bluuebunny/crossref_metadata_2025 huggingface dataset:
The translation of cancer genomics: time for a revolution in clinical cancer care
Authors: Mardis Elaine R
Published: March 2014

The introduction of next-generation sequencing technologies has dramatically impacted the life sciences, perhaps most profoundly in the area of cancer genomics. Clinical applications of next-generation sequencing and associated methods are emerging from ongoing large-scale discovery projects that have catalogued hundreds of genes as having a role in cancer susceptibility, onset and progression. For example, discovery cancer genomics has confirmed that many of the same genes are altered by mutation, copy number gain or loss, or structural variation across multiple tumor types, resulting in a gain or loss of function that likely contributes to cancer development in these tissues. Beyond these frequently mutated genes, we now know there is a ‘long tail’ of less frequently mutated, but probably important, genes that play roles in cancer onset or progression. Here, I discuss some of the remaining barriers to clinical translation, and look forward to new applications of these technologies in cancer care.
Salt delineation via interpreter-guided 3D seismic image segmentation
Authors: Halpert Adam D. , Clapp Robert G. , Biondi Biondo
Published: March 2014

Although it is a crucial component of seismic velocity model building, salt delineation is often a major bottleneck in the interpretation workflow. Automatic methods like image segmentation can help to alleviate this bottleneck, but issues with accuracy and efficiency can hinder their effectiveness. However, a new graph-based segmentation algorithm can, after modifications to account for the unique nature of seismic data, quickly and accurately delineate salt bodies on 3D seismic images. In areas where salt boundaries are poorly imaged, limited manual interpretations can be used to guide the automatic segmentation, allowing for interpreter insight to be combined with modern computational capabilities. A successful 3D field data example demonstrates that this method could become an important tool for interactive interpretation tasks.
Cyp26 enzymes are required to balance the cardiac and vascular lineages within the anterior lateral plate mesoderm
Authors: Rydeen Ariel B. , Waxman Joshua S.
Published: March 2014

Normal heart development requires appropriate levels of retinoic acid (RA) signaling. RA levels in embryos are dampened by Cyp26 enzymes, which metabolize RA into easily degraded derivatives. Loss of Cyp26 function in humans is associated with numerous developmental syndromes that include cardiovascular defects. Although previous studies have shown that Cyp26-deficient vertebrate models also have cardiovascular defects, the mechanisms underlying these defects are not understood. Here, we found that in zebrafish, two Cyp26 enzymes, Cyp26a1 and Cyp26c1, are expressed in the anterior lateral plate mesoderm (ALPM) and predominantly overlap with vascular progenitors (VPs). Although singular knockdown of Cyp26a1 or Cyp26c1 does not overtly affect cardiovascular development, double Cyp26a1 and Cyp26c1 (referred to here as Cyp26)-deficient embryos have increased atrial cells and reduced cranial vasculature cells. Examining the ALPM using lineage tracing indicated that in Cyp26-deficient embryos the myocardial progenitor field contains excess atrial progenitors and is shifted anteriorly into a region that normally solely gives rise to VPs. Although Cyp26 expression partially overlaps with VPs in the ALPM, we found that Cyp26 enzymes largely act cell non-autonomously to promote appropriate cardiovascular development. Our results suggest that localized expression of Cyp26 enzymes cell non-autonomously defines the boundaries between the cardiac and VP fields within the ALPM through regulating RA levels, which ensures a proper balance of myocardial and endothelial lineages. Our study provides novel insight into the earliest consequences of Cyp26 deficiency that underlie cardiovascular malformations in vertebrate embryos.
No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates
Authors: Larson John , Drew Kelly L. , Folkow Lars P. , Milton Sarah L. , Park Thomas J.
Published: March 2014

Many vertebrates are challenged by either chronic or acute episodes of low oxygen availability in their natural environments. Brain function is especially vulnerable to the effects of hypoxia and can be irreversibly impaired by even brief periods of low oxygen supply. This review describes recent research on physiological mechanisms that have evolved in certain vertebrate species to cope with brain hypoxia. Four model systems are considered: freshwater turtles that can survive for months trapped in frozen-over lakes, arctic ground squirrels that respire at extremely low rates during winter hibernation, seals and whales that undertake breath-hold dives lasting minutes to hours, and naked mole-rats that live in crowded burrows completely underground for their entire lives. These species exhibit remarkable specializations of brain physiology that adapt them for acute or chronic episodes of hypoxia. These specializations may be reactive in nature, involving modifications to the catastrophic sequelae of oxygen deprivation that occur in non-tolerant species, or preparatory in nature, preventing the activation of those sequelae altogether. Better understanding of the mechanisms used by these hypoxia-tolerant vertebrates will increase appreciation of how nervous systems are adapted for life in specific ecological niches as well as inform advances in therapy for neurological conditions such as stroke and epilepsy.
Biophysics of directional hearing in the American alligator (Alligator mississippiensis)
Authors: Bierman Hilary S. , Thornton Jennifer L. , Jones Heath G. , Koka Kanthaiah , Young Bruce A. , Brandt Christian , Christensen-Dalsgaard Jakob , Carr Catherine E. , Tollin Daniel J.
Published: March 2014

