bluuebunny/crossref_metadata_2025 huggingface dataset:
Age-Related Differences and Heritability of the Perisylvian Language Networks
Authors: Budisavljevic Sanja , Dell'Acqua Flavio , Rijsdijk Frühling V. , Kane Fergus , Picchioni Marco , McGuire Philip , Toulopoulou Timothea , Georgiades Anna , Kalidindi Sridevi , Kravariti Eugenia , Murray Robin M. , Murphy Declan G. , Craig Michael C. , Catani Marco
Published: September 2015

Acquisition of language skills depends on the progressive maturation of specialized brain networks that are usually lateralized in adult population. However, how genetic and environmental factors relate to the age-related differences in lateralization of these language pathways is still not known. We recruited 101 healthy right-handed subjects aged 9–40 years to investigate age-related differences in the anatomy of perisylvian language pathways and 86 adult twins (52 monozygotic and 34 dizygotic) to understand how heritability factors influence language anatomy. Diffusion tractography was used to dissect and extract indirect volume measures from the three segments of the arcuate fasciculus connecting Wernicke's to Broca's region (i.e., long segment), Broca's to Geschwind's region (i.e., anterior segment), and Wernicke's to Geschwind's region (i.e., posterior segment). We found that the long and anterior arcuate segments are lateralized before adolescence and their lateralization remains stable throughout adolescence and early adulthood. Conversely, the posterior segment shows right lateralization in childhood but becomes progressively bilateral during adolescence, driven by a reduction in volume in the right hemisphere. Analysis of the twin sample showed that genetic and shared environmental factors influence the anatomy of those segments that lateralize earlier, whereas specific environmental effects drive the variability in the volume of the posterior segment that continues to change in adolescence and adulthood. Our results suggest that the age-related differences in the lateralization of the language perisylvian pathways are related to the relative contribution of genetic and environmental effects specific to each segment.

SIGNIFICANCE STATEMENTOur study shows that, by early childhood, frontotemporal (long segment) and frontoparietal (anterior segment) connections of the arcuate fasciculus are left and right lateralized, respectively, and remain lateralized throughout adolescence and early adulthood. In contrast, temporoparietal (posterior segment) connections are right lateralized in childhood, but become progressively bilateral during adolescence. Preliminary twin analysis suggested that lateralization of the arcuate fasciculus is a heterogeneous process that depends on the interplay between genetic and environment factors specific to each segment. Tracts that exhibit higher age effects later in life (i.e., posterior segment) appear to be influenced more by specific environmental factors.
Right Frontoinsular Cortex and Subcortical Activity to Infant Cry Is Associated with Maternal Mental State Talk
Authors: Hipwell Alison E. , Guo Chaohui , Phillips Mary L. , Swain James E. , Moses-Kolko Eydie L.
Published: September 2015

The study objective was to examine neural correlates of a specific component of human caregiving: maternal mental state talk, reflecting a mother's proclivity to attribute mental states and intentionality to her infant. Using a potent, ecologically relevant stimulus of infant cry during fMRI, we tested hypotheses that postpartum neural response to the cry of “own” versus a standard “other” infant in the right frontoinsular cortex (RFIC) and subcortical limbic network would be associated with independent observations of maternal mental state talk. The sample comprised 76 urban-living, low socioeconomic mothers (82% African American) and their 4-month-old infants. Before the fMRI scan, mothers were filmed in face-to-face interaction with their infant, and maternal behaviors were coded by trained researchers unaware of all other information about the participants. The results showed higher functional activity in the RFIC to own versus other infant cry at the group level. In addition, RFIC and bilateral subcortical neural activity (e.g., thalamus, amygdala, hippocampus, putamen) was associated positively with maternal mental state talk but not with more global aspects of observed caregiving. These findings held when accounting for perceptual and contextual covariates, such as maternal felt distress, urge to help, depression severity, and recognition of own infant cry. Our results highlight the need to focus on specific components of caregiving to advance understanding of the maternal brain. Future work will examine the predictive utility of this neural marker for mother–child function.

SIGNIFICANCE STATEMENTThe current study advances extant literature examining the neural underpinning of early parenting behavior. The findings highlight the special functional importance of the right frontoinsular cortex–thalamic–limbic network in a mother's proclivity to engage in mental state talk with her preverbal infant, a circumscribed aspect of maternal caregiving purported to be a prerequisite of sensitive and responsive caregiving. These associations existed specifically for maternal mentalizing behavior and were not evident for more generic aspects of caregiving in this urban sample of 76 postpartum mothers. Finally, the findings were robust even when controlling for potential demographic, perceptual, and contextual confounds, supporting the notion that these regions constitute an innate, specialized maternal mentalizing network.
Brain Region-Specific Trafficking of the Dopamine Transporter
Authors: Block Ethan R. , Nuttle Jacob , Balcita-Pedicino Judith Joyce , Caltagarone John , Watkins Simon C. , Sesack Susan R. , Sorkin Alexander
Published: September 2015

