by perturbed visual feedback, and was correlated with learning rate. In the reward learning task, P300 amplitude was increased by reward relative to non reward and by surprise regardless of feedback valence. We propose that during motor adaptation, the FRN might specifically mark reward prediction error while the P300 might reflect processing which is modulated more generally by prediction error.

New and Noteworthy

We studied the event related potentials evoked by feedback stimuli during motor adaptation tasks that isolate reward and sensory error learning mechanisms. We found that the feedback related negativity was specifically elicited by reward feedback, while the P300 was observed in both tasks. These results reveal neural processes associated with different learning mechanisms and elucidate which classes of errors, from a computational standpoint, elicit the FRN and P300.
Complex evolutionary history of translation Elongation Factor 2 and diphthamide biosynthesis in Archaea and parabasalids
Authors: Narrowe Adrienne B. , Spang Anja , Stairs Courtney W. , Caceres Eva F. , Baker Brett J. , Miller Christopher S. , Ettema Thijs J. G.
Published: February 2018

Diphthamide is a modified histidine residue which is uniquely present in archaeal and eukaryotic elongation factor 2 (EF-2), an essential GTPase responsible for catalyzing the coordinated translocation of tRNA and mRNA through the ribosome. In part due to the role of diphthamide in maintaining translational fidelity, it was previously assumed that diphthamide biosynthesis genes (dph) are conserved across all eukaryotes and archaea. Here, comparative analysis of new and existing genomes reveals that some archaea (i.e., members of the Asgard superphylum,Geoarchaea, andKorarchaeota) and eukaryotes (i.e., parabasalids) lackdph. In addition, while EF-2 was thought to exist as a single copy in archaea, many of thesedph-lacking archaeal genomes encode a second EF-2 paralog missing key-residues required for diphthamide modification and for normal translocase function, perhaps suggesting functional divergence linked to loss of diphthamide biosynthesis. Interestingly, some Heimdallarchaeota previously suggested to be most closely related to the eukaryotic ancestor maintaindphgenes and a single gene encoding canonical EF-2. Our findings reveal that the ability to produce diphthamide, once thought to be a universal feature in archaea and eukaryotes, has been lost multiple times during evolution, and suggest that anticipated compensatory mechanisms evolved independently.
A cortical hierarchy of localized and distributed processes revealed via dissociation of task activations, connectivity changes, and intrinsic timescales
Authors: Ito Takuya , Hearne Luke J. , Cole Michael W.
Published: February 2018

Many studies have identified the role of localized and distributed cognitive functionality by mapping either local task-related activity or distributed functional connectivity (FC). However, few studies have directly explored the relationship between a brain region’s localized task activity and its distributed task FC. Here we systematically evaluated the differential contributions of task-related activity and FC changes to identify a relationship between localized and distributed processes across the cortical hierarchy. We found that across multiple tasks, the magnitude of regional task-evoked activity was high in unimodal areas, but low in transmodal areas. In contrast, we found that task-state FC was significantly reduced in unimodal areas relative to transmodal areas. This revealed a strong negative relationship between localized task activity and distributed FC across cortical regions that was associated with the previously reported principal gradient of macroscale organization. Moreover, this dissociation corresponded to hierarchical cortical differences in the intrinsic timescale estimated from resting-state fMRI and region myelin content estimated from structural MRI. Together, our results contribute to a growing literature illustrating the differential contributions of a hierarchical cortical gradient representing localized and distributed cognitive processes.

Highlights

Task activations and functional connectivity changes are negatively correlated across cortex

Task activation and connectivity dissociations reflect differences in localized and distributed processes in cortex

Differences in localized and distributed processes are associated with differences in intrinsic timescale organization

Differences in localized and distributed processes are associated with differences in cortical myelin content

Cortical heterogeneity in localized and distributed processes revealed by activity flow mapping prediction error
Reciprocal F1 hybrids of two inbred mouse strains reveal parent-of-origin and perinatal diet effects on behavior and expression
Authors: Oreperk Daniel , Schoenrock Sarah A , McMullan Rachel , Ervin Robin , Farrington Joseph , Miller Darla R , Pardo-Manuel de Villena Fernando , Valdar William , Tarantino Lisa M
Published: February 2018

