bluuebunny/crossref_metadata_2025 huggingface dataset:
Internalization of UT-A1 urea transporter is dynamin dependent and mediated by both caveolae- and clathrin-coated pit pathways
Authors: Huang Haidong , Feng Xiuyan , Zhuang Jieqiu , Fröhlich Otto , Klein Janet D. , Cai Hui , Sands Jeff M. , Chen Guangping
Published: September 2010

Dynamin is a large GTPase involved in several distinct modes of cell endocytosis. In this study, we examined the possible role of dynamin in UT-A1 internalization. The direct relationship of UT-A1 and dynamin was identified by coimmunoprecipitation. UT-A1 has cytosolic NH2and COOH termini and a large intracellular loop. Dynamin specifically binds to the intracellular loop of UT-A1, but not the NH2and COOH termini. In cell surface biotinylation experiments, coexpression of dynamin and UT-A1 in HEK293 cells resulted in a decrease of UT-A1 cell surface expression. Conversely, cells expressing dynamin mutant K44A, which is deficient in GTP binding, showed an increased accumulation of UT-A1 protein on the cell surface. Cell plasma membrane lipid raft fractionation experiments revealed that blocking endocytosis with dynamin K44A causes UT-A1 protein accumulation in both the lipid raft and nonlipid raft pools, suggesting that both caveolae- and clathrin-mediated mechanisms may be involved in the internalization of UT-A1. This was further supported by 1) small interfering RNA to knock down either caveolin-1 or μ2 reduced UT-A1 internalization in HEK293 cells and 2) inhibition of either the caveolae pathway by methyl-β-cyclodextrin or the clathrin pathway by concanavalin A caused UT-A1 cell membrane accumulation. Functionally, overexpression of dynamin, caveolin, or μ2 decreased UT-A1 urea transport activity and decreased UT-A1 cell surface expression. We conclude that UT-A1 endocytosis is dynamin-dependent and mediated by both caveolae- and clathrin-coated pit pathways.
Heat acclimation improves cutaneous vascular function and sweating in trained cyclists
Authors: Lorenzo Santiago , Minson Christopher T.
Published: September 2010

The aim of this study was to explore heat acclimation effects on cutaneous vascular responses and sweating to local ACh infusions and local heating. We also sought to examine whether heat acclimation altered maximal skin blood flow. ACh (1, 10, and 100 mM) was infused in 20 highly trained cyclists via microdialysis before and after a 10-day heat acclimation program [two 45-min exercise bouts at 50% maximal O2 uptake (V̇o2max) in 40°C ( n = 12)] or control conditions [two 45-min exercise bouts at 50% V̇o2max in 13°C ( n = 8)]. Skin blood flow was monitored via laser-Doppler flowmetry (LDF), and cutaneous vascular conductance (CVC) was calculated as LDF ÷ mean arterial pressure. Sweat rate was measured by resistance hygrometry. Maximal brachial artery blood flow (forearm blood flow) was obtained by heating the contralateral forearm in a water spray device and measured by Doppler ultrasound. Heat acclimation increased %CVCmax responses to 1, 10, and 100 mM ACh (43.5 ± 3.4 vs. 52.6 ± 2.6% CVCmax, 67.7 ± 3.4 vs. 78.0 ± 3.0% CVCmax, and 81.0 ± 3.8 vs. 88.5 ± 1.1% CVCmax, respectively, all P < 0.05). Maximal forearm blood flow remained unchanged after heat acclimation (290.9 ± 12.7 vs. 269.9 ± 23.6 ml/min). The experimental group showed significant increases in sweating responses to 10 and 100 mM ACh (0.21 ± 0.03 vs. 0.31 ± 0.03 mg·cm−2·min−1 and 0.45 ± 0.05 vs. 0.67 ± 0.06 mg·cm−2·min−1, respectively, all P < 0.05), but not to 1 mM ACh (0.13 ± 0.02 vs. 0.18 ± 0.02 mg·cm−2·min−1, P = 0.147). No differences in any of the variables were found in the control group. Heat acclimation in highly trained subjects induced local adaptations within the skin microcirculation and sweat gland apparatus. Furthermore, maximal skin blood flow was not altered by heat acclimation, demonstrating that the observed changes were attributable to improvement in cutaneous vascular function and not to structural changes that limit maximal vasodilator capacity.
Long-Term Depression at Parallel Fiber to Golgi Cell Synapses
Authors: Robberechts Quinten , Wijnants Mike , Giugliano Michele , De Schutter Erik
Published: September 2010

Golgi cells (GoCs) are the primary inhibitory interneurons of the granular layer of the cerebellum. Their inhibition of granule cells is central to operate the relay of excitatory inputs to the cerebellar cortex. Parallel fibers (PFs) establish synapses to the GoCs in the molecular layer; these synapses contain AMPA, N-methyl-d-aspartate (NMDA), and mostly group II metabotropic glutamate receptors. Long-term changes in the efficacy of synaptic transmission at the PF-GoC synapse have not been described previously. We used whole cell patch-clamp recordings of GoCs in acute rat cerebellar slices to study synaptic plasticity. We report that high-frequency burst stimulation of PFs, using a current-clamp or voltage-clamp induction protocol, gave rise to long-term depression (LTD) at the PF-GoC synapse. This form of LTD was not associated with persistent changes of paired-pulse ratio, suggesting a postsynaptic origin. Furthermore, LTD induction was not dependent on activation of NMDA receptors. PF-GoC LTD does require activation of specifically group II metabotropic glutamate receptors and of protein kinase A.
Topography of Covert Visual Attention in Human Superior Colliculus
Authors: Katyal Sucharit , Zughni Samir , Greene Clint , Ress David
Published: September 2010