The dopamine (DA) transporter (DAT) controls dopaminergic neurotransmission by removing extracellular DA. Although DA reuptake is proposed to be regulated by DAT traffic to and from the cell surface, the membrane trafficking system involved in the endocytic cycling of DAT in the intact mammalian brain has not been characterized. Hence, we performed immunolabeling and quantitative analysis of the subcellular and regional distribution of DAT using the transgenic knock-in mouse expressing hemagglutinin (HA) epitope-tagged DAT (HA-DAT) and by using a combination of electron microscopy and a novel method for immunofluorescence labeling of HA-DAT in acute sagittal brain slices. Both approaches demonstrated that, in midbrain somatodendritic regions, HA-DAT was present in the plasma membrane, endoplasmic reticulum, and Golgi complex, with a small fraction in early and recycling endosomes and an even smaller fraction in late endosomes and lysosomes. In the striatum and in axonal tracts between the midbrain and striatum, HA-DAT was detected predominantly in the plasma membrane, and quantitative analysis revealed increased DAT density in striatal compared with midbrain plasma membranes. Endosomes were strikingly rare and lysosomes were absent in striatal axons, in which there was little intracellular HA-DAT. Acute administration of amphetaminein vivo(60 min) or to slicesex vivo(10–60 min) did not result in detectable changes in DAT distribution. Altogether, these data provide evidence for regional differences in DAT plasma membrane targeting and retention and suggest a surprisingly low level of endocytic trafficking of DAT in the striatum along with limited DAT endocytic activity in somatodendritic areas.

SIGNIFICANCE STATEMENTThe dopamine transporter (DAT) is the key regulator of the dopamine neurotransmission in the CNS. In the present study, we developed a new approach for studying DAT localization and dynamics in intact neurons in acute sagittal brain slices from the knock-in mouse expressing epitope-tagged DAT. For the first time, the fluorescence imaging analysis of DAT was combined with the immunogold labeling of DAT and quantitative electron microscopy. In contrast to numerous studies of DAT trafficking in heterologous expression systems and dissociated cultured neurons, studies in intact neurons revealed a surprisingly low amount of endocytic trafficking of DAT at steady state and after acute amphetamine treatment and suggested that non-vesicular transport could be the main mechanism establishing DAT distribution within the dopaminergic neuron.
Ventromedial Frontal Cortex Is Critical for Guiding Attention to Reward-Predictive Visual Features in Humans
Authors: Vaidya Avinash R. , Fellows Lesley K.
Published: September 2015

Adaptively interacting with our environment requires extracting information that will allow us to successfully predict reward. This can be a challenge, particularly when there are many candidate cues, and when rewards are probabilistic. Recent work has demonstrated that visual attention is allocated to stimulus features that have been associated with reward on previous trials. The ventromedial frontal lobe (VMF) has been implicated in learning in dynamic environments of this kind, but the mechanism by which this region influences this process is not clear. Here, we hypothesized that the VMF plays a critical role in guiding attention to reward-predictive stimulus features based on feedback. We tested the effects of VMF damage in human subjects on a visual search task in which subjects were primed to attend to task-irrelevant colors associated with different levels of reward, incidental to the search task. Consistent with previous work, we found that distractors had a greater influence on reaction time when they appeared in colors associated with high reward in the previous trial compared with colors associated with low reward in healthy control subjects and patients with prefrontal damage sparing the VMF. However, this reward modulation of attentional priming was absent in patients with VMF damage. Thus, an intact VMF is necessary for directing attention based on experience with cue–reward associations. We suggest that this region plays a role in selecting reward-predictive cues to facilitate future learning.

SIGNIFICANCE STATEMENTThere has been a swell of interest recently in the ventromedial frontal cortex (VMF), a brain region critical to associative learning. However, the underlying mechanism by which this region guides learning is not well understood. Here, we tested the effects of damage to this region in humans on a task in which rewards were linked incidentally to visual features, resulting in trial-by-trial attentional priming. Controls and subjects with prefrontal damage sparing the VMF showed normal reward priming, but VMF-damaged patients did not. This work sheds light on a potential mechanism through which this region influences behavior. We suggest that the VMF is necessary for directing attention to reward-predictive visual features based on feedback, facilitating future learning and decision-making.
Identified Serotonin-Releasing Neurons Induce Behavioral Quiescence and Suppress Mating inDrosophila
Authors: Pooryasin Atefeh , Fiala André
Published: September 2015

Animals show different levels of activity that are reflected in sensory responsiveness and endogenously generated behaviors. Biogenic amines have been determined to be causal factors for these states of arousal. It is well established that, inDrosophila, dopamine and octopamine promote increased arousal. However, little is known about factors that regulate arousal negatively and induce states of quiescence. Moreover, it remains unclear whether global, diffuse modulatory systems comprehensively affecting brain activity determine general states of arousal. Alternatively, individual aminergic neurons might selectively modulate the animals' activity in a distinct behavioral context. Here, we show that artificially activating large populations of serotonin-releasing neurons induces behavioral quiescence and inhibits feeding and mating. We systematically narrowed down a role of serotonin in inhibiting endogenously generated locomotor activity to neurons located in the posterior medial protocerebrum. We identified neurons of this cell cluster that suppress mating, but not feeding behavior. These results suggest that serotonin does not uniformly act as global, negative modulator of general arousal. Rather, distinct serotoninergic neurons can act as inhibitory modulators of specific behaviors.