Parent-of-origin effects (POEs) in mammals typically arise from maternal effects or from imprinting. Mutations in imprinted genes have been associated with psychiatric disorders, as well as with changes in a handful of animal behaviors. Nonetheless, POEs on complex traits such as behavior remain largely uncharacterized. Furthermore, although perinatal environmental exposures, such as nutrient deficiency, are known to modify both behavior and epigenetic effects generally, the architecture of environment-by-POE is almost completely unexplored. To study POE and environment-by-POE, we employ a relatively neglected but maximally powerful POE-detection system: a reciprocal F1 hybrid population. We exposed female NOD/ShiLtJxC57Bl/6J and C57Bl/6JxNOD/ShiLtJ mice, in utero, to one of four different diets, then after weaning recorded their whole-brain gene expression, as well as a set of behaviors that model psychiatric disease. Microarray expression data revealed an imprinting-enriched set of over a dozen genes subject to POE; the POE on the most significantly affected gene, Carmil1 (a.k.a. Lrrc16a), was validated using qPCR in the same and in a new set of mice. Several behaviors, especially locomotor behaviors, also showed POE. Interestingly, Bayesian mediation analysis suggests Carmil1 expression suppresses behavioral POE, and Airn suppresses POE on Carmil1 expression. A significant diet-by-POE was observed on one behavior, one imprinted gene, and over a dozen non-imprinted genes. Beyond our particular results, our study demonstrates a reciprocal F1 hybrid framework for studying POE and environment-by-POE on behavior.
Haploinsufficiency of autism candidate gene NUAK1 impairs cortical development and behavior
Authors: Courchet Virginie , Roberts Amanda J , Del Carmine Peggy , Lewis Tommy L. , Polleux Franck , Courchet Julien
Published: February 2018

Recently, numerous rare de novo mutations have been identified in children diagnosed with autism spectrum disorders (ASD). However, despite the predicted loss-of-function nature of some of these de novo mutations, the affected individuals are heterozygous carriers, which would suggest that most of these candidate genes are haploinsufficient and/or that these mutations lead to expression of dominant-negative forms of the protein. Here, we tested this hypothesis with the gene Nuak1, recently identified as a candidate ASD gene and that we previously identified for its role in the development of cortical connectivity. We report that Nuak1 is happloinsufficient in mice in regard to its function in cortical axon branching in vitro and in vivo. Nuak1+/− mice show a combination of abnormal behavioral traits ranging from defective memory consolidation in a spatial learning task, defects in social novelty (but not social preference) and abnormal sensorimotor gating and prepulse inhibition of the startle response. Overall, our results demonstrate that Nuak1 haploinsufficiency leads to defects in the development of cortical connectivity and a complex array of behavorial deficits compatible with ASD, intellectual disability and schizophrenia.
Highly efficient CRISPR gene editing in yeast enabled by double selection
Authors: Després Philippe C , Dubé Alexandre K , Nielly-Thibault Lou , Yachie Nozomu , Landry Christian R
Published: February 2018

CRISPR-Cas9 loss of function (LOF) and base editing screens are powerful tools in genetics and genomics. Yeast is one of the main models in genetics and genomics, yet large-scale approaches remain to be developed in this species because of low mutagenesis rates without donor DNA. We developed a double selection strategy based on co-selection that increases LOF mutation rates, both for CRISPR-Cas9 and the Target-AID base editor. We constructed the pDYSCKO vector, which is amenable to high throughput double selection for both approaches. Using modeling, we show that this improvement provides the required increased in detection power to measure the fitness effects of thousands of mutations in typical yeast pooled screens. We also show that multiplex genome editing with Cas9 causes programmable chromosomal translocations at high frequency, suggesting that multiplex editing should be performed with caution and that base-editors could be preferable tools for LOF screens.
Whole-genome analyses resolve the phylogeny of flightless birds (Palaeognathae) in the presence of an empirical anomaly zone
Authors: Cloutier Alison , Sackton Timothy B. , Grayson Phil , Clamp Michele , Baker Allan J. , Edwards Scott V.
Published: February 2018