Physiological and anatomical studies have suggested that alligators have unique adaptations for spatial hearing. Sound localization cues are primarily generated by the filtering of sound waves by the head. Different vertebrate lineages have evolved external and/or internal anatomical adaptations to enhance these cues, such as pinnae and interaural canals. It has been hypothesized that in alligators, directionality may be enhanced via the acoustic coupling of middle ear cavities, resulting in a pressure difference receiver (PDR) mechanism. The experiments reported here support a role for a PDR mechanism in alligator sound localization by demonstrating that (1) acoustic space cues generated by the external morphology of the animal are not sufficient to generate location cues that match physiological sensitivity, (2) continuous pathways between the middle ears are present to provide an anatomical basis for coupling, (3) the auditory brainstem response shows some directionality, and (4) eardrum movement is directionally sensitive. Together, these data support the role of a PDR mechanism in crocodilians and further suggest this mechanism is a shared archosaur trait, most likely found also in the extinct dinosaurs.
Master of all trades: thermal acclimation and adaptation of cardiac function in a broadly distributed marine invasive species, the European green crab,Carcinus maenas
Authors: Tepolt Carolyn K. , Somero George N.
Published: March 2014

As global warming accelerates, there is increasing concern about how ecosystems may change as a result of species loss and replacement. Here, we examined the thermal physiology of the European green crab (Carcinus maenas Linnaeus 1758), a globally invasive species, along three parallel thermal gradients in its native and invasive ranges. At each site, we assessed cardiac physiology to determine heat and cold tolerance and acclimatory plasticity. We found that, overall, the species is highly tolerant of both heat and cold, and that it survives higher temperatures than co-occurring native marine crustaceans. Further, we found that both heat and cold tolerance are plastic in response to short-term acclimation (18–31 days at either 5 or 25°C). Comparing patterns within ranges, we found latitudinal gradients in thermal tolerance in the native European range and in the invasive range in eastern North America. This pattern is strongest in the native range, and likely evolved there. Because of a complicated invasion history, the latitudinal pattern in the eastern North American invasive range may be due either to rapid adaptation post-invasion or to adaptive differences between the ancestral populations that founded the invasion. Overall, the broad thermal tolerance ranges of green crabs, which may facilitate invasion of novel habitats, derive from high inherent eurythermality and acclimatory plasticity and potentially adaptive differentiation among populations. The highly flexible physiology that results from these capacities may represent the hallmark of a successful invasive species, and may provide a model for success in a changing world.
Resolving Debt Overhang: Political Constraints in the Aftermath of Financial Crises
Authors: Mian Atif , Sufi Amir , Trebbi Francesco
Published: March 2014

Countries become more politically polarized and fractionalized following financial crises, reducing the likelihood of major financial reforms precisely when they might have especially large benefits. The evidence from a large sample of countries provides strong support for the hypotheses that following a financial crisis, voters become more ideologically extreme and ruling coalitions become weaker, independently of whether they were initially in power. The evidence that increased polarization and weaker governments reduce the chances of financial reform and that financial crises lead to legislative gridlock and anemic reform is less clear-cut. The US debt overhang resolution is discussed as an illustration. (JEL D72, E32, E44, G01, H63)
The Practice of Reading Good Books: A Plea to Teachers and Students
Authors: Anton Corey
Published: March 2014

This article is designed to provoke lively discussion between and among teachers and students regarding the growing state of reading atrophy. It best serves as an “inspirational” beginning piece for undergraduate humanities or social science courses that contain difficult, “primary source,” readings. The article consists of two main parts. The first addresses contemporary sources of reading atrophy. The second part offers arguments for why the practice of reading difficult books is worth the effort.
Adapting The Curious Incident of the Dog in the Night-Time: A conversation with Simon Stephens
Authors: Ue Tom
Published: March 2014

The following interview was completed by telephone on 10 September 2012. It focuses on Simon Stephens’ adaptation of Mark Haddon’s novel The Curious Incident of the Dog in the Night-Time. The award-winning book tells the story of fifteen-year-old Christopher, who tries to solve the mystery of his next-door neighbour’s dog’s murder. This conversation gives an account of Stephens’ reading of Haddon’s work; his understanding and realization, onstage, of Christopher, who suffers Asperger Syndrome; his changes to the novel’s ending; and the staging of the play in the intimate setting of the Cottesloe at the National Theatre in London. The critically and commercially acclaimed production transferred to the Apollo Theatre in the West End and ran until December 2013, when part of the theatre’s roof collapsed. The play will move to the Gielgud Theatre in June 2014.
Sweeney Todd: Hypertexuality, intermediality and adaptation
Authors: McGill Craig M.
Published: March 2014

Tim Burton’s 2007 film adaptation of Stephen Sondheim’s 1979 musical thriller Sweeney Todd, the Demon Barber of Fleet Street represents the most recent of a long line of adaptations of the source material. When writing his version, Sondheim constructed the score to function like a horror film and imbued it with other cinematic features. Through the process of hypertexuality, new adaptations (hypertexts) can productively be analysed in relation to their source material (hypotexts), without getting mired in issues of fidelity. Intermediality considers the relationship between two (or more) art-forms, and the interplay that exists between them in a specific text. In this article, I consider the hypertextual relationship between Sondheim’s score (hypotext) and Burton’s film (hypertext) by exploring intermedial aspects of each text. While Burton advanced some of the cinematic attributes of Sondheim’s score, he retained other theatrical conceits that allude to stage aesthetics and are also referents to other mediated genres. In examining these aspects, I consider implications of stage to screen adaptations of musicals.
Tessier number 30 cleft: report of an antenatally diagnosed case
Authors: Kavak Salih Burcin , Celik Ebru , Firat Cemal , Goktolga Gulser , Ilhan Rasit , Orak Ugur
Published: March 2014

