bluuebunny/crossref_metadata_2025 huggingface dataset:
Repression of classical nuclear export by S-nitrosylation of CRM1
Authors: Wang Peng , Liu Guang-Hui , Wu Kaiyuan , Qu Jing , Huang Bo , Zhang Xu , Zhou XiXi , Gerace Larry , Chen Chang
Published: October 2009

The karyopherin chromosomal region maintenance 1 (CRM1) is the major receptor for classical nuclear protein export. However, little is known about the regulation of CRM1 itself. Here, we report that cellular CRM1 became S-nitrosylated after extensive exposure to endogenous or exogenous nitric oxide (NO). This abrogated the interaction of CRM1 with nuclear export signals (NESs) and repressed classical protein export. Analysis by mass spectrometry and involving the use of S-nitrosylation mimetic mutations indicated that modification at either of two specific cysteines of CRM1 was sufficient to abolish the CRM1-NES association. Moreover, ectopic overexpression of the corresponding S-nitrosylation-resistant CRM1 mutants rescued NO-induced repression of nuclear export. We also found that inactivation of CRM1 by NO facilitated the nuclear accumulation of the antioxidant response transcription factor Nrf2 and transcriptional activation of Nrf2-controlled genes. Together, these data demonstrate that CRM1 is negatively regulated by S-nitrosylation under nitrosative stress. We speculate that this is important for promoting a cytoprotective transcriptional response to nitrosative stress.
How Large Are Non-Budget-Constraint Effects of Prices on Demand?
Authors: Heffetz Ori , Shayo Moses
Published: October 2009

Elementary consumer theory assumes prices affect demand only because they affect the budget constraint (BC). Alternative models, and some evidence, suggest prices can affect demand through other, non-BC channels (e.g., by signaling quality). This paper uses a lab and a field experiment to disentangle BC from non-BC effects of prices on demand. In the lab, we find that although prices positively affect stated willingness to pay, non-BC price elasticities are considerably smaller than BC price elasticities, are often statistically insignificant, and do not increase with product uncertainty. We do not detect any non-BC effects in our field experiment. (JEL C93, D12, M31)
The Effects of Peer Group Heterogeneity on the Production of Human Capital at West Point
Authors: Lyle David S
Published: October 2009

Understanding how heterogeneity in peer group composition affects academic attainment has important implications for how schools organize students in group settings. The random assignment of cadets to companies at West Point affords an opportunity to investigate this issue empirically. Estimates of the impact of peer group heterogeneity in math SAT scores on freshmen-year academic performance reveals that more heterogeneous peer groups have positive effects on individual grades. High-ability peers account for most of the positive effect, while low-ability peers have no measureable effect. (JEL I23, J24, M54)
Book Reviews
Authors: Lev Benjamin
Published: October 2009

In Book Reviews, we review an extensive and diverse range of books. They cover theory and applications in operations research, statistics, management science, econometrics, mathematics, computers, and information systems. In addition, we include books in other fields that emphasize technical applications. However, we do not review software. To submit a book for review, please send it to me at the above address. Although we cannot review all books because of space limitations, we do list all books that we receive. We commission all book reviews and do not accept unsolicited reviews. To become a reviewer, please send me your name, address, and specific areas of expertise. We encourage readers to suggest books for review or to ask publishers to send copies of such books.

The authors or editors of books we review in this issue are U. Narayan Bhat, Dilip Chhajed, Timothy J. Lowe, and Richard Schonberger.
Modeling and Optimizing the Public-Health Infrastructure for Emergency Response
Authors: Lee Eva K. , Chen Chien-Hung , Pietz Ferdinand , Benecke Bernard
Published: October 2009

Public-health emergencies, such as bioterrorist attacks or pandemics, demand fast, efficient, large-scale dispensing of critical medical countermeasures. By combining mathematical modeling, large-scale simulation, and powerful optimization engines, and coupling them with automatic graph-drawing tools and a user-friendly interface, we designed and implemented RealOpt©, a fast and practical emergency-response decision-support tool. RealOpt allows public-health emergency coordinators to (1) determine locations for point-of-dispensing (POD) facility setup; (2) design customized and efficient floor plans for PODs via an automatic graph-drawing tool; (3) determine required labor resources and provide efficient placement of staff at individual stations within a POD; (4) perform disease-propagation analysis, understand and monitor the intra-POD disease dilemma, and help to derive dynamic response strategies to mitigate casualties; (5) assess resources and determine minimum needs to prepare for treating their regional populations in emergency situations; (6) carry out large-scale virtual drills and performance analyses, and investigate alternative strategies; and (7) design a variety of dispensing scenarios that include emergency-event exercises to train personnel. These advanced and powerful computational strategies allow emergency coordinators to quickly analyze design decisions, generate feasible regional dispensing plans based on best estimates and analyses available, and reconfigure PODs as an event unfolds. The ability to analyze planning strategies, compare the various options, and determine the most cost-effective combination of dispensing strategies is critical to the ultimate success of any mass dispensing effort.
Use of Duloxetine in Pregnancy and Lactation
Authors: Briggs Gerald G , Ambrose Peter J , llett Kenneth F , Hackett L Peter , Nageotte Michael P , Padilla Guadalupe
Published: October 2009

Objective:

To report a case of a woman who used duloxetine during pregnancy and breast-feeding.