Palaeognathae represent one of the two basal lineages in modern birds, and comprise the volant (flighted) tinamous and the flightless ratites. Resolving palaeognath phylogenetic relationships has historically proved difficult, and short internal branches separating major palaeognath lineages in previous molecular phylogenies suggest that extensive incomplete lineage sorting (ILS) might have accompanied a rapid ancient divergence. Here, we investigate palaeognath relationships using genome-wide data sets of three types of noncoding nuclear markers, together totalling 20,850 loci and over 41 million base pairs of aligned sequence data. We recover a fully resolved topology placing rheas as the sister to kiwi and emu + cassowary that is congruent across marker types for two species tree methods (MP-EST and ASTRAL-II). This topology is corroborated by patterns of insertions for 4,274 CR1 retroelements identified from multi-species whole genome screening, and is robustly supported by phylogenomic subsampling analyses, with MP-EST demonstrating particularly consistent performance across subsampling replicates as compared to ASTRAL. In contrast, analyses of concatenated data supermatrices recover rheas as the sister to all other non-ostrich palaeognaths, an alternative that lacks retroelement support and shows inconsistent behavior under subsampling approaches. While statistically supporting the species tree topology, conflicting patterns of retroelement insertions also occur and imply high amounts of ILS across short successive internal branches, consistent with observed patterns of gene tree heterogeneity. Coalescent simulations indicate that the majority of observed topological incongruence among gene trees is consistent with coalescent variation rather than arising from gene tree estimation error alone, and estimated branch lengths for short successive internodes in the inferred species tree fall within the theoretical range encompassing the anomaly zone. Distributions of empirical gene trees confirm that the most common gene tree topology for each marker type differs from the species tree, signifying the existence of an empirical anomaly zone in palaeognaths.
Structure of the 30S ribosomal decoding complex at ambient temperature
Authors: Dao E. Han , Poitevin Frédéric , Sierra Raymond G. , Gati Cornelius , Rao Yashas , Ciftci Halil Ibrahim , Akşit Fulya , Mcgurk Alex , Obrinski Trevor , Mgbam Paul , Hayes Brandon , Lichtenberg Casper De , Pardo-Avila Fatima , Corsepius Nicholas , Zhang Lindsey , Seaberg Matt , Hunter Mark S. , Liang Mengling , Koglin Jason E. , Wakatsuki Soichi , Demirci Hasan
Published: February 2018

The ribosome translates nucleotide sequences of messenger RNA to proteins through selection of cognate transfer RNA according to the genetic code. To date, structural studies of ribosomal decoding complexes yielding high-resolution data have predominantly relied on experiments performed at cryogenic temperatures. New lightsources like the X-ray free electron laser (XFEL) have enabled data collection from macromolecular crystals at ambient temperature. Here, we report an X-ray crystal structure of the Thermus thermophilus 30S ribosomal subunit decoding complex to 3.45 Å resolution using data obtained at ambient temperature at the Linac Coherent Light Source (LCLS). We find that this ambient-temperature structure is largely consistent with existing cryogenic-temperature crystal structures, with key residues of the decoding complex exhibiting similar conformations, including adenosine residues 1492 and 1493. Minor variations were observed, namely an alternate conformation of cytosine 1397 near the mRNA channel and the A-site. Our serial crystallography experiment illustrates the amenability of ribosomal microcrystals to routine structural studies at ambient temperature, thus overcoming a long-standing experimental limitation.
Environmental determinants of pyoverdine production, exploitation and competition in naturalPseudomonascommunities
Authors: Butaitė Elena , Kramer Jos , Wyder Stefan , Kümmerli Rolf
Published: February 2018

Many bacteria rely on the secretion of siderophores to scavenge iron from the environment. Laboratory studies revealed that abiotic and biotic factors together determine how much siderophores bacteria make, and whether siderophores can be exploited by non-producing cheaters or be deployed by producers to inhibit competitors. Here, we explore whether these insights apply to natural communities, by comparing the production of the siderophore pyoverdine among 930Pseudomonasstrains from 48 soil and pond communities. We found that pH, iron content, carbon concentration, and community diversity determine pyoverdine production levels, and the extent to which strains are either stimulated or inhibited by heterologous (non-self) pyoverdines. While pyoverdine non-producers occurred in both habitats, their prevalence was higher in soils. Environmental and genetic analysis suggest that non-producers can evolve as cheaters, exploiting heterologous pyoverdine, but also due to pyoverdine disuse in environments with increased iron availability. Overall, we found that environmental factors explained between-strain variation in pyoverdine production much better in soils than in ponds, presumably because high strain mixing in ponds prevents local adaption. Our study sheds light on the complexity of natural bacterial communities, and provides first insights into the multivariate nature of siderophore-based iron acquisition and competition among environmental pseudomonads.
Optimizing chemo-scheduling based on tumor growth rates
Authors: West Jeffrey , Newton Paul
Published: February 2018