Tessier no. 30 cleft, also known as median mandibular cleft or lower midline facial cleft, is extremely rare. Less than 100 cases are reported in the literature, which show great variation in severity and associated abnormalities. We herein report a median mandibular cleft extending into the neck. Its importance comes from the fact that it is one of the two cases diagnosed antenatally and it is the first one diagnosed as early as 17 weeks of gestation. Early diagnosis allowed the patient to deliver in a more specialized clinic that was able to deal with immediate postnatal complications. The family was psychologically prepared for the delivery of a baby with a major anomaly.
Atherosclerotic disease and management challenges with nanomedicine: EU FP7 NMP funded “NanoAthero” and “CosmoPHOS-nano” large-scale projects
Authors: Letourneur Didier , Trohopoulos Panagiotis N.
Published: March 2014

Atherosclerosis is the most important arterial wall disease that causes arterial stenosis and may lead to the clinical manifestations of angina, heart attack and stroke. There is a demanding unmet medical need for new approaches for early diagnosis and improved/novel targeted therapies and therapy monitoring of atherosclerosis. This is the focus of two European large scale projects, the NanoAthero and the CosmoPHOS-nano by using nanomedicine. The aim is to demonstrate that nanotechnology-enabled systems can be successfully developed and clinically proven to be safe and effective in tackling cardiovascular diseases.
Synthesis and antifungal activity of camphoric acid-based acylhydrazone compounds
Authors: Ma Xian-Li , Li Fang-Yao , Duan Wen-Gui , Liao Jing-Ni , Lin Zhi-duo , Lin Gui-Shan , Cen Bo , Lei Fu-Hou
Published: March 2014

In the search of novel potent bioactive compounds, 18 novel camphoric acid-based acylhydrazone compounds 4a–4r were designed and synthesized by the condensation reaction of N-amino camphorimide (3) with substituted benzaldehyde based on camphoric acid as the starting material. The target compounds were characterized by means of Fourier transform infrared (FTIR), 1H nuclear magnetic resonance (NMR), 13C NMR, electrospray ionization-mass spectrometry (ESI-MS), and elemental analysis. The preliminary bioassay showed that the following camphoric acid-based compounds exhibited excellent antifungal activity with an inhibition ratio of 95% against Physalospora piricola at the concentration of 50 μg ml-1: o-bromophenyl acylhydrazone (4f), p-bromophenyl acylhydrazone (4g), p-methoxyphenyl acylhydrazone (4m), and p-hydroxyphenyl acylhydrazone (4p).
The leader proteinase of foot-and-mouth disease virus: structure-function relationships in a proteolytic virulence factor
Authors: Steinberger Jutta , Skern Tim
Published: March 2014

The leader proteinase (Lpro) of the foot-and-mouth disease virus inhibits the host innate immune response by at least three different mechanisms. The most well-characterised of these is the prevention of the synthesis of cytokines such as interferons immediately after infection, brought about by specific proteolytic cleavage of the eukaryotic initiation factor 4G. This prevents the recruitment of capped cellular mRNA; however, the viral RNA can be translated under these conditions. The two other mechanisms are the induction of NF-κB cleavage and the deubiquitination of immune signalling molecules. This review focuses on the structure-function relationships in Lpro responsible for these widely divergent activities.
Humanoid Robot Navigation: Getting Localization Information from Vision
Authors: Wirbel Emilie , Bonnabel Silvère , de La Fortelle Arnaud , Moutarde Fabien
Published: March 2014

In this article, we present our work to provide a navigation and localization system on a constrained humanoid platform, the NAO robot, without modifying the robot sensors. First, we tried to implement a simple and light version of classic monocular Simultaneous Localization and Mapping (SLAM) algorithms, while adapting to the CPU and camera quality, which turned out to be insufficient on the platform for the moment. From our work on keypoints tracking, we identified that some keypoints can be still accurately tracked at little cost, and used them to build a visual compass. This compass was then used to correct the robot walk because it makes it possible to control the robot orientation accurately.
Production of lignocellulosic gasoline using fast pyrolysis of biomass and a conventional refining scheme
Authors: de Rezende Pinho Andrea , de Almeida Marlon Brando Bezerra , Mendes Fabio Leal , Ximenes Vitor Loureiro
Published: March 2014

This paper shows how some existing refining technologies such as fluid catalytic cracking (FCC) can be modified to process bio-oil, derived from agricultural lignocellulosic wastes such as the sugar cane straw. Tests carried out in demonstration scale (150 kg/h) show the potential of these alternative materials to produce lignocellulosic gasoline or aromatic compounds, suitable to the petrochemical industry.
Integrated reactions based on the sequential addition to α-imino esters
Authors: Koyama Kaichiro , Mizota Isao , Shimizu Makoto
Published: March 2014

This article summarizes integrated sequential reactions with α-imino esters, where the umpolung addition reaction to the imino nitrogen followed by the second addition or oxidation is the crucial step. The following four types of reactions are discussed: (1) tandem N-ethylation/Mannich reaction; (2) N-alkylation/addition reaction; (3) synthesis of indolin-3-ones and tetrahydro-4-quinolones; (4) regioselective tandem N-alkylation/ C-acylation of β,γ-alkynyl α-imino esters.
On the copolymerization of monomers from renewable resources: l-lactide and ethylene carbonate in the presence of metal alkoxides
Authors: Plichta Andrzej , Florjańczyk Zbigniew , Kundys Anna , Frydrych Anita , Dębowski Maciej , Langwald Norbert
Published: March 2014