Case Summary:

A 29-year-old woman was treated with duloxetine for depression during the second half of an uncomplicated gestation. She gave birth at term to a healthy female infant. A cord blood sample was obtained at birth. The mother continued the antidepressant while exclusively breast-feeding her infant. One month later, we collected blood and milk samples from the mother and a single blood sample from the infant. All samples were analyzed for the presence and concentrations of duloxetine.

Discussion:

Duloxetine crosses the placenta at term and is excreted into breast milk. No evidence of developmental or other type of toxicity was observed in the infant at birth or during the first 32 days after birth. The published literature detailing human pregnancy experience with this antidepressant is limited to 11 cases in which women became pregnant while taking duloxetine. In 10 cases, the drug was discontinued when pregnancy was diagnosed and no outcome data were reported. In the eleventh case, an infant exposed to duloxetine 90 mg/day developed neonatal behavioral syndrome. One study examined the excretion of duloxetine into breast milk, but the mothers discontinued nursing for the study. In the present case, no adverse effects from exposure to the drug in milk were noted in the exclusively breast-fed infant. The possibility of functional/neurobehavioral deficits appearing later in life cannot be excluded because long-term follow-up has not been conducted in infants exposed to duloxetine in utero or during nursing.

Conclusions:

No developmental toxicity or other signs of toxicity were observed in an infant exposed to duloxetine during the second half of gestation and during breast-feeding in the first 32 days after birth. However, the possibility of functional/neurobehavioral deficits appearing later in life cannot be excluded.
Comparative Pharmacodynamics of Intermittent and Prolonged Infusions of Piperacillin/Tazobactam Using Monte Carlo Simulation and Steady-State Pharmacokinetic Data from Hospitalized Patients
Authors: Rotschafer John C , Ullman Mary
Published: October 2009

With increasing antibiotic resistance in gram-negative pathogens, dosing strategies that optimize pharmacodynamic parameters of currently available antibiotics play an important role in treatment. The likelihood of success with piperacillin/tazobactam, a widely used broad-spectrum antibiotic, can be manipulated by increasing the amount of time that unbound drug concentrations remain above the pathogen's minimum inhibitory concentration (MIC). However, this success depends greatly on knowing the MIC value as well as accurately estimating the individual's pharmacokinetic parameters. Clinicians should carefully factor these variables into their decision-making process when considering prolonged infusion strategies with piperacillin/tazobactam.
The Spatial Patterning of Mouse Cone Opsin Expression Is Regulated by Bone Morphogenetic Protein Signaling through Downstream Effector COUP-TF Nuclear Receptors
Authors: Satoh Shinya , Tang Ke , Iida Atsumi , Inoue Mariko , Kodama Tatsuhiko , Tsai Sophia Y. , Tsai Ming-Jer , Furuta Yasuhide , Watanabe Sumiko
Published: October 2009

Cone photopigments, known as opsins, are pivotal elements and the first detection module used in color vision. In mice, cone photoreceptors are distributed throughout the retina, and short-wavelength (S) and medium-wavelength (M) opsins have unique expression patterns in the retina with a gradient along the dorsoventral axis; however, the mechanisms regulating the spatial patterning of cone opsin expression have not been well documented. The purpose of this study was to define the mechanisms regulating the spatial patterning of cone opsin expression. By analyzing knock-outs for bone morphogenetic protein (BMP) signaling, we found an essential role for BMP in forming cone opsin expression patterns in the retina; however, BMP signaling is activated only transiently in the dorsal half of the retina during early retinal development. Thus, BMP is not likely to play a direct role in opsin gene expression, which starts at a later stage of retinal development. We identified the chicken ovalbumin upstream promoter-transcription factor (COUP-TF) nuclear receptor as a link between BMP and opsin expression. BMP signaling is essential for the correct dorsoventral spatial expression of COUP-TFI and COUP-TFII. Through gain- and loss-of-function analyses, we found that both COUP-TFI and COUP-TFII are required to suppress S-opsin expression in the dorsal retina but that only COUP-TFI plays an essential role in suppressing M-opsin expression in the ventral retina. Based on these findings, we propose a new molecular cascade involving BMP and COUP-TFs that conveys dorsoventral information to direct the expression of cone opsins during retinal development.
The Maturation of Task Set-Related Activation Supports Late Developmental Improvements in Inhibitory Control
Authors: Velanova Katerina , Wheeler Mark E. , Luna Beatriz
Published: October 2009

The ability to voluntarily inhibit a single response is evident early in development, even as the ability to maintain an inhibitory “task set” continues to improve. To date, functional neuroimaging studies have detailed developmental changes in systems supporting inhibitory control exerted at the single-trial level, but changes underlying the ability to maintain an inhibitory task set remain little understood. Here we present findings from a functional magnetic resonance imaging study that characterizes the development of systems supporting both transient (trial-related) and sustained (task set-related) activation during performance of the antisaccade task—an oculomotor test of inhibitory control (Hallett, 1978). Transient activation decreased from childhood to adolescence in regions known to support inhibitory processes and oculomotor control, likely reflecting less effortful response production. In contrast, sustained activation increased to adulthood in regions implicated in control. Our results suggest that development of the ability to maintain a task set is primary to the maturation of inhibitory control and, furthermore, that this ability is still immature in adolescence.
A Reporter of Local Dendritic Translocation Shows Plaque- Related Loss of Neural System Function in APP-Transgenic Mice
Authors: Meyer-Luehmann Melanie , Mielke Matthew , Spires-Jones Tara L. , Stoothoff Will , Jones Phill , Bacskai Brian J. , Hyman Bradley T.
Published: October 2009