We review the classic tumor growth and regression laws of Skipper and Schable based on fixed exponential growth assumptions, and Norton and Simon’s law based on a Gompertzian growth assumption. We then discuss ways to optimize chemotherapeutic scheduling using a Moran process evolutionary game-theory model of tumor growth that incorporates more general dynamical and evolutionary features of tumor cell kinetics. Using this model, and employing the quantitative notion of Shannon entropy which assigns high values to low-dose metronomic (LDM) therapies, and low values to maximum tolerated dose (MTD) therapies, we show that low-dose metronomic strategies can outperform maximum tolerated dose strategies, particularly for faster growing tumors. The general concept of designing different chemotherapeutic strategies for tumors with different growth characteristics is discussed.
Cornelia de Lange Syndrome-associated mutations in Smc1 cause both sister chromatid cohesion and cohesion-independent defects
Authors: Chen Jingrong , Wu Frank , Dawson Dean , Rankin Susannah
Published: February 2018

Cornelia de Lange Syndrome is a pervasive developmental disorder characterized by limb truncations, craniofacial abnormalities, and cognitive delays. This syndrome is a member of a class of developmental disorders referred to ascohesinopathies, which result from mutations in the genes encoding subunits or regulators of the cohesin complex. The phenotypic consequences of these mutations may reflect the critical role that cohesin plays in chromosome structure, its ability to tether sister chromatids together during cell cycle progression, or some combination of both. Here we show that a sensitized assay for chromosome loss in budding yeast can be used to assess the impact of Cornelia de Lange syndrome (CdLS)-associated mutations in the core cohesin subunit Smc1 on cohesin function. We find that the CdLS-associated mutations can be grouped into two classes based on their impact on chromosome segregation. One class of mutations includes those that are defective in promoting accurate chromosome segregation, some no better than the null allele. Another class promotes both accurate chromosome cohesion and segregation. Strikingly, the mutations that have no impact chromosome dynamics in this assay are clustered near each other in the context of the folded SMC1 protein suggesting a previously uncharacterized region of functional importance in higher eukaryotes. This analysis illustrates how budding yeast can be used to elucidate mechanisms important in human health and development.
Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP pathways in macrophages
Authors: Muse Evan D. , Yu Shan , Edillor Chantle R. , Tao Jenhan , Spann Nathanael J. , Troutman Ty D. , Seidman Jason S. , Henke Adam , Roland Jason T. , Ozeki Katherine A. , McDonald Jeffrey G. , Bahadorani John , Tsimikas Sotirios , Grossman Tamar R. , Tremblay Matthew S. , Glass Christopher K.
Published: February 2018

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of SREBP1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here, we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytesin vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophagesin vitroandin vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in liver that lead to hypertriglyceridemia.

SIGNIFICANCE STATEMENT

The beneficial effects of LXR pathway activation in the prevention of atherosclerotic heart disease have long been appreciated. However, efforts to translate those effects in humans with synthetic LXR ligands has been met with the unintended consequence of hypertriglyceridemia, a product of co-activation of SREBP1c. Natural LXR ligands such as desmosterol do not promote hypertriglyceridemia because of coordinate down-regulation of the SREBP pathway. Here, we demonstrate that synthetic desmosterol mimetics activate LXR pathways macrophages both in vitro and in vivo without co-stimulation of SREBP1c. Unexpectedly, desmosterol and synthetic desmosterol mimetics almost no effect on LXR activity in hepatocytes in comparison to conventional synthetic LXR ligands. These findings reveal cell-specific differences in LXR responses to natural and synthetic ligands in macrophages and liver cells that provide a conceptually new basis for future drug development.
Computational modeling highlights disordered Formin Homology 1 domain’s role in profilin-actin transfer
Authors: Horan Brandon G. , Zerze Gül H. , Kim Young C. , Vavylonis Dimitrios , Mittal Jeetain
Published: February 2018

Formins accelerate actin polymerization, assumed to occur through flexible FH1 domain mediated transfer of profilin-actin to the barbed end. To study FH1 properties and address sequence effects including varying length/distribution of profilin-binding proline-rich motifs, we performed all-atom simulations of mouse mDia1, mDia2; budding yeast Bni1, Bnr1; fission yeast Cdc12, For3, and Fus1 FH1s. We find FH1 has flexible regions between high propensity polyproline helix regions. A coarse-grained model retaining sequence-specificity, assuming rigid polyproline segments, describes their size. Multiple profilins and profilin-actin complexes can simultaneously bind, expanding mDia1-FH1, which may be important in cells. Simulations of the barbed end bound to Bni1-FH1-FH2 dimer show the leading FH1 can better transfer profilin or profilin-actin, having decreasing probability with increasing distance from FH2.
Long time-scales in primate amygdala neurons support aversive learning
Authors: Taub Aryeh H. , Stolero Tamar , Livneh Uri , Shohat Yossi , Paz Rony
Published: February 2018