Experiments were performed to examine the topography of covert visual attention signals in human superior colliculus (SC), both across its surface and in its depth. We measured the retinotopic organization of SC to direct visual stimulation using a 90° wedge of moving dots that slowly rotated around fixation. Subjects ( n = 5) were cued to perform a difficult speed-discrimination task in the rotating region. To measure the retinotopy of covert attention, we used a full-field array of similarly moving dots. Subjects were cued to perform the same speed-discrimination task within a 90° wedge-shaped region, and only the cue rotated around fixation. High-resolution functional magnetic resonance imaging (fMRI, 1.2 mm voxels) data were acquired throughout SC. These data were then aligned to a high-resolution T1-weighted reference volume. The SC was segmented in this volume so that the surface of the SC could be computationally modeled and to permit calculation of a depth map for laminar analysis. Retinotopic maps were obtained for both direct visual stimulation and covert attention. These maps showed a similar spatial distribution to visual stimulation maps observed in rhesus macaque and were in registration with each other. Within the depth of SC, both visual attention and stimulation produced activity primarily in the superficial and intermediate layers, but stimulation activity extended significantly more deeply than attention.
Orientation Selectivity of Motion-Boundary Responses in Human Visual Cortex
Authors: Larsson Jonas , Heeger David J. , Landy Michael S.
Published: September 2010

Motion boundaries (local changes in visual motion direction) arise naturally when objects move relative to an observer. In human visual cortex, neuroimaging studies have identified a region (the kinetic occipital area [KO]) that responds more strongly to motion-boundary stimuli than to transparent-motion stimuli. However, some functional magnetic resonance imaging (fMRI) studies suggest that KO may encompass multiple visual areas and single-unit studies in macaque visual cortex have identified neurons selective for motion-boundary orientation in areas V2, V3, and V4, implying that motion-boundary selectivity may not be restricted to a single area. It is not known whether fMRI responses to motion boundaries are selective for motion-boundary orientation, as would be expected if these responses reflected the population activity of motion-boundary–selective neurons. We used an event-related fMRI adaptation protocol to measure orientation-selective responses to motion boundaries in human visual cortex. On each trial, we measured the response to a probe stimulus presented after an adapter stimulus (a vertical or horizontal motion-boundary grating). The probe stimulus was either a motion-boundary grating oriented parallel or orthogonal to the adapter stimulus or a transparent-motion stimulus. Orientation-selective adaptation for motion boundaries—smaller responses for trials in which test and adapter stimuli were parallel to each other—was observed in multiple extrastriate visual areas. The strongest adaptation, relative to the unadapted responses, was found in V3A, V3B, LO1, LO2, and V7. Most of the visual areas that exhibited orientation-selective adaptation in our data also showed response preference for motion boundaries over transparent motion, indicating that most of the human visual areas previously shown to respond to motion boundaries are also selective for motion-boundary orientation. These results suggest that neurons selective for motion-boundary orientation are distributed across multiple human visual cortical areas and argue against the existence of a single region or area specialized for motion-boundary processing.
Locomotion After Spinal Cord Injury Depends on Constitutive Activity in Serotonin Receptors
Authors: Fouad K. , Rank M. M. , Vavrek R. , Murray K. C. , Sanelli L. , Bennett D. J.
Published: September 2010

Following spinal cord injury (SCI) neurons caudal to the injury are capable of rhythmic locomotor-related activity that can form the basis for substantial functional recovery of stepping despite the loss of crucial brain stem-derived neuromodulators like serotonin (5-HT). Here we investigated the contribution of constitutive 5-HT2receptor activity (activity in the absence of 5-HT) to locomotion after SCI. We used a staggered hemisection injury model in rats to study this because these rats showed a robust recovery of locomotor function and yet a loss of most descending axons. Immunolabeling for 5-HT showed little remaining 5-HT below the injury, and locomotor ability was not correlated with the amount of residual 5-HT. Furthermore, blocking 5-HT2receptors with an intrathecal (IT) application of the neutral antagonist SB242084 did not affect locomotion (locomotor score and kinematics were unaffected), further indicating that residual 5-HT below the injury did not contribute to generation of locomotion. As a positive control, we found that the same application of SB242084 completely antagonized the muscle activity induced by exogenous application of the 5-HT2receptor agonists alpha-methyl-5-HT (IT). In contrast, blocking constitutive 5-HT2receptor activity with the potent inverse agonist SB206553 (IT) severely impaired stepping as assessed with kinematic recordings, eliminating most hindlimb weight support and overall reducing the locomotor score in both hind legs. However, even in the most severely impaired animals, rhythmic sweeping movements of the hindlimb feet were still visible during forelimb locomotion, suggesting that SB206553 did not completely eliminate locomotor drive to the motoneurons or motoneuron excitability. The same application of SB206553 had no affect on stepping in normal rats. Thus while normal rats can compensate for loss of 5-HT2receptor activity, after severe spinal cord injury rats require constitutive activity in these 5-HT2receptors to produce locomotion.
Orientation-Specific Modulation of Rat Retinal Ganglion Cell Responses and Its Dependence on Relative Orientations of the Center and Surround Gratings
Authors: Girman Sergej , Lund Raymond
Published: September 2010