The copolymerization of l-lactide with ethylene carbonate carried out at 120 °C in the presence of organic derivatives of aluminum, zinc and tin as catalysts leads to the formation of linear polymers of relative molecular masses in the 10 000–30 000 range containing up to 12 mol. % of carbonate monomeric units (m.u.). A decrease in Tg of copolymers down to 48 °C demonstrates the internal plasticization effect for polylactide matrix. In the first reaction step mainly lactide homopolymerization proceeds in the systems studied. Carbonate m.u. incorporate into the growing chain as a result of recurring transesterification processes. Back-biting type intramolecular transesterification reactions dominate in the system and macrocycle compounds containing 1 carbonate m.u. and 3–9 lactic acid m.u. are the main reaction products after prolonged time. On the basis of analysis of the low molecular weight products formed in the polymerization system and products of the model reaction of ethylene carbonate with metal alkoxides, the mechanism of elementary reactions leading to the incorporation of carbonate m.u. into the copolymer chains has been proposed.
Same Evidences, Different Interpretations – A Comparison of the Conflict Index between the Interstate Dyadic Events Data and Militarized Interstate Disputes Data in Peace-Conflict Models
Authors: Lin Scott Y. , Seiglie Carlos
Published: March 2014

Studying the determinants of international conflict, researchers have found a series of influential variables, but few have addressed the robustness of the results to changes in the definition of the dependent variable, conflict. The two main sources for operationalizing conflict in empirical work are data on militarized interstate disputes (MIDs) and events data. In this paper, we find that a χ2-test indicates a correlation between events data and MIDs data. However, detailed regression analysis indicates that there are some contradictory findings depending on whether we use events data as opposed to MIDs data to measure conflict.
A self-similar Gaussian process
Authors: Sghir Aissa
Published: March 2014

In this paper we introduce and study a self-similar Gaussian process
denoted by

S

H
,

K

${{S^{H,\,K}}}$

with parameters

H
∈
(
0
,
1
)

${{H\in (0,1)}}$

and

K
∈
[
0
,
1
]

${{K\in [0,1]}}$

.
This process generalizes the well-known fractional Brownian motion
introduced by Mandelbrot and
Van Ness [SIAM Rev. 10 (1968), no. 4, 422–437], the sub-fractional Brownian motion introduced by Bojdecki, Gorostiza and Talarczyket [Statist. Probab. Lett. 69 (2004), 405–419]
and the Gaussian process introduced by Lei and Nualart [Statist. Probab. Lett. 79 (2009), 619–624] in
order to obtain a decomposition in law of the bifractional Brownian motion.
Dewatering and Stabilizing Fine-Grained Soils with Very High Moisture Content
Authors: Howard Isaac L. , Carruth William D.
Published: March 2014

The primary objective of this paper is to evaluate the feasibility and subsequent properties of rapidly dewatering fine-grained soils with polymers and stabilizing them with Portland cement. Rapidly dewatering very high moisture soil (VHMS) from 10 % to 30 % solids for immediate re-use in a disaster environment appears feasible. The most feasible application would be saltwater slurry with a relatively low organic content [e.g., high-plasticity clay (CH) soil along a coastline]. Handling contaminated sediments in a disaster environment appears to be a suitable application. Using polymers improved shear strength and elastic modulus of cement-stabilized VHMS. On average, shear strength and elastic modulus improved 25 % and 63 %, respectively. Shear strengths of the materials produced ranged from soft to stiff clay after up to 7 days of curing, which is a useable strength for several applications.
Torsional Shear Strength and Size Effect in Laminated Veneer Lumber
Authors: Yang Bonnie (Zhuo) , Clouston Peggi L. , Arwade Sanjay R.
Published: March 2014

This study investigates the effect that specimen depth has on the torsional shear strength of full-size Eastern Species Laminated Veneer Lumber (LVL). Characterization of this effect is valuable for structural design purposes as well as for use in constitutive modeling when predicting member strength of one depth based on member strength of a different depth derived from testing. To this end, torsion tests were carried out on three depths (140, 184, and 235 mm) of 1.98 m long by 44 mm thick 1.9E Eastern Species LVL. The shear strength of each depth was determined based on homogeneous, orthotropic theory for beams of rectangular cross-section. Despite a perceptible trend of slightly decreasing shear strength with increasing depth, an analysis of variance test indicated that no statistically significant depth effect exists as it relates to torsional shear strength. Further, a three dimensional finite element model of the 44 mm by 140 mm specimen indicated that stresses are uniform within the shear span of 2 times the depth plus the grip distance away from each end of the specimen. The predicted average maximum shear stress in this region compared well to the maximum shear stresses obtained experimentally.
Volume-Change Behavior of a Compacted Low-Plasticity Clay From Double-Odometer Tests
Authors: Kim Wan Soo , Borden Roy H.
Published: March 2014