SIGNIFICANCE STATEMENTAn animal's responsiveness to external stimuli and its various types of endogenously generated, motivated behavior are highly dynamic and change between states of high activity and states of low activity. It remains unclear whether these states are mediated by unitary modulatory systems globally affecting brain activity, or whether distinct neurons modulate specific neuronal circuits underlying particular types of behavior. Using the model organismDrosophila melanogaster, we find that activating large proportions of serotonin-releasing neurons induces behavioral quiescence. Moreover, distinct serotonin-releasing neurons that we genetically isolated and identified negatively affect aspects of mating behavior, but not food uptake. This demonstrates that individual serotoninergic neurons can modulate distinct types of behavior selectively.
Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons
Authors: Ehrich Jonathan M. , Messinger Daniel I. , Knakal Cerise R. , Kuhar Jamie R. , Schattauer Selena S. , Bruchas Michael R. , Zweifel Larry S. , Kieffer Brigitte L. , Phillips Paul E.M. , Chavkin Charles
Published: September 2015

The endogenous dynorphin-κ opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38α MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38α MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR−/−mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38α MAPK activation did not. Surprisingly, while p38α MAPK inactivation blocked U50,488-CPA, p38α MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38α MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that κ opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38α MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release.

SIGNIFICANCE STATEMENTKappa opioid receptor (KOR) agonists have the potential to be effective, nonaddictive analgesics, but their therapeutic utility is greatly limited by adverse effects on mood. Understanding how KOR activation produces dysphoria is key to the development of better analgesics and to defining how the endogenous dynorphin opioids produce their depression-like effects. Results in this study show that the aversive effects of κ receptor activation required arrestin-dependent p38α MAPK activation in dopamine neurons but did not require inhibition of dopamine release in the nucleus accumbens. Thus, contrary to the prevailing view, inhibition of mesolimbic dopamine release does not mediate the aversive effects of KOR activation and functionally selective κ opioids that do not activate arrestin signaling may be effective analgesics lacking dysphoric effects.
Representation of Muscle Synergies in the Primate Brain
Authors: Overduin Simon A. , d'Avella Andrea , Roh Jinsook , Carmena Jose M. , Bizzi Emilio
Published: September 2015

Evidence suggests that the CNS uses motor primitives to simplify movement control, but whether it actually stores primitives instead of computing solutions on the fly to satisfy task demands is a controversial and still-unanswered possibility. Also in contention is whether these primitives take the form of time-invariant muscle coactivations (“spatial” synergies) or time-varying muscle commands (“spatiotemporal” synergies). Here, we examined forelimb muscle patterns and motor cortical spiking data in rhesus macaques (Macaca mulatta) handling objects of variable shape and size. From these data, we extracted both spatiotemporal and spatial synergies using non-negative decomposition. Each spatiotemporal synergy represents a sequence of muscular or neural activations that appeared to recur frequently during the animals' behavior. Key features of the spatiotemporal synergies (including their dimensionality, timing, and amplitude modulation) were independently observed in the muscular and neural data. In addition, both at the muscular and neural levels, these spatiotemporal synergies could be readily reconstructed as sequential activations of spatial synergies (a subset of those extracted independently from the task data), suggestive of a hierarchical relationship between the two levels of synergies. The possibility that motor cortex may execute even complex skill using spatiotemporal synergies has novel implications for the design of neuroprosthetic devices, which could gain computational efficiency by adopting the discrete and low-dimensional control that these primitives imply.

SIGNIFICANCE STATEMENTWe studied the motor cortical and forearm muscular activity of rhesus macaques (Macaca mulatta) as they reached, grasped, and carried objects of varied shape and size. We applied non-negative matrix factorization separately to the cortical and muscular data to reduce their dimensionality to a smaller set of time-varying “spatiotemporal” synergies. Each synergy represents a sequence of cortical or muscular activity that recurred frequently during the animals' behavior. Salient features of the synergies (including their dimensionality, timing, and amplitude modulation) were observed at both the cortical and muscular levels. The possibility that the brain may execute even complex behaviors using spatiotemporal synergies has implications for neuroprosthetic algorithm design, which could become more computationally efficient by adopting the discrete and low-dimensional control that they afford.
Unmasking Proteolytic Activity for Adult Visual Cortex Plasticity by the Removal of Lynx1
Authors: Bukhari Noreen , Burman Poromendro N. , Hussein Ayan , Demars Michael P. , Sadahiro Masato , Brady Daniel M. , Tsirka Stella E. , Russo Scott J. , Morishita Hirofumi
Published: September 2015