In the primary visual cortex (V1), it has been shown that the neuronal response elicited by a grating patch in the receptive field (RF) center can be suppressed or facilitated by an annular grating presented in the RF surround area; the effect depends on the relative orientations of the two gratings. The effect is thought to play a role in figure-ground segregation. Here we have found that response modulation similar to that reported in cortical area V1 can also be found in all major classes of retinal ganglion cells (RGCs), including “concentric” cells. Orientation-specific response modulation of this kind cannot result from interactions of independent RF mechanisms; therefore more complex mechanism, which takes into account the relative orientations of the gratings in the RF center and surround, or sensing the borders between texture regions, has to be present in RFs of RGCs, even of the concentric type. This challenges the consensus notion that their responses to visual stimuli are governed entirely by a RF composed of separate mechanisms: center, antagonistic surround, and modulatory extraclassical surround. Our findings raise the question of whether initial stages of complex analysis of visual input, normally attributed to the visual cortex, can be achieved within the retina.
Reward Magnitude Coding in Primate Amygdala Neurons
Authors: Bermudez Maria A. , Schultz Wolfram
Published: September 2010

Animals assess the values of rewards to learn and choose the best possible outcomes. We studied how single neurons in the primate amygdala coded reward magnitude, an important variable determining the value of rewards. A single, Pavlovian-conditioned visual stimulus predicted fruit juice to be delivered with one of three equiprobable volumes ( P = 1/3). A population of amygdala neurons showed increased activity after reward delivery, and almost one half of these responses covaried with reward magnitude in a monotonically increasing or decreasing fashion. A subset of the reward responding neurons were tested with two different probability distributions of reward magnitude; the reward responses in almost one half of them adapted to the predicted distribution and thus showed reference-dependent coding. These data suggest parametric reward value coding in the amygdala as a characteristic component of its function in reinforcement learning and economic decision making.
Altered Purinergic Signaling in Colorectal Dorsal Root Ganglion Neurons Contributes to Colorectal Hypersensitivity
Authors: Shinoda Masamichi , La Jun-Ho , Bielefeldt Klaus , Gebhart G. F.
Published: September 2010

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by pain and hypersensitivity in the relative absence of colon inflammation or structural changes. To assess the role of P2X receptors expressed in colorectal dorsal root ganglion (c-DRG) neurons and colon hypersensitivity, we studied excitability and purinergic signaling of retrogradely labeled mouse thoracolumbar (TL) and lumbosacral (LS) c-DRG neurons after intracolonic treatment with saline or zymosan (which reproduces 2 major features of IBS—persistent colorectal hypersensitivity without inflammation) using patch-clamp, immunohistochemical, and RT-PCR techniques. Although whole cell capacitances did not differ between LS and TL c-DRG neurons and were not changed after zymosan treatment, membrane excitability was increased in LS and TL c-DRG neurons from zymosan-treated mice. Purinergic agonist adenosine-5′-triphosphate (ATP) and α,β-methylene ATP [α,β-meATP] produced inward currents in TL c-DRG neurons were predominantly P2X3-like fast (∼70% of responsive neurons); P2X2/3-like slow currents were more common in LS c-DRG neurons (∼35% of responsive neurons). Transient currents were not produced by either agonist in c-DRG neurons from P2X3−/− mice. Neither total whole cell Kv current density nor the sustained or transient Kv components was changed in c-DRG neurons after zymosan treatment. The number of cells expressing P2X3 protein and its mRNA and the kinetic properties of ATP- and α,β-meATP-evoked currents in c-DRG neurons were not changed by zymosan treatment. However, the EC50 of α,β-meATP for the fast current decreased significantly in TL c-DRG neurons. These findings suggest that colorectal hypersensitivity produced by intracolonic zymosan increases excitability and enhances purinergic signaling in c-DRG neurons.
cAMP Modulates Intracellular Ca2+ Sensitivity of Fast-Releasing Synaptic Vesicles at the Calyx of Held Synapse
Authors: Yao Lijun , Sakaba Takeshi
Published: September 2010

cAMP potentiates neurotransmitter release from the presynaptic terminal in many CNS synapses, but the underlying mechanisms remain unclear. Here we addressed this issue quantitatively by performing double patch-clamp recordings from the pre- and postsynaptic compartments of the calyx of Held synapse in rat brain stem slices in combination with Ca2+ uncaging. We found that elevation of cAMP increased intracellular Ca2+ sensitivity for transmitter release especially at lower Ca2+ concentrations. The change in Ca2+ sensitivity was limited to the fast-releasing synaptic vesicles, which could be released rapidly on action potentials. cAMP did not affect the slowly releasing vesicles. Fit of the data using a simplified allosteric model indicated that cAMP increased the fusion “willingness,” thereby facilitating transmitter release. We suggest that synaptic vesicles have to be positionally primed to the release sites close to the Ca2+ channel cluster for cAMP to modulate intracellular Ca2+ sensitivity of transmitter release.
Validation of Independent Component Analysis for Rapid Spike Sorting of Optical Recording Data
Authors: Hill Evan S. , Moore-Kochlacs Caroline , Vasireddi Sunil K. , Sejnowski Terrence J. , Frost William N.
Published: September 2010