Associative learning forms when there is temporal relationship between a stimulus and a reinforcer, yet the inter-trial-interval (ITI), which is usually much longer than the stimulus-reinforcer-interval, contributes to learning-rate and memory strength. The neural mechanisms that enable maintenance of time between trials remain unknown, and it is unclear if the amygdala can support time scales at the order of dozens of seconds. We show that the ITI indeed modulates rate and strength of aversive-learning, and that single-units in the primate amygdala and dorsal-anterior-cingulate-cortex signal confined periods within the ITI, strengthen this coding during acquisition of aversive-associations, and diminish during extinction. Additionally, pairs of amygdala-cingulate neurons synchronize during specific periods suggesting a shared circuit that maintains the long temporal gap. The results extend the known roles of this circuit and suggest a mechanism that maintains trial-structure and temporal-contingencies for learning. It further suggests a novel model for maladaptive behaviors.
Validation and Topic-driven Ranking for Biomedical Hypothesis Generation Systems
Authors: Sybrandt Justin , Safro Ilya
Published: February 2018

Literature underpins research, providing the foundation for new ideas. But as the pace of science accelerates, many researchers struggle to stay current. To expedite their searches, some scientists leverage hypothesis generation (HG) systems, which can automatically inspect published papers to uncover novel implicit connections. With no foreseeable end to the driving pace of research, we expect these systems will become crucial for productive scientists, and later form the basis of intelligent automated discovery systems. Yet, many resort to expert analysis to validate such systems. This process is slow, hard to reproduce, and takes time away from other researchers. Therefore, we present a novel method to validate HG systems, which both scales to large validation sets and does not require expert input. We also introduce a number of new metrics to automatically identify plausible generated hypotheses. Through the study of published, highly cited, and noise predicates, we devise a validation challenge, which allows us to evaluate the performance of a HG system. Using an in-progress system, MOLIERE, as a case-study, we show the utility of our validation and ranking methods. So that others may reproduce our results, we provide our code, validation data, and results at bit.ly/2EtVshN.
Age-dependent dormant resident progenitors are stimulated by injury to regenerate Purkinje neurons
Authors: Bayin N. Sumru , Wojcinski Alexandre , Mourton Aurelien , Saito Hiromitsu , Suzuki Noboru , Joyner Alexandra L.
Published: February 2018

Outside of the neurogenic niches of the brain, postmitotic neurons have not been found to undergo efficient regeneration. Here we demonstrate that Purkinje cells (PCs), which are born at midgestation and are crucial for both development and function of cerebellar circuits, are rapidly and fully regenerated following their ablation at birth. New PCs are produced by a previously unidentified progenitor population and support normal cerebellum development. The number of PC progenitors and their regenerative capacity, however, diminish soon after birth, and consequently PCs are poorly replenished when ablated at postnatal day 5. Nevertheless, the PC-depleted cerebella reach a normal size by increasing cell size, but scaling of neuron types is disrupted and cerebellar function is impaired. Our findings thus provide a new paradigm in the field of neuron regeneration by identifying a unipotent neural progenitor that buffers against perinatal brain injury in a stage-dependent process.

One sentence summary

Injury induces a dormant progenitor population present at birth to regenerate cerebellar neurons in a time-dependent manner.
Faculty responses to business school branding: a discursive approach
Authors: Frandsen Sanne , Gotsi Manto , Johnston Allanah , Whittle Andrea , Frenkel Stephen , Spicer André
Published: February 2018

Purpose

The branding of universities is increasingly recognized to present a different set of challenges than in corporate, for-profit sectors. The purpose of this paper is to investigate how faculty make sense of branding in the context of higher education, specifically considering branding initiatives in business schools.

Design/methodology/approach

The paper is based on qualitative interviews with faculty regarding their responses to organizational branding at four business schools. Discourse analysis was used to analyze the interview data.

Findings

The study reveals varied, fluid and reflexive faculty interpretations of organizational branding. Faculty interviewed in the study adopted a number of stances towards their schools’ branding efforts. In particular, the study identifies three main faculty responses to branding: endorsement, ambivalence and cynicism.