Experience-dependent cortical plasticity declines with age. At the molecular level, experience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain if mice are raised in standard cages. Understanding the mechanism for the loss of permissive proteolytic activity is therefore a key link for improving function in adult brains. Using the mouse primary visual cortex (V1) as a model, we demonstrate that tPA activity in V1 can be unmasked following 4 d of monocular deprivation when the mice older than 2 months are raised in standard cages by the genetic removal of Lynx1, a negative regulator of adult plasticity. This was also associated with the reduction of stubby and thin spine density and enhancement of ocular dominance shift in adult V1 of Lynx1 knock-out (KO) mice. These structural and functional changes were tPA-dependent because genetic removal of tPA in Lynx1 KO mice can block the monocular deprivation-dependent reduction of dendritic spine density, whereas both genetic and adult specific inhibition of tPA activity can ablate the ocular dominance shift in Lynx1 KO mice. Our work demonstrates that the adult brain has an intrinsic potential for experience-dependent elevation of proteolytic activity to express juvenile-like structural and functional changes but is effectively limited by Lynx1 if mice are raised in standard cages. Insights into the Lynx1-tPA plasticity mechanism may provide novel therapeutic targets for adult brain disorders.

SIGNIFICANCE STATEMENTExperience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain in correlation with the decline in cortical plasticity when mice are raised in standard cages. We demonstrated that removal of Lynx1, one of negative regulators of plasticity, unmasks experience-dependent tPA elevation in visual cortex of adult mice reared in standard cages. This proteolytic elevation facilitated dendritic spine reduction and ocular dominance plasticity in adult visual cortex. This is the first demonstration of adult brain to retain the intrinsic capacity to elevate tPA in an experience-dependent manner but is effectively limited by Lynx1. tPA-Lynx1 may potentially be a new candidate mechanism for interventions that were shown to activate plasticity in adult brain.
Decorum and the Meanings of Materials in Triumphal Architecture of Republican Rome
Authors: Popkin Maggie L.
Published: September 2015

In Decorum and the Meanings of   Materials in Triumphal Architecture of Republican Rome, Maggie L. Popkin argues that the literal and figurative values of materials in republican triumphal architecture stemmed from complex interactions among patron, architect, audience, and sociohistorical context. Several case studies—the Temple of Fortuna Equestris, the Porticus Metelli, the Round Temple on the Tiber, and Temple B in the Area Sacra di Largo Argentina—demonstrate that the juxtaposition of multiple materials, changing historical circumstances, and new groups of viewers resulted in constantly shifting meanings of materials in republican architecture. The Roman notion of decorum helps explain the shifting uses and valuations of materials. Factors such as the monument’s patron, the event that sparked its construction, its location, the monument type, the availability of materials, and the intended audiences affected the choice of materials and their intended and perceived meanings, which had rich conceptual and imaginative potential to evoke Roman conquest, piety, and spectacle.
Leon Battista Alberti, Mental Rotation, and the Origins of Three-Dimensional Computer Modeling
Authors: Mitrović Branko
Published: September 2015

One of the most fundamental assumptions of modern architectural practice is that all spatial relationships on a building are mathematically definable and can be systematically described by means of two-dimensional representations generated using procedures based on quantification. It is this assumption that makes three-dimensional computer modeling possible. In Leon Battista Alberti, Mental Rotation, and the Origins of Three-Dimensional Computer Modeling, Branko Mitrović analyzes the historical origins of this approach to visual communication about architectural works and its first explicit articulation in the work of Leon Battista Alberti.
Whitman’s Atlantic Noise
Authors: Hanlon Christopher
Published: September 2015

Christopher Hanlon, “Whitman’s Atlantic Noise” (pp. 194–220)

This essay considers Walt Whitman’s “A Word Out of the Sea,” from the 1860 edition of Leaves of Grass, for its aural qualities—acoustically twittering birds, the hissing “undertone” of the ocean, for example—linking the poem to a wider antebellum interest in the electronic noise of telegraphy. I argue that this poem’s auditory effects bring Whitman into discussion with many others during the 1850s and 1860s who were interested in the sonic qualities of telegraphic noise quite apart from the words those noises encoded. Calling upon an array of cultural documents including songsheets, poems, fiction, and technical commentary, I suggest that “A Word Out of the Sea” condenses a singular moment in American intellectual life wherein the widespread deployment of telegraphic technology honed much interest in the interplay of sound and meaning. In this way, “A Word Out of the Sea” helps further current discussions over the resonance of nineteenth-century information technology among U.S. commentators (including poets), first-generation users who were less constantly focused than we might suppose upon the epistemological ramifications of the telegraph as a harbinger of unthinkably efficient, global communication. In many other ways, these observers of the telegraph were just as struck by the telegraph’s ontological properties, and especially the kinds of sounds it generated.
Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis
Authors: Strosberg Jonathan R , Yao James C , Bajetta Emilio , Aout Mounir , Bakker Bert , Hainsworth John D , Ruszniewski Philippe B , Van Cutsem Eric , Öberg Kjell , Pavel Marianne E
Published: September 2015