The compressibility of compacted soils is not only a function of soil type and density but also stress state, which is influenced by the existing matric suction and can be described using the fundamentals of unsaturated soil mechanics. This paper presents data from double-odometer tests on low-plasticity clay that demonstrates the effects of dry density and water content on volume-change behavior. Using the data set developed, the drained constrained modulus is determined using the stress–strain relations obtained from conventional odometer tests on soaked specimens, as well as specimens at their molding moisture content. The change of modulus with respect to degree of saturation is discussed and placed in context with the model used in the Guide for Mechanistic-Empirical Design of New and Rehabilitated Pavement Structures [ARA, ERES Consultants Division, 2004, “Guide for Mechanistic-Empirical Design of New and Rehabilitated Pavement Structures,” Final Report NCHRP Project 1-37A, Transportation Research Board of the National Academies, Washington, D.C.]. A procedure for predicting the undrained modulus from the constitutive relation for drained loading and the predicted excess pore pressure caused by loading based on a modification of Hilf’s equation [Hilf, J. W., 1948, “Estimating Construction Pore Pressures in Rolled Earth Dams,” Proceedings of the 2nd International Conference on Soil Mechanics and Foundation Engineering, Vol. 3, International Society for Soil Mechanics and Foundation Engineering (ISSMGE), London, pp. 234–240] is also presented and discussed.
Performance Assessment of Geosynthetics and Cement as Subgrade Stabilization Measures
Authors: Cowell Tim , Pyo Sangchul , Gabr Mohammed A. , Borden Roy H. , Kim K. J.
Published: March 2014

Work in this paper presents the results of field testing on four instrumented roadway sections constructed on poor subgrade soils and stabilized with select fill, geosynthetics, or cement. Loading was applied using 1000 consecutive truck passes and profile surveying was performed to provide permanent deformation (rutting) data. Peak vertical stresses at the subgrade as well as moisture conditions were also monitored during testing. Results indicated that the deep undercut (31 in./790 mm) with select material backfill section produced the largest cumulative rut depths due to shallow incremental plastic strains induced during each axle pass. The use of a thin Aggregate Base Course (ABC) surface layer (3 in./75 mm) over the select material reduced the rate of rutting. The biaxial geogrid and the high strength geotextile showed a relatively equal performance in all aspects of the study. The cement stabilized section produced a slightly larger average rut depth than the geosynthetically-reinforced sections due to localized areas of pronounced cumulative rutting. However, there were several areas of the soil-cement test section that performed as well as the geosynthetically-reinforced sections.
Model Tests on Geocell Walls Under Strip Loading
Authors: Ram Rathan Lal B. , Mandal J. N.
Published: March 2014

Thermal power stations in India produce an enormous quantity of fly ash as a by-product. Fly ash utilization and disposal in an environmental friendly manner is a foremost concern in India. In the present study, an attempt has been made for proper utilization of fly ash as an alternative backfill material in geocell walls. This study also provides an approach for the use of waste plastic water bottles as geocells. The geocell diameter and height used in the model testing is 70 mm. Two types of structural geometry were considered in the study: gravity wall type and facing wall type. The lateral deformation of geocell wall and settlement of the backfill were studied under strip loading by varying facing angle of the wall, with and without reinforcement in the backfill. For both the type of walls, model testing results show that the maximum lateral deformation of geocell wall, backfill settlement, and failure surcharge pressures increased with decreasing facing angle of wall. For the reinforced case, the lateral deformation of the geocell wall was reduced considerably. When the reinforcement placed at top and total layers, the maximum lateral deformation of the geocell wall occurred at mid height of the wall. However, for bottom layers reinforced backfill, the maximum lateral deformation occurred at the top.
microRNA-206 in Rat Medial Prefrontal Cortex Regulates BDNF Expression and Alcohol Drinking
Authors: Tapocik Jenica D. , Barbier Estelle , Flanigan Meghan , Solomon Matthew , Pincus Alexandra , Pilling Andrew , Sun Hui , Schank Jesse R. , King Courtney , Heilig Markus
Published: March 2014

Escalation of voluntary alcohol consumption is a hallmark of alcoholism, but its neural substrates remain unknown. In rats, escalation occurs following prolonged exposure to cycles of alcohol intoxication, and is associated with persistent, wide-ranging changes in gene expression within the medial prefrontal cortex (mPFC). Here, we examined whether induction of microRNA (miR) 206 in mPFC contributes to escalated alcohol consumption. Following up on a microarray screen, quantitative real-time reverse transcription PCR (qPCR) confirmed that a history of dependence results in persistent (>3weeks) up-regulation of miR-206 expression in the mPFC, but not in the ventral tegmental area, amygdala, or nucleus accumbens. Viral-mediated overexpression of miR-206 in the mPFC of nondependent rats reproduced the escalation of alcohol self-administration seen following a history of dependence and significantly inhibited BDNF expression. Bioinformatic analysis identified three conserved target sites for miR-206 in the 3′-UTR of the rat BDNF transcript. Accordingly, BDNF was downregulated in post-dependent rats on microarray analysis, and this was confirmed by qPCR.In vitro, BDNF expression was repressed by miR-206 but not miR-9 in a 3′-UTR reporter assay, confirming BDNF as a functional target of miR-206. Mutation analysis showed that repression was dependent on the presence of all three miR-206 target sites in the BDNF 3′-UTR. Inhibition of miR-206 expression in differentiated rat cortical primary neurons significantly increased secreted levels of BDNF. In conclusion, recruitment of miR-206 in the mPFC contributes to escalated alcohol consumption following a history of dependence, with BDNF as a possible mediator of its action.
Changes in mGlu5 Receptor-Dependent Synaptic Plasticity and Coupling to Homer Proteins in the Hippocampus of Ube3A Hemizygous Mice Modeling Angelman Syndrome
Authors: Pignatelli Marco , Piccinin Sonia , Molinaro Gemma , Di Menna Luisa , Riozzi Barbara , Cannella Milena , Motolese Marta , Vetere Gisella , Catania Maria Vincenza , Battaglia Giuseppe , Nicoletti Ferdinando , Nisticò Robert , Bruno Valeria
Published: March 2014