Originality/value

The study contributes by highlighting the ambiguities and ambivalence generated by brand management initiatives in the higher education context, offering original insights into the multiple ways that faculty exploit, frame and resist attempts to brand their organizations. The authors conclude by discussing the implications of these findings for branding in university contexts.
Design of a wearable pain management system with embroidered TENS electrodes
Authors: Goncu Berk Gozde
Published: February 2018

Purpose

The purpose of this paper is to develop a user friendly, wearable pain management system by optimizing CAD embroidery parameters for manufacturing high performance dry transcutaneous electrical neural stimulation (TENS) electrodes.

Design/methodology/approach

User-centered design methodology is employed to identify user needs related to TENS devices. Optimization of CAD embroidery parameters was done by measuring and calculating resistance and signal-to-noise values for electrodes manufactured with different conductive thread, stitch pattern, and stitch density types.

Findings

Characteristics of the conductive thread such as thickness and irregularity, embroidery stitch pattern, stitch density therefore the amount of conductive thread used all effect resistance values and signal-to-noise values of TENS electrodes. Low resistance of TENS electrode surface does not mean high signal-to-noise ratio and high TENS signal quality. Satin stitch type with low stitch density provides the best resistance and signal-to-noise ratio for a TENS electrode.

Originality/value

This study reported the design process of a wearable pain management system with a focus on optimization of embroidery manufacturing parameters for development of TENS electrodes. The design process not only required technical optimization but also understanding user problems related to use of conventional TENS devices. Proposed end product is a user friendly, electronic textile based, wireless wearable pain management system in different forms suitable for major pain areas such as knee, elbow and neck.
External knowledge sources as antecedents of organizational innovation in firm workplaces: a knowledge-based perspective
Authors: Simao Lurdes , Franco Mário
Published: February 2018

Purpose

This paper aims to analyse the impact of different knowledge sources used by firms to adopt organizational innovation, in relation to organization of responsibilities and decision-making in the workplace.

Design/methodology/approach

To fulfil the proposed objective, quantitative research, based on a sample of 2,591 Portuguese firms, has been undertaken. Data have been obtained from the Community Innovation Survey 2012.

Findings

The results show the importance of external knowledge from suppliers, clients, consultants and commercial laboratories in new innovation practices in firm workplace. Knowledge from competitors, universities, the State and research institutes does not present a significant effect.

Practical implications

Knowledge sources can stimulate the introduction of new management practices in the workplace, consistent with the external search literature on technological innovation, which argues that many of the ideas and implementation skills for organizational innovation come from outside sources.

Originality/value

Within the innovation management literature, very few studies tried to explore organizational innovation in firm workplaces. This paper is innovative and makes a novel contribution mainly to the knowledge management field by highlighting the importance of external knowledge sources in organizational innovation in firm workplaces from a knowledge-based perspective.
Tourism and the new generations: emerging trends and social implications in Italy
Authors: Monaco Salvatore
Published: February 2018

Purpose

The purpose of this paper is to outline the profile of Italian tourists belonging to the new generations: Millennials or Generation Y (approximately people born in the 1980-1995 period) and post-Millennials or Generation Z (approximately people born in the 1996-2010 period).

Design/methodology/approach

After reviewing some of the more interesting research on Millennials and post-Millennials, the paper will present the results of an unpublished online empirical survey conducted on a sample of 200 Italian web users who agreed to participate. The questionnaire, administered via computer-assisted web interviewing system, consists of structured questions concerning the practices, attitudes, emerging needs and use of new technologies that characterize Millennials and post-Millennials, with a special focus on tourism.

Findings

The research will consider the differences between the two groups, as well as possible differences within each group linked to other socio-demographic variables (such as gender and area of residence).

Originality/value

The paper addresses a series of innovative questions: what are the practices of Millennials and Post-Millennials as tourists? What are the needs of these generations that the tourist industry must respond to? How do new technologies support Millennials and post-Millennials in their tourism choices? What are the main differences between Millennials and post-Millennials?
Teaching handwriting skills to children with intellectual disabilities using an adapted handwriting programme
Authors: Grindle Corinna F. , Cianfaglione Rina , Corbel Liz , Wormald Emily V. , Brown Freddy Jackson , Hastings Richard P. , Carl Hughes J.
Published: February 2018

Children with intellectual disabilities often struggle with handwriting, but there is very little research to inform intervention approaches. In this study, we developed a teaching manual based on Handwriting Without Tears®, a comprehensive handwriting programme designed for typically developing children. Three children with intellectual disabilities participated in the study and received handwriting instruction based on the manual three times a week over a 32‐week period. Our aims were to explore whether Handwriting Without Tears® can be used as a comprehensive handwriting curriculum for children with intellectual disabilities and to evaluate improvement in handwriting skills. We found that the intervention was successfully incorporated into small group teaching sessions within the child's regular classroom, and that all three children made improvements. Our data show promising results and support the need for larger evaluation studies.
Action research to improve phonological recognition at Key Stage 1 with reference to pupils with special educational needs
Authors: Clark Charlotte
Published: February 2018