Independent component analysis (ICA) is a technique that can be used to extract the source signals from sets of signal mixtures where the sources themselves are unknown. The analysis of optical recordings of invertebrate neuronal networks with fast voltage-sensitive dyes could benefit greatly from ICA. These experiments can generate hundreds of voltage traces containing both redundant and mixed recordings of action potentials originating from unknown numbers of neurons. ICA can be used as a method for converting such complex data sets into single-neuron traces, but its accuracy for doing so has never been empirically evaluated. Here, we tested the accuracy of ICA for such blind source separation by simultaneously performing sharp electrode intracellular recording and fast voltage-sensitive dye imaging of neurons located in the central ganglia of Tritonia diomedea and Aplysia californica, using a 464-element photodiode array. After running ICA on the optical data sets, we found that in 34 of 34 cases the intracellularly recorded action potentials corresponded 100% to the spiking activity of one of the independent components returned by ICA. We also show that ICA can accurately sort action potentials into single neuron traces from a series of optical data files obtained at different times from the same preparation, allowing one to monitor the network participation of large numbers of individually identifiable neurons over several recording episodes. Our validation of the accuracy of ICA for extracting the neural activity of many individual neurons from noisy, mixed, and redundant optical recording data sets should enable the use of this powerful large-scale imaging approach for studies of invertebrate and suitable vertebrate neuronal networks.
Sleep-Like States Modulate Functional Connectivity in the Rat Olfactory System
Authors: Wilson Donald A. , Yan Xiaodan
Published: September 2010

The present study was an examination of state-dependent functional connectivity during spontaneous activity between the piriform cortex and its upstream and downstream connections. Rats were anesthetized with urethan and allowed to spontaneously cycle between fast- and slow-wave states similar to fast- and slow-wave sleep states. Local field potential recordings were made from the olfactory bulb, piriform cortex, dorsal hippocampus, amygdala, and primary visual cortex. The results demonstrate that during slow-wave sleep-like states, when the piriform cortex shows reduced sensitivity to odor input via the olfactory bulb, there is enhanced coherence with other forebrain structures. Granger causality analyses suggest that the link between piriform cortical and hippocampal activity during slow-wave state is in the direction of the hippocampus to the piriform cortex rather than the reverse. The results suggest that slow-wave sleep-like states may provide an opportunity for the transfer and/or consolidation of information related to odor memories, specifically at a time when the piriform cortex is less sensitive to sensory input.
Changes in the Estimated Time Course of the Motoneuron Afterhyperpolarization Induced by Tendon Vibration
Authors: MacDonell Christopher W. , Ivanova Tanya D. , Garland S. Jayne
Published: September 2010

Group Ia afferents are activated vigorously with high-frequency tendon vibration and provide excitatory input to the agonist muscle and inhibitory input to the antagonist muscle group via inhibitory interneurons. The purpose of this experiment was to determine whether the afterhyperpolarization (AHP) time course in humans is altered in response to tendon vibration. The AHP time course is estimated using the interval death rate (IDR) analysis, a transform of the motor unit action potential train. Single motor units from tibialis anterior (TA) were recorded as subjects held low force dorsiflexor contractions for 600 s with and without vibration. The vibratory stimulus was superimposed on the low force contraction either to the tendon of the TA or the antagonist Achilles tendon. During TA tendon vibration, the time course of the AHP, as expressed by its time constant (τ), decreased from 35.5 ms in the previbration control condition to 31.3 ms during the vibration ( P = 0.003) and returned to 36.3 ms after the vibration was removed ( P = 0.002). The AHP τ during vibration of the antagonist Achilles tendon (38.6 ms) was greater than the previbration control condition (33.6 ms; P = 0.001). It is speculated that the reduction in AHP time constant with TA vibration may have resulted alone or in combination with a modulation of motoneuron gain, an alteration of persistent inward currents and/or the restructuring of synaptic noise. A decrease in firing probability, possibly reflecting Ia reciprocal inhibition, may have been responsible for the larger AHP time constant.
Driver′s Behavior Modeling Using Fuzzy Logic
Authors: Ghaemi Sehraneh , Khanmohammadi Sohrab , Tinati Mohammadali
Published: September 2010

In this study, we propose a hierarchical fuzzy system for human in a driver‐vehicle‐environment system to model takeover by different drivers. The driver′s behavior is affected by the environment. The climate, road and car conditions are included in fuzzy modeling. For obtaining fuzzy rules, experts′ opinions are benefited by means of questionnaires on effects of parameters such as climate, road and car conditions on driving capabilities. Also the precision, age and driving individuality are used to model the driver′s behavior. Three different positions are considered for driving and decision making. A fuzzy model calledModel Iis presented for modeling the change of steering angle and speed control by considering time distances with existing cars in these three positions, the information about the speed and direction of car, and the steering angle of car. Also we obtained two other models based on fuzzy rules calledModel IIandModel IIIby using Sugeno fuzzy inference.Model IIandModel IIIhave less linguistic terms thanModel Ifor the steering angle and direction of car. The results of three models are compared for a driver who drives based on driving laws.
Insulin Resistance, Inflammation, and Obesity: Role of Monocyte Chemoattractant Protein-1 (orCCL2) in the Regulation of Metabolism
Authors: Rull Anna , Camps Jordi , Alonso-Villaverde Carlos , Joven Jorge
Published: September 2010

