bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractMany 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.HighlightsTask activations and functional connectivity changes are negatively correlated across cortexTask activation and connectivity dissociations reflect differences in localized and distributed processes in cortexDifferences in localized and distributed processes are associated with differences in intrinsic timescale organizationDifferences in localized and distributed processes are associated with differences in cortical myelin contentCortical 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

ABSTRACTParent-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

SUMMARYRecently, 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

AbstractCRISPR-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

AbstractPalaeognathae 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

ABSTRACTThe 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

SummaryMany 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

AbstractWe 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

AbstractCornelia 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

ABSTRACTActivation 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 STATEMENTThe 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.
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

AbstractAssociative 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

AbstractLiterature 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

AbstractOutside 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 summaryInjury 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.