Although neuronal communication is thought to be summated within local dendritic segments, no technique is currently available to monitor activityin vivoat this level of resolution. To overcome this challenge, we developed an optical reporter of neuronal activity using the coding sequence of Venus, flanked by short stretches of the 5′- and 3′-untranslated regions from calcium/calmodulin-dependent kinase IIα (CAMKIIα). This reporter takes advantage of the fact that CAMKIIα mRNA is transported to the dendrite and locally translated in an activity-dependent manner. Using adeno-associated virus, we used this reporter to study neuronal activity in adult mice. Exposure of the mice to an enriched environment led to enhancement of Venus expression in dendritic segments of somatosensory cortex, demonstratingin vivothat dendritic mRNA translocation and local translation occur in response to physiologically relevant stimuli. We then used this system to examine the impact of Alzheimer-related local amyloid-β deposits on neural system function to test the hypothesis that plaques are toxic. In APPswe/PS1dE9 (APP/PS1) mice, neurons close to plaques, and dendritic segments close to plaques, both showed diminished fluorescent intensity and therefore neuronal activity. In contrast to wild-type mice, fluorescent intensity in neurons near plaques in transgenic mice did not increase after environmental enrichment. These data indicate that neuronal activity in dendritic segments and neurons in the vicinity of a plaque is decreased compared with wild-type mice, supporting the idea that plaques are a focal lesion leading to impaired neural system function.
Cocaine ExposureIn UteroAlters Synaptic Plasticity in the Medial Prefrontal Cortex of Postnatal Rats
Authors: Lu Hui , Lim Byungkook , Poo Mu-ming
Published: October 2009

Cocaine exposure during pregnancy causes abnormality in fetal brain development, leading to cognitive dysfunction of the offspring, but the underlying cellular mechanism remains mostly unclear. In this study, we examined synaptic functions in the medial prefrontal cortex (mPFC) of postnatal rats that were exposed to cocainein utero, using whole-cell recording from mPFC layer V pyramidal neurons in acute brain slices. Cocaine exposurein uteroresulted in a facilitated activity-induced long-term potentiation (LTP) of excitatory synapses on these pyramidal neurons and an elevated neuronal excitability in postnatal rat pups after postnatal day 15 (P15). This facilitated LTP could be primarily attributed to the reduction of GABAergic inhibition. Biochemical assays of isolated mPFC tissue from postnatal rats further showed that cocaine exposurein uterocaused a marked reduction in the surface expression of GABAAreceptor subunits α1, β2, and β3, but had no effect on glutamate receptor subunit GluR1. Both facilitated LTP and reduced surface expression of GABAAreceptors persisted in rats up to at least P42. Finally, the behavioral consequence of cocaine exposurein uterowas reflected by the reduction in the sensitivity of locomotor activity in postnatal rats to cocaine and the dopamine receptor agonist apomorphine. Since the mPFC is an important part of the reward circuit in the rat brain and plays important roles in cognitive functions, these findings offer new insights into the cellular mechanism underlying the adverse effects of cocaine exposurein uteroon brain development and cognitive functions.
Alteration of Theta Timescale Dynamics of Hippocampal Place Cells by a Cannabinoid Is Associated with Memory Impairment
Authors: Robbe David , Buzsáki György
Published: October 2009

The integrity of the hippocampus is critical for both spatial navigation and episodic memory, but how its neuronal firing patterns underlie those functions is not well understood. In particular, the modality by which hippocampal place cells contribute to spatial memory is debated. We found that administration of the cannabinoid receptor agonist CP55940 (2-[(1S,2R,5S)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol) induced a profound and reversible behavioral deficit in the hippocampus-dependent delayed spatial alternation task. On the one hand, despite severe memory impairment, the location-dependent firing of CA1 hippocampal place cells remained mostly intact. On the other hand, both spike-timing coordination between place cells at the theta timescale and theta phase precession of spikes were reversibly reduced. These results raise the possibility that cannabinoids impair memory primarily by altering short-term temporal dynamics of hippocampal neurons. We hypothesize that precise temporal coordination of hippocampal neurons is necessary for guiding behavior in spatial memory tasks.
Semaphorin 3F Is a Bifunctional Guidance Cue for Dopaminergic Axons and Controls Their Fasciculation, Channeling, Rostral Growth, and Intracortical Targeting
Authors: Kolk Sharon M. , Gunput Rou-Afza F. , Tran Tracy S. , van den Heuvel Dianne M. A. , Prasad Asheeta A. , Hellemons Anita J. C. G. M. , Adolfs Youri , Ginty David D. , Kolodkin Alex L. , Burbach J. Peter H. , Smidt Marten P. , Pasterkamp R. Jeroen
Published: October 2009