Angelman syndrome (AS) is caused by the loss of Ube3A, an ubiquitin ligase that commits specific proteins to proteasomal degradation. How this defect causes autism and other pathological phenotypes associated with AS is unknown. Long-term depression (LTD) of excitatory synaptic transmission mediated by type 5 metabotropic glutamate (mGlu5) receptors was enhanced in hippocampal slices of Ube3Am−/p+mice, which model AS. No changes were found in NMDA-dependent LTD induced by low-frequency stimulation. mGlu5 receptor-dependent LTD in AS mice was sensitive to the protein synthesis inhibitor anisomycin, and relied on the same signaling pathways as in wild-type mice, e.g., the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycine pathway, and protein tyrosine phosphatase. Neither the stimulation of MAPK and PI3K nor the increase in Arc (activity-regulated cytoskeleton-associated protein) levels in response to mGlu5 receptor activation were abnormal in hippocampal slices from AS mice compared with wild-type mice. mGlu5 receptor expression and mGlu1/5 receptor-mediated polyphosphoinositide hydrolysis were also unchanged in the hippocampus of AS mice. In contrast, AS mice showed a reduced expression of the short Homer protein isoform Homer 1a, and an increased coupling of mGlu5 receptors to Homer 1b/c proteins in the hippocampus. These findings support the link between Homer proteins and monogenic autism, and lay the groundwork for the use of mGlu5 receptor antagonists in AS.
Altered Neural Processing of the Need to Stop in Young Adults at Risk for Stimulant Dependence
Authors: Harlé Katia M. , Shenoy Pradeep , Stewart Jennifer L. , Tapert Susan F. , Yu Angela J. , Paulus Martin P.
Published: March 2014

Identification of neurocognitive predictors of substance dependence is an important step in developing approaches to prevent addiction. Given evidence of inhibitory control deficits in substance abusers (Monterosso et al., 2005; Fu et al., 2008; Lawrence et al., 2009; Tabibnia et al., 2011), we examined neural processing characteristics in human occasional stimulant users (OSU), a population at risk for dependence. A total of 158 nondependent OSU and 47 stimulant-naive control subjects (CS) were recruited and completed a stop signal task while undergoing functional magnetic resonance imaging (fMRI). A Bayesian ideal observer model was used to predict probabilistic expectations of inhibitory demand,P(stop), on a trial-to-trial basis, based on experienced trial history. Compared with CS, OSU showed attenuated neural activation related toP(stop) magnitude in several areas, including left prefrontal cortex and left caudate. OSU also showed reduced neural activation in the dorsal anterior cingulate cortex (dACC) and right insula in response to an unsigned Bayesian prediction error representing the discrepancy between stimulus outcome and the predicted probability of a stop trial. These results indicate that, despite minimal overt behavioral manifestations, OSU use fewer brain processing resources to predict and update the need for response inhibition, processes that are critical for adjusting and optimizing behavioral performance, which may provide a biomarker for the development of substance dependence.
ATM-Dependent Phosphorylation of MEF2D Promotes Neuronal Survival after DNA Damage
Authors: Chan Shing Fai , Sances Sam , Brill Laurence M. , Okamoto Shu-ichi , Zaidi Rameez , McKercher Scott R. , Akhtar Mohd W. , Nakanishi Nobuki , Lipton Stuart A.
Published: March 2014

Mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a kinase critical for the normal DNA damage response, cause the neurodegenerative disorder ataxia-telangiectasia (AT). The substrates of ATM in the brain are poorly understood. Here we demonstrate that ATM phosphorylates and activates the transcription factor myocyte enhancer factor 2D (MEF2D), which plays a critical role in promoting survival of cerebellar granule cells. ATM associates with MEF2D after DNA damage and phosphorylates the transcription factor at four ATM consensus sites. Knockdown of endogenous MEF2D with a short-hairpin RNA (shRNA) increases sensitivity to etoposide-induced DNA damage and neuronal cell death. Interestingly, substitution of endogenous MEF2D with an shRNA-resistant phosphomimetic MEF2D mutant protects cerebellar granule cells from cell death after DNA damage, whereas an shRNA-resistant nonphosphorylatable MEF2D mutant does not.In vivo, cerebella inMef2dknock-out mice manifest increased susceptibility to DNA damage. Together, our results show that MEF2D is a substrate for phosphorylation by ATM, thus promoting survival in response to DNA damage. Moreover, dysregulation of the ATM–MEF2D pathway may contribute to neurodegeneration in AT.
Integrative Moral Judgment: Dissociating the Roles of the Amygdala and Ventromedial Prefrontal Cortex
Authors: Shenhav Amitai , Greene Joshua D.
Published: March 2014