Somatostatin analogues (SSA) have demonstrated antiproliferative activity in addition to efficacy for carcinoid symptom control in functional neuroendocrine tumors (NET). Apost hocanalysis of the placebo arm of the RAD001 In Advanced Neuroendocrine Tumors-2 (RADIANT-2) study was conducted to assess the efficacy of octreotide long-acting repeatable (LAR) on progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan–Meier method. Out of 213 patients randomized to placebo plus octreotide LAR in RADIANT-2, 196 patients with foregut, midgut, or hindgut NET were considered for present analysis. Of these, 41 patients were SSA-treatment naïve and 155 had received SSA therapy before study entry. For SSA-naïve patients, median PFS by adjudicated central review was 13.6 (95% CI 8.2–22.7) months. For SSA-naïve patients with midgut NET (n=24), median PFS was 22.2 (95% CI 8.3–29.5) months. For patients who had received SSA previously, the median PFS was 11.1 (95% CI 8.4–14.3) months. Among the SSA-pretreated patients who had midgut NET (n=119), the median PFS was 12.0 (95% CI 8.4–19.3) months. Median OS was 35.8 (95% CI 32.5–48.9) months for patients in the placebo plus octreotide LAR arm; 50.6 (36.4 – not reached) months for SSA-naïve patients and 33.5 (95% CI 27.5–44.7) months for those who had received prior SSA. Thispost hocanalysis of the placebo arm of the large phase 3 RADIANT-2 study provides data on PFS and OS among patients with progressive NET treated with octreotide therapy.
SUMO-Enriched Proteome for Drosophila Innate Immune Response
Authors: Handu Mithila , Kaduskar Bhagyashree , Ravindranathan Ramya , Soory Amarendranath , Giri Ritika , Elango Vijay Barathi , Gowda Harsha , Ratnaparkhi Girish S
Published: September 2015

Small ubiquitin-like modifier (SUMO) modification modulates the expression of defense genes in Drosophila, activated by the Toll/nuclear factor-κB and immune-deficient/nuclear factor-κB signaling networks. We have, however, limited understanding of the SUMO-modulated regulation of the immune response and lack information on SUMO targets in the immune system. In this study, we measured the changes to the SUMO proteome in S2 cells in response to a lipopolysaccharide challenge and identified 1619 unique proteins in SUMO-enriched lysates. A confident set of 710 proteins represents the immune-induced SUMO proteome and analysis suggests that specific protein domains, cellular pathways, and protein complexes respond to immune stress. A small subset of the confident set was validated by in-bacto SUMOylation and shown to be bona-fide SUMO targets. These include components of immune signaling pathways such as Caspar, Jra, Kay, cdc42, p38b, 14-3-3ε, as well as cellular proteins with diverse functions, many being components of protein complexes, such as prosß4, Rps10b, SmD3, Tango7, and Aats-arg. Caspar, a human FAF1 ortholog that negatively regulates immune-deficient signaling, is SUMOylated at K551 and responds to treatment with lipopolysaccharide in cultured cells. Our study is one of the first to describe SUMO proteome for the Drosophila immune response. Our data and analysis provide a global framework for the understanding of SUMO modification in the host response to pathogens.
Genomic-Enabled Prediction of Ordinal Data with Bayesian Logistic Ordinal Regression
Authors: Montesinos-López Osval A , Montesinos-López Abelardo , Crossa José , Burgueño Juan , Eskridge Kent
Published: September 2015

Most genomic-enabled prediction models developed so far assume that the response variable is continuous and normally distributed. The exception is the probit model, developed for ordered categorical phenotypes. In statistical applications, because of the easy implementation of the Bayesian probit ordinal regression (BPOR) model, Bayesian logistic ordinal regression (BLOR) is implemented rarely in the context of genomic-enabled prediction [sample size (n) is much smaller than the number of parameters (p)]. For this reason, in this paper we propose a BLOR model using the Pólya-Gamma data augmentation approach that produces a Gibbs sampler with similar full conditional distributions of the BPOR model and with the advantage that the BPOR model is a particular case of the BLOR model. We evaluated the proposed model by using simulation and two real data sets. Results indicate that our BLOR model is a good alternative for analyzing ordinal data in the context of genomic-enabled prediction with the probit or logit link.
Genes with Restricted Introgression in a Field Cricket (Gryllus firmus/Gryllus pennsylvanicus) Hybrid Zone Are Concentrated on the X Chromosome and a Single Autosome
Authors: Maroja Luana S , Larson Erica L , Bogdanowicz Steven M , Harrison Richard G
Published: September 2015