Given the focus on phonological attainment in the National Phonics Screening Check, small‐scale school‐based action research was undertaken to improve phonological recognition and assess the impact on progress and attainment in a sample drawn from Key Stage 1 which included pupils on the Special Educational Needs (SEN) Register. The research objective was to assess the effectiveness of a phonological awareness intervention. A mixed methodologies and methods research strategy was adopted, involving the collection of quantitative score measures, phonics assessments, qualitative intervention records and questionnaire responses. Findings indicated a strong positive correlation between progress in intervention score measures and progress in phonics summative assessment scores. It was concluded that provision for phonological development should be extended throughout the school and its impact closely monitored. The reported research contributed to the National Award for Special Educational Needs Coordination accreditation.
Challenges Encountered by 17 Autistic Young Adults in Hong Kong
Authors: Wong Shui‐wai
Published: February 2018

The self‐portrayals of 17 young persons with autism spectrum disorder reveal the challenges encountered by them, including study problems, inter‐personal relationships, being bullied by classmates at school, discrimination by the public in general and teachers, social workers, and peers in particular, obstacles to post‐secondary education, difficulties in securing and maintaining employment, psychological distress, and so on. This may indicate ineffective inclusive education and practice even though the government has injected a significant quantity of resources to implement inclusive education in Hong Kong. Clearly, more can be done by the government to help them overcome these challenges, especially regarding the issues of bullying at school and transition from school to work. Of course, the subjective self‐portrayals of youngsters on the spectrum in limited numbers can never allow us to view the whole picture. However, the book opens up a means for us to better understand them. Hopefully, it can trigger more concerns from the public, especially the government officials, and more research from scholars in Hong Kong.
Students’ experiences of academic success with dyslexia: A call for alternative intervention
Authors: Pitt Sophie , Soni Anita
Published: February 2018

This article describes a small‐scale study exploring the perspectives of five undergraduate students with dyslexia. Semi‐structured interviews were conducted in two universities in the UK. The interviews explored participants’ perceptions of their dyslexia label and how it had affected their academic success. The aim of the research was to identify facilitating factors that supported participants with dyslexia during their education. The following themes were identified: age of dyslexia identification, family support, dyslexic identity, self‐advocacy skills and learning resources. The study makes a case for an intervention for children and young people (CYP) with dyslexia that, in addition to remedial literacy support, explores self‐advocacy, thinking and study skills and facilitates positive academic self‐concepts. Future research could evaluate such an intervention for its effectiveness on CYP's social emotional well‐being and literacy skills.
Diamond burs versus curettes in root planing: a randomized clinical trial
Authors: Türktekin F , Buduneli N , Lappin DF , Türk T , Buduneli E
Published: February 2018

Background

This study compares diamond burs and curettes by clinical, microbiological, biochemical and scanning electron microscopic parameters and treatment time data in the non‐surgical periodontal treatment of patients with chronic periodontitis.

Methods

Two quadrants of each of the 12 patients received root planing with diamond burs, whereas the other two quadrants were treated with curettes. Clinical periodontal measurements were recorded at baseline and then 1, 3 and 6 months after completion of non‐surgical periodontal treatment. Subgingival plaque and gingival crevicular fluid samples were obtained at baseline and 1‐month control. Twenty‐one hopeless teeth received root planing with diamond burs or curettes or no treatment and then extracted for microscopic evaluations.

Results

Clinical periodontal parameters improved similarly with both treatment modalities. Microbiological analyses revealed similar findings for the bacterial load (16S gene copy numbers) and ratio of each bacterium to the total bacterial count at baseline and 1‐month control. Cytokine levels in the gingival crevicular fluid samples exhibited differences between the two treatments. Scanning electron microscopic analyses indicated that diamond burs were better in terms of calculus removal and loss of tooth substance indices but roughness index values were better for curettes.

Conclusions

Diamond burs provide findings comparable with curettes in root planing.
Osteonecrosis of the jaws: a 14‐year retrospective survey of hospital admissions
Authors: McGowan K , Ivanovski S , Acton C
Published: February 2018

Background

Osteonecrosis of the jaw (ONJ) is a serious complication of both radiation and antiresorptive therapies. This study aimed to determine how many patients have been treated for medication‐related osteonecrosis of the jaws (MRONJ) and osteoradionecrosis (ORN), and whether the number of diagnoses has decreased over time with improved awareness and preventative measures.