Dopaminergic neurons in the mesodiencephalon (mdDA neurons) make precise synaptic connections with targets in the forebrain via the mesostriatal, mesolimbic, and mesoprefrontal pathways. Because of the functional importance of these remarkably complex ascending axon pathways and their implication in human disease, the mechanisms underlying the development of these connections are of considerable interest. Despite extensivein vitrostudies, the molecular determinants that ensure the perfect formation of these pathwaysin vivoremain mostly unknown. Here, we determine the embryonic origin and ontogeny of the mouse mesoprefrontal pathway and use these data to reveal an unexpected requirement for semaphorin 3F (Sema3F) and its receptor neuropilin-2 (Npn-2) during mdDA pathway development using tissue culture approaches and analysis ofsema3F−/−,npn-2−/−, andnpn-2−/−;TH-Cremice. We show that Sema3F is a bifunctional guidance cue for mdDA axons, some of which have the remarkable ability to regulate their responsiveness to Sema3F as they develop. During early developmental stages, Sema3F chemorepulsion controls previously uncharacterized aspects of mdDA pathway development through both Npn-2-dependent (axon fasciculation and channeling) and Npn-2-independent (rostral growth) mechanisms. Later on, chemoattraction mediated by Sema3F and Npn-2 is required to orient mdDA axon projections in the cortical plate of the medial prefrontal cortex. This latter finding demonstrates that regulation of axon orientation in the target field occurs by chemoattractive mechanisms, and this is likely to also apply to other neural systems. In all, this study provides a framework for additional dissection of the molecular basis of mdDA pathway development and disease.
Vestibular Asymmetry as the Cause of Idiopathic Scoliosis: A Possible Answer fromXenopus
Authors: Lambert François M. , Malinvaud David , Glaunès Joan , Bergot Catherine , Straka Hans , Vidal Pierre-Paul
Published: October 2009

Human idiopathic scoliosis is characterized by severe deformations of the spine and skeleton. The occurrence of vestibular-related deficits in these patients is well established but it is unclear whether a vestibular pathology is the common cause for the scoliotic syndrome and the gaze/posture deficits or if the latter behavioral deficits are a consequence of the scoliotic deformations. A possible vestibular origin was tested in the frogXenopus laevisby unilateral removal of the labyrinthine endorgans at larval stages. After metamorphosis into young adult frogs, X-ray images and three-dimensional reconstructed micro-computer tomographic scans of the skeleton showed deformations similar to those of scoliotic patients. The skeletal distortions consisted of a curvature of the spine in the frontal and sagittal plane, a transverse rotation along the body axis and substantial deformations of all vertebrae. In terrestrial vertebrates, the initial postural syndrome after unilateral labyrinthectomy recovers over time and requires body weight-supporting limb proprioceptive information. In an aquatic environment, however, this information is absent. Hence, the lesion-induced asymmetric activity in descending spinal pathways and the resulting asymmetric muscular tonus persists. As a consequence the mostly cartilaginous skeleton of the frog tadpoles progressively deforms. Lack of limb proprioceptive signals in an aquatic environment is thus the element, which links theXenopusmodel with human scoliosis because a comparable situation occurs during gestationin utero. A permanently imbalanced activity in descending locomotor/posture control pathways might be the common origin for the observed structural and behavioral deficits in humans as in the different animal models of scoliosis.
Neural Correlates of Value, Risk, and Risk Aversion Contributing to Decision Making under Risk
Authors: Christopoulos George I. , Tobler Philippe N. , Bossaerts Peter , Dolan Raymond J. , Schultz Wolfram
Published: October 2009

Decision making under risk is central to human behavior. Economic decision theory suggests that value, risk, and risk aversion influence choice behavior. Although previous studies identified neural correlates of decision parameters, the contribution of these correlates to actual choices is unknown. In two different experiments, participants chose between risky and safe options. We identified discrete blood oxygen level-dependent (BOLD) correlates of value and risk in the ventral striatum and anterior cingulate, respectively. Notably, increasing inferior frontal gyrus activity to low risk and safe options correlated with higher risk aversion. Importantly, the combination of these BOLD responses effectively decoded the behavioral choice. Striatal value and cingulate risk responses increased the probability of a risky choice, whereas inferior frontal gyrus responses showed the inverse relationship. These findings suggest that the BOLD correlates of decision factors are appropriate for an ideal observer to detect behavioral choices. More generally, these biological data contribute to the validity of the theoretical decision parameters for actual decisions under risk.
Effects of Lorazepam and Citalopram on Human Defensive Reactions: Ethopharmacological Differentiation of Fear and Anxiety
Authors: Perkins Adam M. , Ettinger Ulrich , Davis Robert , Foster Russell , Williams Steven C. R. , Corr Philip J.
Published: October 2009

Drugs that are clinically effective against generalized anxiety disorder preferentially alter rodent risk assessment behavior, whereas drugs that are clinically effective against panic disorder preferentially alter rodent flight behavior. The theoretical principle of “defensive direction” explains the pattern of associations between emotion and defensive behavior in terms of the differing functional demands arising from cautious approach to threat (anxiety) versus departure from threat (fear), offering the prospect that clinically important emotions may be explained using a single rubric of defense. We used a within-subjects, placebo-controlled, design to test this theory, measuring the effects of citalopram and lorazepam on the defensive behavior of 30 healthy adult male humans. We indexed human defensive behavior with a translation of an active avoidance task used to measure rodent defense and found that lorazepam significantly reduced the intensity of defensive behavior during approach to threat (hypothetically anxiety-related) but not departure from threat (hypothetically fear-related). Contrary to prediction, citalopram did not affect either form of defensive reaction. Since lorazepam is a drug with well established anxiety reducing properties, these data support the hypothesis that anxiety is an emotion elicited by threat stimuli that require approach. These data also contribute to the validation of a novel human analog of an established experimental model of rodent fear and anxiety.
Neural Dynamics of Saccadic Suppression
Authors: Bremmer Frank , Kubischik Michael , Hoffmann Klaus-Peter , Krekelberg Bart
Published: October 2009