To maintain homeostasis under diverse metabolic conditions, it is necessary to coordinate nutrient-sensing pathways with the immune response. This coordination requires a complex relationship between cells, hormones, and cytokines in which inflammatory and metabolic pathways are convergent at multiple levels. Recruitment of macrophages to metabolically compromised tissue is a primary event in which chemokines play a crucial role. However, chemokines may also transmit cell signals that generate multiple responses, most unrelated to chemotaxis, that are involved in different biological processes. We have reviewed the evidence showing that monocyte chemoattractant protein-1 (MCP-1 or CCL2) may have a systemic role in the regulation of metabolism that sometimes is not necessarily linked to the traffic of inflammatory cells to susceptible tissues. Main topics cover the relationship between MCP-1/CCL2, insulin resistance, inflammation, obesity, and related metabolic disturbances.
Tree Growth Prediction in Relation to Simple Set of Site Quality Indicators for Six Native Tree Species in the Philippines
Authors: Santos Martin F. , Lusiana B. , van Noordwijk M.
Published: September 2010

The gain in precision to explain the variation on tree growth performance as a function of a set of site indicators was analysed in a stepwise form, increasing its complexity and costs. Six native timber tree species were commonly found on farmer's fields and planted under different types of agroforestry systems. Localization of trees to be used for measurement was achieved through individual interviews to assess timing of introduction of trees. Results proved that native tree species planted on farmers' fields have similar growth rate other exotic timber species asSwietenia macrophyllathat are widely spread in the Philippines. Nevertheless, the large fraction of the variation in tree performance that could not be explained by the biophysical site indicators measured implies that farmers take considerable risk in planting trees on the basis of current “scientific” knowledge. The complement of “site characteristics” is probably “management”, and the low determination of tree growth by site properties may in fact be good news for the farmers.
Least Squares for Practitioners
Authors: Blais J. A. Rod
Published: September 2010

In experimental science and engineering, least squares are ubiquitous in analysis and digital data processing applications. Minimizing sums of squares of some quantities can be interpreted in very different ways and confusion can arise in practice, especially concerning the optimality and reliability of the results. Interpretations of least squares in terms of norms and likelihoods need to be considered to provide guidelines for general users. Assuming minimal prerequisites, the following expository discussion is intended to elaborate on some of the mathematical characteristics of the least‐squares methodology and some closely related questions in the analysis of the results, model identification, and reliability for practical applications. Examples of simple applications are included to illustrate some of the advantages, disadvantages, and limitations of least squares in practice. Concluding remarks summarize the situation and provide some indications of practical areas of current research and development.
Sociodemographic Variation of Caries Risk Factors in Toddlers and Caregivers
Authors: Eckert G. J. , Jackson R. , Fontana M.
Published: September 2010

Objectives. Dental caries is the most common chronic childhood disease, with numerous identified risk factors. Risk factor differences could indicate the need to target caregiver/patient education/preventive care intervention strategies based on population and/or individual characteristics. The purpose of this study was to evaluate caries risk factors differences by race/ethnicity, income, and education.Methods. We enrolled 396 caregiver-toddler pairs and administered a 105-item questionnaire addressing demographics, access to care, oral bacteria transmission, caregiver's/toddler's dental and medical health practices, caregiver's dental beliefs, and caregiver's/toddler's snacking/drinking habits. Logistic regressions and ANOVAs were used to evaluate the associations of questionnaire responses with caregiver's race/ethnicity, income, and education.Results. Caregivers self-identified as Non-Hispanic African-American (44%), Non-Hispanic White (36%), Hispanic (19%), and other” (1%). Differences related to race/ethnicity, income, and education were found in all risk factor categories.Conclusions. Planning of caregiver/patient education/preventive care intervention strategies should be undertaken with these caries risk factor differences kept in mind.
Corporal Punishment of Children in Nine Countries as a Function of Child Gender and Parent Gender
Authors: Lansford Jennifer E. , Alampay Liane Peña , Al-Hassan Suha , Bacchini Dario , Bombi Anna Silvia , Bornstein Marc H. , Chang Lei , Deater-Deckard Kirby , Di Giunta Laura , Dodge Kenneth A. , Oburu Paul , Pastorelli Concetta , Runyan Desmond K. , Skinner Ann T. , Sorbring Emma , Tapanya Sombat , Tirado Liliana Maria Uribe , Zelli Arnaldo
Published: September 2010

Background. The purpose of this paper is to contribute to a global perspective on corporal punishment by examining differences between mothers' and fathers' use of corporal punishment with daughters and sons in nine countries.Methods. Interviews were conducted with 1398 mothers, 1146 fathers, and 1417 children (age range=7to 10 years) in China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand, and the United States.Results. Across the entire sample, 54% of girls and 58% of boys had experienced mild corporal punishment, and 13% of girls and 14% of boys had experienced severe corporal punishment by their parents or someone in their household in the last month. Seventeen percent of parents believed that the use of corporal punishment was necessary to rear the target child. Overall, boys were more frequently punished corporally than were girls, and mothers used corporal punishment more frequently than did fathers. There were significant differences across countries, with reports of corporal punishment use lowest in Sweden and highest in Kenya.Conclusion. This work establishes that the use of corporal punishment is widespread, and efforts to prevent corporal punishment from escalating into physical abuse should be commensurately widespread.
Rapid Increase in Ownership and Use of Long-Lasting Insecticidal Nets and Decrease in Prevalence of Malaria in Three Regional States of Ethiopia (2006-2007)
Authors: Shargie Estifanos Biru , Ngondi Jeremiah , Graves Patricia M. , Getachew Asefaw , Hwang Jimee , Gebre Teshome , Mosher Aryc W. , Ceccato Pietro , Endeshaw Tekola , Jima Daddi , Tadesse Zerihun , Tenaw Eskindir , Reithinger Richard , Emerson Paul M. , Richards Frank O. , Ghebreyesus Tedros Adhanom
Published: September 2010