Characterizing the extent of genomic differentiation between recently diverged lineages provides an important context for understanding the early stages of speciation. When such lineages form discrete hybrid zones, patterns of differential introgression allow direct estimates of which genome regions are likely involved in speciation and local adaptation. Here we use a backcross experimental design to construct a genetic linkage map for the field crickets Gryllus firmus and Gryllus pennsylvanicus, which interact in a well-characterized hybrid zone in eastern North America. We demonstrate that loci with major allele frequency differences between allopatric populations are not randomly distributed across the genome. Instead, most are either X-linked or map to a few small autosomal regions. Furthermore, the subset of those highly differentiated markers that exhibit restricted introgression across the cricket hybrid zone are also concentrated on the X chromosome (39 of 50 loci) and in a single 7-cM region of one autosome. Although the accumulation on the sex chromosome of genes responsible for postzygotic barriers is a well-known phenomenon, less attention has been given to the genomic distribution of genes responsible for prezygotic barriers. We discuss the implications of our results for speciation, both in the context of the role of sex chromosomes and also with respect to the likely causes of heterogeneous genomic divergence. Although we do not yet have direct evidence for the accumulation of ecological, behavioral, or fertilization prezygotic barrier genes on the X chromosome, faster-X evolution could make these barriers more likely to be X-linked.
Genetic Networks Required to Coordinate Chromosome Replication by DNA Polymerases α, δ, and ε in Saccharomyces cerevisiae
Authors: Dubarry Marion , Lawless Conor , Banks A Peter , Cockell Simon , Lydall David
Published: September 2015

Three major DNA polymerases replicate the linear eukaryotic chromosomes. DNA polymerase α-primase (Pol α) and DNA polymerase δ (Pol δ) replicate the lagging-strand and Pol α and DNA polymerase ε (Pol ε) the leading-strand. To identify factors affecting coordination of DNA replication, we have performed genome-wide quantitative fitness analyses of budding yeast cells containing defective polymerases. We combined temperature-sensitive mutations affecting the three replicative polymerases, Pol α, Pol δ, and Pol ε with genome-wide collections of null and reduced function mutations. We identify large numbers of genetic interactions that inform about the roles that specific genes play to help Pol α, Pol δ, and Pol ε function. Surprisingly, the overlap between the genetic networks affecting the three DNA polymerases does not represent the majority of the genetic interactions identified. Instead our data support a model for division of labor between the different DNA polymerases during DNA replication. For example, our genetic interaction data are consistent with biochemical data showing that Pol ε is more important to the Pre-Loading complex than either Pol α or Pol δ. We also observed distinct patterns of genetic interactions between leading- and lagging-strand DNA polymerases, with particular genes being important for coupling proliferating cell nuclear antigen loading/unloading (Ctf18, Elg1) with nucleosome assembly (chromatin assembly factor 1, histone regulatory HIR complex). Overall our data reveal specialized genetic networks that affect different aspects of leading- and lagging-strand DNA replication. To help others to engage with these data we have generated two novel, interactive visualization tools, DIXY and Profilyzer.
The Nature, Extent, and Consequences of Genetic Variation in the opa Repeats of Notch in Drosophila
Authors: Rice Clinton , Beekman Danielle , Liu Liping , Erives Albert
Published: September 2015

Polyglutamine (pQ) tracts are abundant in proteins co-interacting on DNA. The lengths of these pQ tracts can modulate their interaction strengths. However, pQ tracts >40 residues are pathologically prone to amyloidogenic self-assembly. Here, we assess the extent and consequences of variation in the pQ-encoding opa repeats of Notch in Drosophila melanogaster. We use Sanger sequencing to genotype opa sequences (5′-CAX repeats), which have resisted assembly using short sequence reads. While most sampled lines carry the major allele opa31 encoding Q13HQ17 or the opa32 allele encoding Q13HQ18, many lines carry rare alleles encoding pQ tracts >32 residues: opa33a (Q14HQ18), opa33b (Q15HQ17), opa34 (Q16HQ17), opa35a1/opa35a2 (Q13HQ21), opa36 (Q13HQ22), and opa37 (Q13HQ23). Only one rare allele encodes a tract <31 residues: opa23 (Q13–Q10). This opa23 allele shortens the pQ tract while simultaneously eliminating the interrupting histidine. We introgressed these opa variant alleles into common backgrounds and measured the frequency of Notch-type phenotypes. Homozygotes for the short and long opa alleles have defects in embryonic survival and sensory bristle organ patterning, and sometimes show wing notching. Consistent with functional differences between Notch opa variants, we find that a scute inversion carrying the rare opa33b allele suppresses the bristle patterning defect caused by achaete/scute insufficiency, while an equivalent scute inversion carrying opa31 manifests the patterning defect. Our results demonstrate the existence of potent pQ variants of Notch and the need for long read genotyping of key repeat variables underlying gene regulatory networks.
Genomic Correlates of Virulence Attenuation in the Deadly Amphibian Chytrid Fungus,Batrachochytrium dendrobatidis
Authors: Refsnider Jeanine M , Poorten Thomas J , Langhammer Penny F , Burrowes Patricia A , Rosenblum Erica Bree
Published: September 2015