We make fast, ballistic eye movements called saccades more often than our heart beats. Although every saccade causes a large movement of the image of the environment on our retina, we never perceive this motion. This aspect of perceptual stability is often referred to as saccadic suppression: a reduction of visual sensitivity around the time of saccades. Here, we investigated the neural basis of this perceptual phenomenon with extracellular recordings from awake, behaving monkeys in the middle temporal, medial superior temporal, ventral intraparietal, and lateral intraparietal areas. We found that, in each of these areas, the neural response to a visual stimulus changes around an eye movement. The perisaccadic response changes are qualitatively different in each of these areas, suggesting that they do not arise from a change in a common input area. Importantly, our data show that the suppression in the dorsal stream starts well before the eye movement. This clearly shows that the suppression is not just a consequence of the changes in visual input during the eye movement but rather must involve a process that actively modulates neural activity just before a saccade.
Chronic Nicotine Selectively Enhances α4β2* Nicotinic Acetylcholine Receptors in the Nigrostriatal Dopamine Pathway
Authors: Xiao Cheng , Nashmi Raad , McKinney Sheri , Cai Haijiang , McIntosh J. Michael , Lester Henry A.
Published: October 2009

These electrophysiological experiments, in slices and intact animals, study the effects ofin vivochronic exposure to nicotine on functional α4β2* nAChRs in the nigrostriatal dopaminergic (DA) pathway. Recordings were made in wild-type and α4 nicotinic acetylcholine receptor (nAChR) subunit knock-out mice. Chronic nicotine enhanced methyllycaconitine citrate hydrate-resistant, dihydro-β-erythroidine hydrobromide-sensitive nicotinic currents elicited by 3–1000 μmACh in GABAergic neurons of the substantia nigra pars reticulata (SNr), but not in DA neurons of the substantia nigra pars compacta (SNc). This enhancement leads to higher firing rates of SNr GABAergic neurons and consequently to increased GABAergic inhibition of the SNc DA neurons. In the dorsal striatum, functional α4* nAChRs were not found on the neuronal somata; however, nicotine acts via α4β2* nAChRs in the DA terminals to modulate glutamate release onto the medium spiny neurons. Chronic nicotine also increased the number and/or function of these α4β2* nAChRs. These data suggest that in nigrostriatal DA pathway, chronic nicotine enhancement of α4β2* nAChRs displays selectivity in cell type and in nAChR subtype as well as in cellular compartment. These selective events augment inhibition of SNc DA neurons by SNr GABAergic neurons and also temper the release of glutamate in the dorsal striatum. The effects may reduce the risk of excitotoxicity in SNc DA neurons and may also counteract the increased effectiveness of corticostriatal glutamatergic inputs during degeneration of the DA system. These processes may contribute to the inverse correlation between tobacco use and Parkinson's disease.
Disruption of Functional Connectivity in Clinically Normal Older Adults Harboring Amyloid Burden
Authors: Hedden Trey , Van Dijk Koene R. A. , Becker J. Alex , Mehta Angel , Sperling Reisa A. , Johnson Keith A. , Buckner Randy L.
Published: October 2009

Amyloid deposition is present in 20–50% of nondemented older adults yet the functional consequences remain unclear. The current study found that amyloid accumulation is correlated with functional disruption of the default network as measured by intrinsic activity correlations. Clinically normal participants (n= 38, aged 60–88 years) were characterized using11C-labeled Pittsburgh Compound B positron emission tomography imaging to estimate fibrillar amyloid burden and, separately, underwent functional magnetic resonance imaging (fMRI). The integrity of the default network was estimated by correlating rest-state fMRI time courses extracted from a priori regions including the posterior cingulate, lateral parietal, and medial prefrontal cortices. Clinically normal participants with high amyloid burden displayed significantly reduced functional correlations within the default network relative to participants with low amyloid burden. These reductions were also observed when amyloid burden was treated as a continuous, rather than a dichotomous, measure and when controlling for age and structural atrophy. Whole-brain analyses initiated by seeding the posterior cingulate cortex, a region of high amyloid burden in Alzheimer's disease, revealed significant disruption in the default network including functional disconnection of the hippocampal formation.
Temporal Order Processing of Syllables in the Left Parietal Lobe
Authors: Moser Dana , Baker Julie M. , Sanchez Carmen E. , Rorden Chris , Fridriksson Julius
Published: October 2009

Speech processing requires the temporal parsing of syllable order. Individuals suffering from posterior left hemisphere brain injury often exhibit temporal processing deficits as well as language deficits. Although the right posterior inferior parietal lobe has been implicated in temporal order judgments (TOJs) of visual information, there is limited evidence to support the role of the left inferior parietal lobe (IPL) in processing syllable order. The purpose of this study was to examine whether the left inferior parietal lobe is recruited during temporal order judgments of speech stimuli. Functional magnetic resonance imaging data were collected on 14 normal participants while they completed the following forced-choice tasks: (1) syllable order of multisyllabic pseudowords, (2) syllable identification of single syllables, and (3) gender identification of both multisyllabic and monosyllabic speech stimuli. Results revealed increased neural recruitment in the left inferior parietal lobe when participants made judgments about syllable order compared with both syllable identification and gender identification. These findings suggest that the left inferior parietal lobe plays an important role in processing syllable order and support the hypothesized role of this region as an interface between auditory speech and the articulatory code. Furthermore, a breakdown in this interface may explain some components of the speech deficits observed after posterior damage to the left hemisphere.
Modulation of Neuritogenesis by a Protein Implicated in X-Linked Mental Retardation
Authors: Jiao Xinfu , Chen Hongxin , Chen Jianmin , Herrup Karl , Firestein Bonnie L. , Kiledjian Megerditch
Published: October 2009