Following recent large scale-up of malaria control interventions in Ethiopia, this study aimed to compare ownership and use of long-lasting insecticidal nets (LLIN), and the change in malaria prevalence using two population-based household surveys in three regions of the country. Each survey used multistage cluster random sampling with 25 households per cluster. Household net ownership tripled from 19.6% in 2006 to 68.4% in 2007, with mean LLIN per household increasing from 0.3 to 1.2. Net use overall more than doubled from 15.3% to 34.5%, but in households owning LLIN, use declined from 71.7% to 48.3%. Parasitemia declined from 4.1% to 0.4%. Large scale-up of net ownership over a short period of time was possible. However, a large increase in net ownership was not necessarily mirrored directly by increased net use. Better targeting of nets to malaria-risk areas and sustained behavioural change communication are needed to increase and maintain net use.
A Substrate Current Less Control Method for CMOS Integration of Power Bridges
Authors: Krupar Joerg , Hauswald Heiko , Naumann Ronny
Published: September 2010

Modern electronical devices use high integration to decrease device size and cost and to increase reliability. More and more
devices appear that integrate even power devices into VLSI circuits. When driving inductive loads, this is a critical step because
freewheeling at a power device appears. In these applications usually special technologies with extra wells for the power devices,
SOI technologies, or BiCMOS technologies are required to suppress any substrate current. However, the use of these technologies
results in higher production cost for the device. We present a method to control the freewheeling actively. Using this approach we
are able to integrate the power devices using a normal CMOS technology.
Exogenous Cellulase Contributes to Mycoherbicidal Activity ofFusarium arthrosporioidesonOrobanche aegyptiaca
Authors: Babalola Olubukola O.
Published: September 2010

This paper investigates an association between the tubercle size ofOrobanche aegyptiaca, tubercle death, and days to tubercle death in relation to cellulase-assisted mycoherbicide.Fusarium arthrosporioideskilled 56% of tubercles when applied with cellulase compared to 35% when no cellulase was added. Death was inversely correlated with days over the two fungal treatment types.O. aegyptiacatubercle size significantly correlated with the two other infection parameters studied. ForF. arthrosporioides, only 9% () of the variation in days to death was explained by variation in tubercle size, whereas with cellulase it reaches 14%. In this study, mycelia ofF. arthrosporioidesdid not show apparent damage to the tomato roots.
Upper and Lower Solutions Method for a Class of Singular Fractional Boundary Value Problems with p‐Laplacian Operator
Authors: Wang Jinhua , Xiang Hongjun
Published: September 2010

The upper and lower solutions method is used to study the p‐Laplacian fractional boundary value problem , 0 < t < 1, u(0) = 0, u(1) = au(ξ), , and , where 1 < α, γ ⩽ 2, 0 ⩽ a, b ⩽ 1, 0 < ξ, η < 1. Some new results on the existence of at least one positive solution are obtained. It is valuable to point out that the nonlinearity f can be singular at t = 0,1 or u = 0.
Impact of Regular Exercise and Attempted Weight Loss on Quality of Life among Adults with and without Type 2 Diabetes Mellitus
Authors: Green Andrew J. , Fox Kathleen M. , Grandy Susan
Published: September 2010

Objective. To examine the association between exercising regularly and trying to lose weight, and quality of life among individuals with and without type 2 diabetes mellitus (T2DM).Methods. Respondents to the US SHIELD baseline survey reported whether they had tried to lose weight during the previous 12 months and whether they exercised regularly for >6 months. Respondents completed the SF-12 quality-of-life survey one year later. Differences between T2DM respondents (n=2419) and respondents with no diabetes (n=6750) were tested usingt-tests and linear regression models adjusting for demographics, body mass index (BMI), and diabetes status.Results. After adjustment, exercising regularly was significantly associated with higher subsequent physical and mental component scores (P<.001). After adjustment, trying to lose weight was not associated with higher physical component scores (P=.87), but was associated with higher mental component scores (P=.01).Conclusion. Respondents who reported exercising regularly had significantly better physical and mental quality of life, compared with respondents who did not exercise regularly. Despite exercising regularly, respondents with T2DM had significantly worse quality of life, compared with respondents without diabetes who exercised regularly.
PML-RARα and Dnmt3a1 Cooperate in vivo to Promote Acute Promyelocytic Leukemia
Authors: Subramanyam Deepa , Belair Cassandra D. , Barry-Holson Keegan Q. , Lin Haijiang , Kogan Scott C. , Passegué Emmanuelle , Blelloch Robert
Published: September 2010

The PML-RARα oncogene is the central effector of acute promyelocytic leukemia (APL). PML-RARα physically interacts with epigenetic-modifying enzymes including DNA methyltransferases (Dnmt) to suppress critical downstream targets. Here, we show that increased expression of Dnmt3a1 cooperates with PML-RARα in vivo to promote early lethality secondary to myeloid expansion and dysfunction in primary mice. Bone marrow cells from these mice cause leukemogenesis with a shortened latency and a higher penetrance on transplantation into irradiated recipients. Furthermore, leukemic cells overexpressing PML-RARα and Dnmt3a1 display increased methylation at a target promoter compared with PML-RARα or Dnmt3a1 controls. Our findings show a cooperation between the PML-RARα oncogene and the Dnmt3a1 enzyme in vivo and that Dnmt levels can be rate limiting in APL progression. Cancer Res; 70(21); 8792–801. ©2010 AACR.
Histone Methyltransferase MLL1 Regulates MDR1 Transcription and Chemoresistance
Authors: Huo Hairong , Magro Pellegrino G. , Pietsch E. Christy , Patel Brijesh B. , Scotto Kathleen W.
Published: September 2010

The multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of antitumor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such as histone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as the factors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It has also been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone H3 (H3K4). In this study, we further investigated histone methylation in MDR1 regulation and function. We show that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4, is required for MDR1 promoter methylation, as knockdown of MLL1 resulted in a decrease in MDR1 expression. The regulation of MDR1 by MLL1 has functional consequences in that downregulation of MLL1 led to increased retention of the Pgp-specific substrate DIOC2(3), as well as increased cellular sensitivity to several Pgp substrates. Regulation of MDR1 by MLL1 was dependent on the CCAAT box within the proximal MDR1 promoter, similar to what we had shown for MDR1 promoter acetylation, and also requires NF-Y. Finally, overexpression of the most prevalent MLL fusion protein, MLL-AF4, led to increased MDR1 expression. This is the first identification of a histone methyltransferase and its leukemogenic rearrangement that regulates expression of an ABC drug transporter, suggesting a new target for circumvention of tumor multidrug resistance. Cancer Res; 70(21); 8726–35. ©2010 AACR.
Regulation of DNA Polymerase POLD4 Influences Genomic Instability in Lung Cancer
Authors: Huang Qin Miao , Tomida Shuta , Masuda Yuji , Arima Chinatsu , Cao Ke , Kasahara Taka-aki , Osada Hirotaka , Yatabe Yasushi , Akashi Tomohiro , Kamiya Kenji , Takahashi Takashi , Suzuki Motoshi
Published: September 2010

Genomic instability is an important factor in cancer susceptibility, but a mechanistic understanding of how it arises remains unclear. We examined hypothesized contributions of the replicative DNA polymerase δ (pol δ) subunit POLD4 to the generation of genomic instability in lung cancer. In examinations of 158 lung cancers and 5 mixtures of 10 normal lungs, cell cycle- and checkpoint-related genes generally showed mRNA expression increases in cancer, whereas POLD4 showed reduced mRNA in small cell lung cancer (SCLC). A fraction of non–small cell lung cancer patients also showed low expression comparable with that in SCLC, which was associated with poor prognosis. The lung cancer cell line ACC-LC-48 was found to have low POLD4 expression, with higher histone H3K9 methylation and lower acetylation in the POLD4 promoter, as compared with the A549 cell line with high POLD4 expression. In the absence of POLD4, pol δ exhibited impaired in vitro DNA synthesis activity. Augmenting POLD4 expression in cells where it was attenuated altered the sensitivity to the chemical carcinogen 4-nitroquinoline-1-oxide. Conversely, siRNA-mediated reduction of POLD4 in cells with abundant expression resulted in a cell cycle delay, checkpoint activation, and an elevated frequency of chromosomal gap/break formation. Overexpression of an engineered POLD4 carrying silent mutations at the siRNA target site rescued these phenotypes, firmly establishing the role of POLD4 in these effects. Furthermore, POLD4 overexpression reduced intrinsically high induction of γ-H2AX, a well-accepted marker of double-stranded DNA breaks. Together, our findings suggest that reduced expression of POLD4 plays a role in genomic instability in lung cancer. Cancer Res; 70(21); 8407–16. ©2010 AACR.
Tyrosine Phosphorylation Profiling Reveals the Signaling Network Characteristics of Basal Breast Cancer Cells
Authors: Hochgräfe Falko , Zhang Luxi , O'Toole Sandra A. , Browne Brigid C. , Pinese Mark , Porta Cubas Ana , Lehrbach Gillian M. , Croucher David R. , Rickwood Danny , Boulghourjian Alice , Shearer Robert , Nair Radhika , Swarbrick Alexander , Faratian Dana , Mullen Peter , Harrison David J. , Biankin Andrew V. , Sutherland Robert L. , Raftery Mark J. , Daly Roger J.
Published: September 2010

To identify therapeutic targets and prognostic markers for basal breast cancers, breast cancer cell lines were subjected to mass spectrometry–based profiling of protein tyrosine phosphorylation events. This revealed that luminal and basal breast cancer cells exhibit distinct tyrosine phosphorylation signatures that depend on pathway activation as well as protein expression. Basal breast cancer cells are characterized by elevated tyrosine phosphorylation of Met, Lyn, EphA2, epidermal growth factor receptor (EGFR), and FAK, and Src family kinase (SFK) substrates such as p130Cas. SFKs exert a prominent role in these cells, phosphorylating key regulators of adhesion and migration and promoting tyrosine phosphorylation of the receptor tyrosine kinases EGFR and Met. Consistent with these observations, SFK inhibition attenuated cellular proliferation, survival, and motility. Basal breast cancer cell lines exhibited differential responsiveness to small molecule inhibitors of EGFR and Met that correlated with the degree of target phosphorylation, and reflecting kinase coactivation, inhibiting two types of activated network kinase (e.g., EGFR and SFKs) was more effective than single agent approaches. FAK signaling enhanced both proliferation and invasion, and Lyn was identified as a proinvasive component of the network that is associated with a basal phenotype and poor prognosis in patients with breast cancer. These studies highlight multiple kinases and substrates for further evaluation as therapeutic targets and biomarkers. However, they also indicate that patient stratification based on expression/activation of drug targets, coupled with use of multi-kinase inhibitors or combination therapies, may be required for effective treatment of this breast cancer subgroup. Cancer Res; 70(22); 9391–401. ©2010 AACR.
DLC1 Negatively Regulates Angiogenesis in a Paracrine Fashion
Authors: Shih Yi-Ping , Liao Yi-Chun , Lin Yuan , Lo Su Hao
Published: September 2010