A decade's research highlights a critical dissociation between automatic and controlled influences on moral judgment, which is subserved by distinct neural structures. Specifically, negative automatic emotional responses to prototypically harmful actions (e.g., pushing someone off of a footbridge) compete with controlled responses favoring the best consequences (e.g., saving five lives instead of one). It is unknown how such competitions are resolved to yield “all things considered” judgments. Here, we examine such integrative moral judgments. Drawing on insights from research on self-interested, value-based decision-making in humans and animals, we test a theory concerning the respective contributions of the amygdala and ventromedial prefrontal cortex (vmPFC) to moral judgment. Participants undergoing fMRI responded to moral dilemmas, separately evaluating options for their utility (Which does the most good?), emotional aversiveness (Which feels worse?), and overall moral acceptability. Behavioral data indicate that emotional aversiveness and utility jointly predict “all things considered” integrative judgments. Amygdala response tracks the emotional aversiveness of harmful utilitarian actions and overall disapproval of such actions. During such integrative moral judgments, the vmPFC is preferentially engaged relative to utilitarian and emotional assessments. Amygdala-vmPFC connectivity varies with the role played by emotional input in the task, being the lowest for pure utilitarian assessments and the highest for pure emotional assessments. These findings, which parallel those of research on self-interested economic decision-making, support the hypothesis that the amygdala provides an affective assessment of the action in question, whereas the vmPFC integrates that signal with a utilitarian assessment of expected outcomes to yield “all things considered” moral judgments.
Intracellular mGluR5 Can Mediate Synaptic Plasticity in the Hippocampus
Authors: Purgert Carolyn A. , Izumi Yukitoshi , Jong Yuh-Jiin I. , Kumar Vikas , Zorumski Charles F. , O'Malley Karen L.
Published: March 2014

Metabotropic glutamate receptor 5 (mGluR5) is widely expressed throughout the CNS and participates in regulating neuronal function and synaptic transmission. Recent work in the striatum led to the groundbreaking discovery that intracellular mGluR5 activation drives unique signaling pathways, including upregulation of ERK1/2, Elk-1 (Jong et al., 2009) and Arc (Kumar et al., 2012). To determine whether mGluR5 signals from intracellular membranes of other cell types, such as excitatory pyramidal neurons in the hippocampus, we used dissociated rat CA1 hippocampal cultures and slice preparations to localize and characterize endogenous receptors. As in the striatum, CA1 neurons exhibited an abundance of mGluR5 both on the cell surface and intracellular membranes, including the endoplasmic reticulum and the nucleus where it colocalized with the sodium-dependent excitatory amino acid transporter, EAAT3. Inhibition of EAAT3 or sodium-free buffer conditions prevented accumulations of radiolabeled agonist. Using a pharmacological approach to isolate different pools of mGluR5, both intracellular and cell surface receptors induced oscillatory Ca2+responses in dissociated CA1 neurons; however, only intracellular mGluR5 activation triggered sustained high amplitude Ca2+rises in dendrites. Consistent with the notion that mGluR5 can signal from intracellular membranes, uncaging glutamate on a CA1 dendrite led to a local Ca2+rise, even in the presence of ionotropic and cell surface metabotropic receptor inhibitors. Finally, activation of intracellular mGluR5 alone mediated both electrically induced and chemically induced long-term depression, but not long-term potentiation, in acute hippocampal slices. These data suggest a physiologically relevant and important role for intracellular mGluR5 in hippocampal synaptic plasticity.
Human EEG Uncovers Latent Generalizable Rule Structure during Learning
Authors: Collins Anne G. E. , Cavanagh James F. , Frank Michael J.
Published: March 2014

Human cognition is flexible and adaptive, affording the ability to detect and leverage complex structure inherent in the environment and generalize this structure to novel situations. Behavioral studies show that humans impute structure into simple learning problems, even when this tendency affords no behavioral advantage. Here we used electroencephalography to investigate the neural dynamics indicative of such incidental latent structure. Event-related potentials over lateral prefrontal cortex, typically observed for instructed task rules, were stratified according to individual participants' constructed rule sets. Moreover, this individualized latent rule structure could be independently decoded from multielectrode pattern classification. Both neural markers were predictive of participants' ability to subsequently generalize rule structure to new contexts. These EEG dynamics reveal that the human brain spontaneously constructs hierarchically structured representations during learning of simple task rules.
Effect of Maternal Care on Hearing Onset Induced by Developmental Changes in the Auditory Periphery
Authors: Adise Shana , Saliu Aminat , Maldonado Natalia , Khatri Vivek , Cardoso Luis , Rodríguez-Contreras Adrián
Published: March 2014

Handling (H) and cross-fostering (CF) rodent pups during postnatal development triggers changes in maternal behavior which in turn trigger long-term physiological changes in the offspring. However, less is known about the short-term effects of H and CF on infant development. In this study we hypothesized that manipulations of maternal care affect the onset of hearing in Wistar rats. To test this hypothesis we obtained auditory brainstem responses (ABRs) and micro-CT x-ray scans to measure changes in the development of the auditory periphery in H and CF pups manipulated at postnatal day (P)1, P5, or P9. We found evidence of changes in hearing development in H and CF pups compared with naive pups, including changes in the percentage of animals with ABRs during development, a decrease in ABR thresholds between P13 and P15, and anatomical results consistent with an accelerated formation of the middle ear cavity and opening of the ear canal. Biochemical measurements showed elevated levels of thyroid hormone in plasma from naive and CF pups. These results provide evidence that manipulations of maternal care accelerate hearing onset in Wistar rats. Understanding the mechanisms by which maternal care affects hearing onset opens new opportunities to study experience-dependent development of mammalian hearing.
Conditional Ablation of Raptor or Rictor Has Differential Impact on Oligodendrocyte Differentiation and CNS Myelination
Authors: Bercury Kathryn K. , Dai JinXiang , Sachs Hilary H. , Ahrendsen Jared T. , Wood Teresa L. , Macklin Wendy B.
Published: March 2014