Posttranscriptional regulation is an important control mechanism governing gene expression in neurons. We recently demonstrated that VCX-A, a protein implicated in X-linked mental retardation, is an RNA-binding protein that specifically binds the 5′ end of capped mRNAs to prevent their decapping and decay. Previously, expression of VCX-A was reported to be testes restricted. Consistent with a role in cognitive function, we demonstrate that VCX-A is ubiquitously expressed in human tissues including the brain. Moreover, retinoic acid-induced differentiation of human SH-SY5Y neuroblastoma cells promoted the accumulation of VCX-A in distinct cytoplasmic foci within neurites that colocalize with staufen1-containing RNA granules, suggesting a role in translational suppression and/or mRNA transport. Exogenous expression of VCX-A in rat primary hippocampal neurons, which normally do not express the primate-restricted VCX proteins, promoted neurite arborization, and shRNA-directed knockdown of the VCX genes in SH-SY5Y cells resulted in a reduction of both primary and secondary neurite projections upon differentiation. We propose that the cap-binding property of VCX-A reflects a role of this protein in mRNA translational regulation. In support of this hypothesized role, we demonstrate that VCX-A can specifically bind a subset of mRNAs involved in neuritogenesis and is also capable of promoting translational silencing. Thus, VCX-A contains the capacity to modulate the stability and translation of a subset of target mRNAs involved in neuronal differentiation and arborization. It is plausible that defects of these functions in the absence of the VCX genes could contribute to a mental retardation phenotype.
Do we need still more trials on T4 and T3 combination therapy in hypothyroidism?
Authors: Wiersinga Wilmar M
Published: October 2009

Approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine replacement. It is unlikely that slight over- or under-treatment with thyroxine (T4) explains remaining complaints. Meta-analysis of randomized clinical trials shows no advantage of T4/tri-iodothyronine (T3) combination therapy over T4 monotherapy. However, each of these trials can be criticized, and none is perfect: most of them failed to mimic the physiological ratio of serum free T4 (FT4) to free T3 (FT3) concentrations. Development of a sustained-release T3 preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT4–FT3 ratio's throughout 24 h. Genetic polymorphisms in deiodinase 2 and thyroid hormone transporters have been associated with well-being, fatigue, depression, and greater improvement on combination therapy. Future trials should target carriers of these polymorphisms to see whether they do better on T4/T3 combination therapy than on T4 monotherapy.
The Association between Parent Communication and College Freshmen's Alcohol Use
Authors: Boyle Jennifer R. , Boekeloo Bradley O.
Published: October 2009

Using a cross-sectional survey, data were collected from 265 first-year college students to determine if parent-student alcohol communication is associated with college drinking or drinking consequences and if this relationship is mediated by students' parental subjective norms, attitudes toward drinking, and perceived risk. Structural equation modeling was used to test hypotheses. Students whose parents talked with them more about the negative effects of alcohol reported more extensive college drinking (ß = 0.12, p < 0.05). Favorable alcohol attitudes were significantly related to both more extensive college drinking (ß = 0.49, p < 0.05) and more drinking consequences (ß = 0.39, p < 0.05). Lower reported perceived risk was significantly related to more drinking consequences (ß = −0.24, p < 0.05). Findings indicate that parental communication regarding the negative effects of alcohol may be ineffective at reducing college drinking or drinking consequences.
Comparing Entering Freshmen's Perceptions of Campus Marijuana and Alcohol Use to Reported Use
Authors: Gold Gregg J. , Nguyen Alyssa T.
Published: October 2009

Use of marijuana and alcohol among current college students ( N = 1101) was compared to the perceptions and use of entering freshmen ( N = 481) surveyed before the start of classes. Entering freshmen significantly misperceived campus norms for marijuana use, over-estimating that almost every student used in the last 30 days, p < .001. Perceptions of alcohol use were relatively accurate. These discrepancies in perception could account for why 40.5% of entering students perceived the campus atmosphere to be promoting marijuana use, whereas only 16.2% perceived the campus atmosphere to be promoting alcohol use. How these misperceptions of social norms might be influenced by the reputation of the campus—and how this might affect potential applicants and enrolled students' behaviors are discussed.
A Conceptual Framework for Studying Alcohol Intake and Blood Pressure on Historically Black College and University Campuses
Authors: Carter-Edwards Lori , Godette Dionne C. , White Sumitra Shantakumar , Tyson William
Published: October 2009