Emerging infectious diseasespose a significant threat to global health, but predicting disease outcomes for particular species can be complicated when pathogen virulence varies across space, time, or hosts. The pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd) has caused worldwide declines in frog populations. Not only do Bd isolates from wild populations vary in virulence, but virulence shifts can occur over short timescales when Bd is maintained in the laboratory. We leveraged changes in Bd virulence over multiple generations of passage to better understand mechanisms of pathogen virulence. We conducted whole-genome resequencing of two samples of the same Bd isolate, differing only in passage history, to identify genomic processes associated with virulence attenuation. The isolate with shorter passage history (and greater virulence) had greater chromosome copy numbers than the isolate maintained in culture for longer, suggesting that virulence attenuation may be associated with loss of chromosome copies. Our results suggest that genomic processes proposed as mechanisms for rapid evolution in Bd are correlated with virulence attenuation in laboratory culture within a single lineage of Bd. Moreover, these genomic processes can occur over extremely short timescales. On a practical level, our results underscore the importance of immediately cryo-archiving new Bd isolates and using fresh isolates, rather than samples cultured in the laboratory for long periods, for laboratory infection experiments. Finally, when attempting to predict disease outcomes for this ecologically important pathogen, it is critical to consider existing variation in virulence among isolates and the potential for shifts in virulence over short timescales.
Slit Binding via the Ig1 Domain Is Essential for Midline Repulsion by Drosophila Robo1 but Dispensable for Receptor Expression, Localization, and Regulation in Vivo
Authors: Brown Haley E , Reichert Marie C , Evans Timothy A
Published: September 2015

The midline repellant ligand Slit and its Roundabout (Robo) family receptors constitute the major midline repulsive pathway in bilaterians. Slit proteins produced at the midline of the central nervous system (CNS) signal through Robo receptors expressed on axons to prevent them from crossing the midline, and thus regulate connectivity between the two sides of the nervous system. Biochemical structure and interaction studies support a model in which Slit binding to the first immunoglobulin-like (Ig1) domain of Robo receptors activates a repulsive signaling pathway in axonal growth cones. Here, we examine the in vivo functional importance of the Ig1 domain of the Drosophila Robo1 receptor, which controls midline crossing of axons in response to Slit during development of the embryonic CNS. We show that deleting Ig1 from Robo1 disrupts Slit binding in cultured Drosophila cells, and that a Robo1 variant lacking Ig1 (Robo1∆Ig1) is unable to promote ectopic midline repulsion in gain-of-function studies in the Drosophila embryonic CNS. We show that the Ig1 domain is not required for proper expression, axonal localization, or Commissureless (Comm)-dependent regulation of Robo1 in vivo, and we use a genetic rescue assay to show that Robo1∆Ig1 is unable to substitute for full-length Robo1 to properly regulate midline crossing of axons. These results establish a direct link between in vitro biochemical studies of Slit–Robo interactions and in vivo genetic studies of Slit-Robo signaling during midline axon guidance, and distinguish Slit-dependent from Slit-independent aspects of Robo1 expression, regulation, and activity during embryonic development.
The Double-Reduction Landscape in Tetraploid Potato as Revealed by a High-Density Linkage Map
Authors: Bourke Peter M , Voorrips Roeland E , Visser Richard G F , Maliepaard Chris
Published: September 2015

The creation of genetic linkage maps in polyploid species has been a long-standing problem for which various approaches have been proposed. In the case of autopolyploids, a commonly used simplification is that random bivalents form during meiosis. This leads to relatively straightforward estimation of recombination frequencies using maximum likelihood, from which a genetic map can be derived. However, autopolyploids such as tetraploid potato (Solanum tuberosum L.) may exhibit additional features, such as double reduction, not normally encountered in diploid or allopolyploid species. In this study, we produced a high-density linkage map of tetraploid potato and used it to identify regions of double reduction in a biparental mapping population. The frequency of multivalents required to produce this degree of double reduction was determined through simulation. We also determined the effect that multivalents or preferential pairing between homologous chromosomes has on linkage mapping. Low levels of multivalents or preferential pairing do not adversely affect map construction when highly informative marker types and phases are used. We reveal the double-reduction landscape in tetraploid potato, clearly showing that this phenomenon increases with distance from the centromeres.
Las transformaciones en la concepción de universidad y el caso brasileño
Authors: Durão Fabio Akcelrud
Published: September 2015

La creciente división del trabajo intelectual ha conducido a la proliferación de sub(sub)campos de estudio, los cuales ganan en poder de caracterización aquello que pierden en su visión de un todo (un todo que, ahora, es visto prácticamente como anatema). El presente texto discute, en primer lugar, las amplias mutaciones por las cuales han pasado la idea y la práctica de la universidad. En seguida, aborda los reflejos de esa dinámica en el ámbito de los estudios literarios, con el contexto brasilero como trasfondo.
Lo relativo y lo universal en la defensa de las humanidades para la democracia
Authors: Galindo Liliana
Published: September 2015

Cuando se pone en duda la importancia del estudio de las humanidades aparecen varios argumentos en su defensa. En este ensayo se analiza uno de ellos: la democracia las necesita. A partir del modelo educativo para la democracia que Martha Nussbaum propone en Sin fines de lucro: por qué la democracia necesita de las humanidades se explora la noción de educación liberal, la necesidad de la democracia y la idea de humanidad que aparecen en este argumento, con el fin de preguntarnos sobre la importancia que se le da al estudio especializado de las humanidades en la educación superior, lo que se entiende por ellas, su autonomía frente a su función para la democracia, y la manera en que educan la forma en que vemos a los otros y nos relacionamos con ellos. 
TFF Peptides Play a Role in the Immune Response Following Oral Infection of Mice with Toxoplasma gondii
Authors: Fu Ting , Znalesniak Eva B. , Kalinski Thomas , Möhle Luisa , Biswas Aindrila , Salm Franz , Dunay Ildiko Rita , Hoffmann Werner
Published: September 2015