The Rho GTPase-activating protein DLC1 is a tumor suppressor that is often deleted in liver cancer and downregulated in other cancers. DLC1 regulates the actin cytoskeleton, cell shape, adhesion, migration, and proliferation through its Rho GTPase-activating protein activity and focal adhesion localization. In this study, we silenced DLC1 in nonmalignant prostate epithelial cells to explore its tumor suppression functions. Small hairpin RNA-mediated silencing of DLC1 was insufficient to promote more aggressive phenotypes associated with tumor cell growth. In contrast, DLC1 silencing promoted pro-angiogenic responses through vascular endothelial growth factor (VEGF) upregulation, accompanied by the accumulation of hypoxia-inducible factor 1α and its nuclear localization. Notably, modulation of VEGF expression by DLC1 was dependent on epidermal growth factor receptor–MAP/ERK kinase–hypoxia-inducible factor 1 signaling but on RhoA pathways. Clinically, VEGF upregulation is a highly significant event in prostate cancers in which DLC1 is downregulated. Thus, our results strongly suggest that loss of DLC1 may serve as a “second hit” in promoting angiogenesis in a paracrine fashion during tumorigenesis. Cancer Res; 70(21); 8270–5. ©2010 AACR.
Maternal Embryonic Leucine Zipper Kinase Is Upregulated and Required in Mammary Tumor-Initiating Cells In vivo
Authors: Hebbard Lionel W. , Maurer Jochen , Miller Amber , Lesperance Jacqueline , Hassell John , Oshima Robert G. , Terskikh Alexey V.
Published: September 2010

Maternal embryonic leucine zipper kinase (MELK) is expressed in several developing tissues, in the adult germ line, and in adult neural progenitors. MELK expression is elevated in aggressive undifferentiated tumors, correlating with poor patient outcome in human breast cancer. To investigate the role of MELK in mammary tumorigenesis in vivo, we used a MELK-green fluorescent protein (GFP) reporter mouse, which allows prospective isolation of MELK-expressing cells based on GFP fluorescence. We found that in the normal mammary gland, cells expressing high levels of MELK were enriched in proliferating cells that express markers of mammary progenitors. The isolation of cells with high levels of MELK in mammary tumors from MMTV-Wnt1/MELK-GFP bitransgenic mice resulted in a significant enrichment of tumorsphere formation in culture and tumor initiation after transplantation into mammary fat pads of syngeneic mice. Furthermore, using lentiviral delivery of MELK-specific shRNA and limiting dilution cell transplantations, we showed that MELK function is required for mammary tumorigenesis in vivo. Our findings identify MELK as a potential target in breast tumor-initiating cells. Cancer Res; 70(21); 8863–73. ©2010 AACR.
Tumor-Reactive CD8+ Early Effector T Cells Identified at Tumor Site in Primary and Metastatic Melanoma
Authors: Anichini Andrea , Molla Alessandra , Vegetti Claudia , Bersani Ilaria , Zappasodi Roberta , Arienti Flavio , Ravagnani Fernando , Maurichi Andrea , Patuzzo Roberto , Santinami Mario , Pircher Hanspeter , Di Nicola Massimo , Mortarini Roberta
Published: September 2010

CD8+ T cells at the earliest stage of effector generation have not been identified at tumor site of melanoma patients. Such early effectors, if present, should be characterized by a specific phenotype, distinct from that expressed at later stages of the antigen-induced differentiation program, by short-lived effector cells, memory precursors, and terminal effectors. Here, we show that neoplastic tissues from primary and metastatic lesions of melanoma patients contain a subset of CD8+ T cells expressing FOXP3. CD8+ FOXP3+ CD25+ T lymphocytes were found in tumor-invaded lymph nodes (TILN), s.c. metastases, and advanced primary lesions. Their frequency was significantly higher in TILN compared with tumor-free lymph nodes or with peripheral blood and in primary tumors compared with TILN. CD8+ FOXP3+ T cells did not express markers of regulatory [CTLA-4, CCL4, interleukin-10 (IL-10), transforming growth factor-β1], exhausted (PD-1), or senescent (CD57) CD8+ T lymphocytes. Instead, this subset showed an antigen-experienced “EM1” phenotype (CCR7− CD45RA− CD28+ CD27+) and exhibited a CD127−, KLRG1−, HLA-DR+, CD38+, T-bet+, perforin+ “early effector” profile predicted by current models. CD8+ FOXP3+ T cells produced IFN-γ on short in vitro activation, recognized autologous tumor by CD107a mobilization, and expressed Ki-67 on ex vivo analysis. In response to autologous tumor plus IL-2/IL-15, the CD8+ FOXP3+ T cells proliferated promptly and showed competence for differentiation (downregulation of CD27 and upregulation of T-bet). These results suggest development of early phases of antitumor immunity even in advanced melanoma. Moreover, the CD8+ FOXP3+ “early effector” subset may be an invaluable tool for monitoring immunity at tumor site. Cancer Res; 70(21); 8378–87. ©2010 AACR.