During CNS development, oligodendrocytes, the myelinating glia of the CNS, progress through multiple transitory stages before terminating into fully mature cells. Oligodendrocyte differentiation and myelination is a tightly regulated process requiring extracellular signals to converge to elicit specific translational and transcriptional changes. Our lab has previously shown that the protein kinases, Akt and mammalian Target of Rapamycin (mTOR), are important regulators of CNS myelinationin vivo. mTOR functions through two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, by binding to either Raptor or Rictor, respectively. To establish whether the impact of mTOR on CNS myelination results from unique functions of mTORC1 or mTORC2 during CNS myelination, we conditionally ablated either Raptor or Rictor in the oligodendrocyte lineage,in vivo. We show that Raptor (mTORC1) is a positive regulator of developmental CNS mouse myelination when mTORC2 is functional, whereas Rictor (mTORC2) ablation has a modest positive effect on oligodendrocyte differentiation, and very little effect on myelination, when mTORC1 is functional. Also, we show that loss of Raptor in oligodendrocytes results in differential dysmyelination in specific areas of the CNS, with the greatest impact on spinal cord myelination.
Goal-Dependent Modulation of Fast Feedback Responses in Primary Motor Cortex
Authors: Pruszynski J. Andrew , Omrani Mohsen , Scott Stephen H.
Published: March 2014

Many human studies have demonstrated that rapid motor responses (i.e., muscle-stretch reflexes) to mechanical perturbations can be modified by a participant's intended response. Here, we used a novel experimental paradigm to investigate the neural mechanisms that underlie such goal-dependent modulation. Two monkeys positioned their hand in a central area against a constant load and responded to mechanical perturbations by quickly placing their hand into visually defined spatial targets. The perturbation was chosen to excite a particular proximal arm muscle or isolated neuron in primary motor cortex and two targets were placed so that the hand was pushed away from one target (OUT target) and toward the other (IN target). We chose these targets because they produced behavioral responses analogous to the classical verbal instructions used in human studies. A third centrally located target was used to examine responses with a constant goal. Arm muscles and neurons robustly responded to the perturbation and showed clear goal-dependent responses ∼35 and 70 ms after perturbation onset, respectively. Most M1 neurons and all muscles displayed larger perturbation-related responses for the OUT target than the IN target. However, a substantial number of M1 neurons showed more complex patterns of target-dependent modulation not seen in muscles, including greater activity for the IN target than the OUT target, and changes in target preference over time. Together, our results reveal complex goal-dependent modulation of fast feedback responses in M1 that are present early enough to account for goal-dependent stretch responses in arm muscles.
Circadian Perinatal Photoperiod Has Enduring Effects on Retinal Dopamine and Visual Function
Authors: Jackson Chad R. , Capozzi Megan , Dai Heng , McMahon Douglas G.
Published: March 2014

Visual system development depends on neural activity, driven by intrinsic and light-sensitive mechanisms. Here, we examined the effects on retinal function due to exposure to summer- and winter-like circadian light cycles during development and adulthood. Retinal light responses, visual behaviors, dopamine content, retinal morphology, and gene expression were assessed in mice reared in seasonal photoperiods consisting of light/dark cycles of 8:16, 16:8, and 12:12 h, respectively. Mice exposed to short, winter-like, light cycles showed enduring deficits in photopic retinal light responses and visual contrast sensitivity, but only transient changes were observed for scotopic measures. Dopamine levels were significantly lower in short photoperiod mice, and dopaminergic agonist treatment rescued the photopic light response deficits. Tyrosine hydroxylase and Early Growth Response factor-1 mRNA expression were reduced in short photoperiod retinas. Therefore, seasonal light cycles experienced during retinal development and maturation have lasting influence on retinal and visual function, likely through developmental programming of retinal dopamine.
Selective Localization ofArcmRNA in Dendrites Involves Activity- and Translation-Dependent mRNA Degradation
Authors: Farris Shannon , Lewandowski Gail , Cox Conor D. , Steward Oswald
Published: March 2014

Arcis an immediate early gene that is unique among neuronal mRNAs because its transcripts are transported into dendrites and accumulate near activated synapses, presumably to be translated locally. These qualities poseArcas playing an important, yet not fully understood, role in the activity-dependent modifications of synapses that are thought to underlie memory storage. Here we showin vivoin rats that newly synthesizedArcmRNA accumulates at activated synapses and that synaptic activity simultaneously triggers mRNA decay that eliminatesArcmRNA from inactive dendritic domains.ArcmRNA degradation occurs throughout the dendrite and requires both NMDA receptor activation and active translation. Synaptic activation did not lead to decreases in another dendritic mRNA (αCaMKII), indicating that there is not a general activation of mRNA degradation in dendrites. These data reveal a novel mechanism for controlling mRNA distribution within dendrites and highlight activity-dependent mRNA degradation as a regulatory process involved in synaptic plasticity.