The peptide trefoil factor family 3 (TFF3) is a major constituent of the intestinal mucus, playing an important role in the repair of epithelial surfaces. To further understand the role of TFF3 in the protection of intestinal epithelium, we tested the influence of TFF3 in a murine Toxoplasma gondii-induced ileitis model. Surprisingly, TFF3KO mice showed a reduced immune response in the ileum when compared to wild-type animals. Interleukin-12 and interferon-γ expression levels as well as the number of CD4+ lymphocytes were reduced in the infected TFF3KO mice. These effects were in line with the trend of elevated parasite levels in the ileum. Moreover, TFF1 expression was upregulated in the spleen of infected mice. These initial results indicate that TFF3 is involved in the immune pathology of T. gondii infection-induced intestinal inflammation. Thus far, the mechanisms of how TFF3 influences the immune response are not fully understood. Further studies should identify if TFF3 affects mucus sensing of dendritic cells and how TFF3 is involved in regulating the immune response as an intrinsic secretory peptide of immune cells.
Coronary anomalies: what the radiologist should know
Authors: Neves Priscilla Ornellas , Andrade Joalbo , Monção Henry
Published: September 2015

Abstract Coronary anomalies comprise a diverse group of malformations, some of them asymptomatic with a benign course, and the others related to symptoms as chest pain and sudden death. Such anomalies may be classified as follows: 1) anomalies of origination and course; 2) anomalies of intrinsic coronary arterial anatomy; 3) anomalies of coronary termination. The origin and the proximal course of anomalous coronary arteries are the main prognostic factors, and interarterial course or a coronary artery is considered to be malignant due its association with increased risk of sudden death. Coronary computed tomography angiography has become the reference method for such an assessment as it detects not only anomalies in origination of these arteries, but also its course in relation to other mediastinal structures, which plays a relevant role in the definition of the therapeutic management. Finally, it is essential for radiologists to recognize and characterize such anomalies.
Accuracy of computer-aided ultrasound as compared with magnetic resonance imaging in the evaluation of nonalcoholic fatty liver disease in obese and eutrophic adolescents
Authors: Nascimento José Hermes Ribas do , Soder Ricardo Bernardi , Epifanio Matias , Baldisserotto Matteo
Published: September 2015

Abstract Objective: To compare the accuracy of computer-aided ultrasound (US) and magnetic resonance imaging (MRI) by means of hepatorenal gradient analysis in the evaluation of nonalcoholic fatty liver disease (NAFLD) in adolescents. Materials and Methods: This prospective, cross-sectional study evaluated 50 adolescents (aged 11–17 years), including 24 obese and 26 eutrophic individuals. All adolescents underwent computer-aided US, MRI, laboratory tests, and anthropometric evaluation. Sensitivity, specificity, positive and negative predictive values and accuracy were evaluated for both imaging methods, with subsequent generation of the receiver operating characteristic (ROC) curve and calculation of the area under the ROC curve to determine the most appropriate cutoff point for the hepatorenal gradient in order to predict the degree of steatosis, utilizing MRI results as the gold-standard. Results: The obese group included 29.2% girls and 70.8% boys, and the eutrophic group, 69.2% girls and 30.8% boys. The prevalence of NAFLD corresponded to 19.2% for the eutrophic group and 83% for the obese group. The ROC curve generated for the hepatorenal gradient with a cutoff point of 13 presented 100% sensitivity and 100% specificity. As the same cutoff point was considered for the eutrophic group, false-positive results were observed in 9.5% of cases (90.5% specificity) and false-negative results in 0% (100% sensitivity). Conclusion: Computer-aided US with hepatorenal gradient calculation is a simple and noninvasive technique for semiquantitative evaluation of hepatic echogenicity and could be useful in the follow-up of adolescents with NAFLD, population screening for this disease as well as for clinical studies.
Pressupostos, Fundamentos Teóricos e Legado do Curso de Mestrado em Planejamento Governamental Desenvolvido por Alberto Guerreiro Ramos
Authors: Salm José Francisco
Published: September 2015

Resumo:Este artigo identifica e discute os pressupostos e os fundamentos teóricos que orientaram o Curso de Mestrado em Planejamento Governamental, desenvolvido por Alberto Guerreiro Ramos na Universidade Federal de Santa Catarina (UFSC), em 1980 e 1981. Os dados foram obtidos por meio de documentos, material bibliográfico e entrevistas semiestruturadas realizadas com professores e alunos que participaram do curso. Os pressupostos e fundamentos teóricos resultantes dessa pesquisa compõem o conjunto de conhecimentos a partir do qual se desenvolveram os enunciados e as proposições de nossas considerações finais. Tais enunciados e proposições formam um excerto do legado que esse intelectual proporcionou à academia, em especial para a organização e o desenvolvimento de cursos stricto sensu de pós-graduação em Administração.