Drinking increases the risk of elevated blood pressure, a risk factor for chronic ailments such as hypertension and cardiovascular disease. The experience of elevated blood pressure in young adulthood may be critical for the development of these diseases later in life. College campuses are venues replete with young adults, and drinking is a popular activity in these settings. Because Historically Black Colleges and Universities (HBCU) produce a large proportion of black college graduates, understanding the social context of drinking among young blacks attending HBCUs is important in understanding the role and characteristics of drinking as a risk factor for the development of elevated blood pressure. This article reviews existing literature on alcohol and blood pressure and proposes a conceptual framework linking socioenvironmental factors, stress, and alcohol consumption at HBCUs in the context of elevated blood pressure among young blacks. Recommendations for future research are also proposed.
Influence of Skip Patterns on Item Non-Response in a Substance Use Survey of 7th to 12th Grade Students
Authors: Ding Kele , Olds R. Scott , Thombs Dennis L.
Published: October 2009

This retrospective case study assessed the influence of item non-response error on subsequent response to questionnaire items assessing adolescent alcohol and marijuana use. Post-hoc analyses were conducted on survey results obtained from 4,371 7th to 12th grade students in Ohio in 2005. A skip pattern design in a conventional questionnaire appeared to increase non-response error rates at first introduction. In previous cigarette users, these errors were associated with under-reporting of alcohol and marijuana use on subsequent questions. These effects were less prevalent in high-achieving students. Skip patterns can contribute to substantial underestimation of alcohol and marijuana use in adolescents.
Enali: A Research and Design Framework for Virtual Characters and Pedagogical Agents
Authors: Veletsianos George , Miller Charles , Doering Aaron
Published: October 2009

Conflicts occur when learners interact with pedagogical agents and virtual characters. Such conflicts—arising from technological limitations, psychosocial perceptions, and pedagogical inadequacies—hinder communication and interaction between virtual characters and learners, and impede successful engagement with learning tasks and experiences. To enhance communication and interaction between virtual characters and learners, we propose a three-tier framework of 15 research-based guidelines. This framework enables theorists, researchers, and designers to view virtual characters with a holistic lens, informing the analysis, design, development, implementation, and evaluation of virtual characters in electronic learning contexts.
Style Matching or Ability Building? An Empirical Study on FD Learners' Learning in Well-Structured and Ill-Structured Asynchronous Online Learning Environments
Authors: Zheng Robert Z. , Flygare Jill A. , Dahl Laura B.
Published: October 2009

The present study investigated (1) the impact of cognitive styles on learner performance in well-structured and ill-structured learning, and (2) scaffolding as a cognitive tool to improve learners' cognitive abilities, especially field dependent (FD) learners' ability to thrive in an ill-structured learning environment. Two experiments were conducted with 116 college students recruited from a large research I university in the west of the United States. Experiment 1 ( n = 42) employed the group learning strategy to match learners' cognitive styles in asynchronous online learning. The results showed that the style matching strategy failed to yield expected gains in ill-structured asynchronous learning for FD learners. Different from the style-matching strategy, experiment 2 ( n = 74) used a scaffolding model proposed by Cazden (1988) to improve FD learners' cognitive abilities in asynchronous online learning. Results indicated that focusing on learners' cognitive abilities proved to be more effective than style-matching strategy for FD learners in both ill-structured and well-structured asynchronous online learning. Implications of the findings were discussed with suggestions for future research.
Production of Shelf-Stable Annurca Apple Juice with Pulp by High Pressure Homogenization
Authors: Donsì Francesco , Esposito Luigi , Lenza Ermelinda , Senatore Beatrice , Ferrari Giovanna
Published: October 2009

Annurca apple juice was processed by high pressure homogenization (HPH) to inactivate the endogenous microbial flora, with the aim of maintaining the organoleptic properties and the polyphenolic content of the fresh juice. In particular, it was shown that the shelf life of clear juice can be prolonged for many weeks of storage both at 4°C and 37°C upon HPH treatment at 250 MPa. Instead, the juice with pulp required higher pressure levels (300 MPa) for microbial stabilization both at 4°C and 37°C. The sample stored at 37°C exhibited a physical instability, with deviation in color and pH, which reduced the shelf life, but the samples stored at 4°C exhibited an excellent microbial stability and no observable variation of pH and color, suggesting that HPH can represent a good option for non thermal pasteurization of Annurca apple juice.Interestingly, the HPH treatment delivered also significant changes to the distribution of suspended particles, whose comminution had a measurable effect on viscosity.
Tpl2 Kinase Is Upregulated in Adipose Tissue in Obesity and May Mediate Interleukin-1β and Tumor Necrosis Factor-α Effects on Extracellular Signal–Regulated Kinase Activation and Lipolysis
Authors: Jager Jennifer , Grémeaux Thierry , Gonzalez Teresa , Bonnafous Stéphanie , Debard Cyrille , Laville Martine , Vidal Hubert , Tran Albert , Gual Philippe , Le Marchand-Brustel Yannick , Cormont Mireille , Tanti Jean-François
Published: October 2009

OBJECTIVE

Activation of extracellular signal–regulated kinase-(ERK)-1/2 by cytokines in adipocytes is involved in the alterations of adipose tissue functions participating in insulin resistance. This study aims at identifying proteins regulating ERK1/2 activity, specifically in response to inflammatory cytokines, to provide new insights into mechanisms leading to abnormal adipose tissue function.

RESEARCH DESIGN AND METHODS

Kinase activities were inhibited with pharmacological inhibitors or siRNA. Lipolysis was monitored through glycerol production. Gene expression in adipocytes and adipose tissue of obese mice and subjects was measured by real-time PCR.