Methods

Medical records at the Royal Brisbane and Women's Hospital, Gold Coast University Hospital and Robina Hospital were reviewed to identify patients diagnosed with MRONJ and ORN between January 2003 and May 2017. Data on patient demographics, year of admission and primary disease were analysed.

Results

Two hundred and thirty‐eight patients were diagnosed with ONJ, of which 74.4% were ORN and 25.6% were MRONJ. Tongue (24.6%), floor of mouth (17.3%) and tonsillar (15.1%) squamous cell carcinomas were the most common primary diseases associated with ORN, with a strong male predominance (80%). Of patients diagnosed with MRONJ, 52.5% were taking low‐dose antiresorptives for osteoporosis (44.2%), rheumatoid arthritis (4.6%) or Paget's disease (3.3%), while 47.5% were oncology patients receiving high‐dose antiresorptives.

Conclusions

The number of patients diagnosed with MRONJ and ORN has trended upwards since 2003. ORN affected three times more patients than MRONJ, and patients on low‐dose antiresorptives accounted for over half of the MRONJ cases.
Gestures of taxidermy: Morphological approximation as interspecies affinity
Authors: KALSHOVEN PETRA TJITSKE
Published: February 2018

Anthropologists have recently begun to highlight human relatedness with other animal species, arguing for a more inclusive posthumanism in which boundaries between different categories of “life” become blurred. Taxidermy in Britain and western Europe both troubles and supports assumptions about interspecies entanglements. In taxidermy, living humans meet dead animals in ways that suggest kinship relations beyond death, expressed in morphological analogies. Lifelike animation occurs both discursively and plastically, and the recent influx of artists into taxidermy has given it particular prominence. A specific ethics of the body emerges, one that makes a professed environmental affinity among artist‐taxidermists pale in comparison with the “morphological approximation” performed by professional taxidermists in relation to the animals whose lives they claim to prolong. [morphology,ethics of the body,taxidermy,interspecies affinity,morphological approximation,Britain,western Europe]
Iron Nutrition in Childhood: the Interplay of Genes, Development and Environment
Authors: WHARTON B. A.
Published: February 2018

Wharton, B. A. (University of Glasgow Department of Human Nutrition, Yorkhill Hospitals, Glasgow, G3 8SJ). Iron nutrition in childhood: the interplay of genes, development and environment.

The state of a child's iron nutrition depends on his genetic endowment, the stage of development he has reached and the environment in which he lives. Genetic disorders lead more commonly to iron overload than to deficiency. Generally interplay between genes and environment is apparently of little importance when considering iron deficiency; are we missing something? The greatest demands for iron are at the time of most rapid growth, i.e. during infancy and puberty, but during early infancy body stores can meet the demand without a need for dietary iron. Oxygen, diet and microbes are the important environmental factors related to iron nutrition. The relationship of oxygen toxicity to iron nutrition in the newborn has received only fleeting study, the availability of iron from many foods is unclear; the clinical significance of iron overload and deficiency in the evolution of an infection is also unclear despite a wealth of in vitro observation. I am not convinced that the bottle fed baby should receive iron in his diet during the first 4–6 months of life. Thereafter, while the concept of universal unselective supplementation causes some uneasiness there are considerable epidemiological arguments for fortification of food with iron.
Biochemical Effects of Iron Deprivation
Authors: HERCBERG S. , GALAN P.
Published: February 2018

Hercberg, S. and Galán, P. (Centre de Recherches sur les Anémies Nutritionnelles, Institut Scientifique et Technique de l'Alimentation, CNAM, 2, rue Conté, F‐75003 Paris, France). Biochemical effects of iron deprivation.

The consequences of iron deprivation on iron‐containing enzymes of different tissues in rat and/or human is reviewed. Iron participates in a wide variety of biochemical processes, including mitochondrial electron transport, catecholamine metabolism and DNA synthesis. Recently, a broad spectrum of biochemical abnormalities resulting from iron deficiency have been described. Effects on skeletal muscle, cardiac muscle, brain tissue, liver tissue gastrointestinal tractus, body temperature regulation, DNA synthesis are successively discussed. The key liabilities of tissue iron deficiency, even at a mild degree relate to decrease in intellectual performance, and in physical capacity during exercise, alteration of temperature regulation, immune function.