RESULTS

IκB kinase-(IKK)-β inhibition prevented mitogen-activated protein (MAP) kinase kinase (MEK)/ERK1/2 activation in response to interleukin (IL)-1β and tumor necrosis factor (TNF)-α but not insulin in 3T3-L1 and human adipocytes, suggesting that IKKβ regulated a MAP kinase kinase kinase (MAP3K) involved in ERK1/2 activation induced by inflammatory cytokines. We show that the MAP3K8 called Tpl2 was expressed in adipocytes and that IL-1β and TNF-α activated Tpl2 and regulated its expression through an IKKβ pathway. Pharmacological inhibition or silencing of Tpl2 prevented MEK/ERK1/2 activation by these cytokines but not by insulin, demonstrating its involvement in ERK1/2 activation specifically in response to inflammatory stimuli. Importantly, Tpl2 was implicated in cytokine-induced lipolysis and in insulin receptor substrate-1 serine phosphorylation. Tpl2 mRNA expression was upregulated in adipose tissue of obese mice and patients and correlated with TNF-α expression.

CONCLUSIONS

Tpl2 is selectively involved in inflammatory cytokine–induced ERK1/2 activation in adipocytes and is implicated in their deleterious effects on adipocyte functions. The deregulated expression of Tpl2 in adipose tissue suggests that Tpl2 may be a new actor in adipose tissue dysfunction in obesity.
Grp78 Heterozygosity Promotes Adaptive Unfolded Protein Response and Attenuates Diet-Induced Obesity and Insulin Resistance
Authors: Ye Risheng , Jung Dae Young , Jun John Y. , Li Jianze , Luo Shengzhan , Ko Hwi Jin , Kim Jason K. , Lee Amy S.
Published: October 2009

OBJECTIVE

To investigate the role of the endoplasmic reticulum (ER) chaperone glucose-regulated protein (GRP) 78/BiP in the pathogenesis of obesity, insulin resistance, and type 2 diabetes.

RESEARCH DESIGN AND METHODS

Male Grp78+/− mice and their wild-type littermates were subjected to a high-fat diet (HFD) regimen. Pathogenesis of obesity and type 2 diabetes was examined by multiple approaches of metabolic phenotyping. Tissue-specific insulin sensitivity was analyzed by hyperinsulinemic-euglycemic clamps. Molecular mechanism was explored via immunoblotting and tissue culture manipulation.

RESULTS

Grp78 heterozygosity increases energy expenditure and attenuates HFD-induced obesity. Grp78+/− mice are resistant to diet-induced hyperinsulinemia, liver steatosis, white adipose tissue (WAT) inflammation, and hyperglycemia. Hyperinsulinemic-euglycemic clamp studies revealed that Grp78 heterozygosity improves glucose metabolism independent of adiposity and following an HFD increases insulin sensitivity predominantly in WAT. As mechanistic explanations, Grp78 heterozygosity in WAT under HFD stress promotes adaptive unfolded protein response (UPR), attenuates translational block, and upregulates ER degradation-enhancing α-mannosidase–like protein (EDEM) and ER chaperones, thus improving ER quality control and folding capacity. Further, overexpression of the active form of ATF6 induces protective UPR and improves insulin signaling upon ER stress.

CONCLUSIONS

HFD-induced obesity and type 2 diabetes are improved in Grp78+/− mice. Adaptive UPR in WAT could contribute to this improvement, linking ER homeostasis to energy balance and glucose metabolism.
Adaptive Cerebral Neovascularization in a Model of Type 2 Diabetes
Authors: Li Weiguo , Prakash Roshini , Kelly-Cobbs Aisha I. , Ogbi Safia , Kozak Anna , El-Remessy Azza B. , Schreihofer Derek A. , Fagan Susan C. , Ergul Adviye
Published: October 2009

OBJECTIVE

The effect of diabetes on neovascularization varies between different organ systems. While excessive angiogenesis complicates diabetic retinopathy, impaired neovascularization contributes to coronary and peripheral complications of diabetes. However, how diabetes influences cerebral neovascularization is not clear. Our aim was to determine diabetes-mediated changes in the cerebrovasculature and its impact on the short-term outcome of cerebral ischemia.

RESEARCH DESIGN AND METHODS

Angiogenesis (capillary density) and arteriogenesis (number of collaterals and intratree anostomoses) were determined as indexes of neovascularization in the brain of control and type 2 diabetic Goto-Kakizaki (GK) rats. The infarct volume, edema, hemorrhagic transformation, and short-term neurological outcome were assessed after permanent middle–cerebral artery occlusion (MCAO).

RESULTS

The number of collaterals between middle and anterior cerebral arteries, the anastomoses within middle–cerebral artery trees, the vessel density, and the level of brain-derived neurotrophic factor were increased in diabetes. Cerebrovascular permeability, matrix metalloproteinase (MMP)-9 protein level, and total MMP activity were augmented while occludin was decreased in isolated cerebrovessels of the GK group. Following permanent MCAO, infarct size was smaller, edema was greater, and there was no macroscopic hemorrhagic transformation in GK rats.

CONCLUSIONS

The augmented neovascularization in the GK model includes both angiogenesis and arteriogenesis. While adaptive arteriogenesis of the pial vessels and angiogenesis at the capillary level may contribute to smaller infarction, changes in the tight junction proteins may lead to the greater edema following cerebral ischemia in diabetes.