bluuebunny/crossref_metadata_2025 huggingface dataset:
CCL26/eotaxin-3 is more effective to induce the migration of eosinophils of asthmatics than CCL11/eotaxin-1 and CCL24/eotaxin-2
Authors: Provost Véronique , Larose Marie-Chantal , Langlois Anick , Rola-Pleszczynski Marek , Flamand Nicolas , Laviolette Michel
Published: March 2013

CCL11, CCL24, and CCL26 are chemokines involved in the recruitment of eosinophils into tissues and mainly activate CCR3. Whereas the genomic or pharmacological inhibition of CCR3 prevents the development of experimental asthma in rodents, it only impairs the recruitment of eosinophils by ∼40% in humans. As humans, but not rodents, express CCL26, we investigated the impact of CCL11, CCL24, and CCL26 on human eosinophils recruitment and evaluated the involvement of CCR3. The migration of eosinophils of healthy volunteers was similar for the three eotaxins. Eosinophils of mild asthmatics had a greater response to CCL11 and a much greater response to CCL26. Whereas all eotaxins induced the migration of eosinophil of asthmatics from 0 to 6 h, CCL26 triggered a second phase of migration between 12 and 18 h. Given that the CCR3 antagonists SB 328437 and SB 297006 inhibited the 5-oxo-eicosatetraenoate-induced migration of eosinophils and that the CCR3 antagonist UCB 35625 was not specific for CCR3, CCR3 blockade was performed with the CCR3 mAb. This antibody completely blocked the effect of all eotaxins on eosinophils of healthy subjects and the effect of CCL24 on the eosinophils of asthmatics. Interestingly, CCR3 blockade did not affect the second migration phase induced by CCL26 on eosinophils of asthmatics. In conclusion, CCL26 is a more effective chemoattractant than CCL11 and CCL24 for eosinophils of asthmatics. The mechanism of this greater efficiency is not yet defined. However, these results suggest that CCL26 may play a unique and important role in the recruitment of eosinophils in persistent asthma.
Neutrophils in local and systemic antibody-dependent inflammatory and anaphylactic reactions
Authors: Jönsson Friederike , Mancardi David A , Albanesi Marcello , Bruhns Pierre
Published: March 2013

Neutrophils are notorious for their efficacy in microbial killing. Various mechanisms, such as phagocytosis, production of ROS, cytokines/chemokines and lipid mediators, degranulation of antimicrobials and enzymes, as well as NETosis contribute to this capacity. However, every incidence of neutrophil activation bears a risk to cause damage to the host. Several distinct steps, i.e., adhesion to endothelial cells, transmigration, chemotaxis, cytokine stimulation, and TLR signaling, are thought to control the extent of neutrophil activation. In the absence of a microbial stimulus, other pathways can induce neutrophil activation, among which FcR-induced activation when neutrophils encounter ICs. In these situations (inflammation, autoimmunity, allergy), neutrophils may act as primary or secondary effectors of immune reactions. In the presence of circulating ICs, neutrophils can indeed get stimulated directly in the bloodstream and trigger an immune response. Upon deposition of antibody complexes inside of tissues, neutrophils are first recruited and primed before being highly activated to amplify the ongoing inflammation. This review focuses on the engagement, activation, and responses of neutrophils to antibody ICs, inside of tissues or in the vasculature.
Impact of ocean acidification on metabolism and energetics during early life stages of the intertidal porcelain crab Petrolisthes cinctipes
Authors: Carter Hayley A. , Ceballos-Osuna Lina , Miller Nathan A. , Stillman Jonathon H.
Published: March 2013

Absorption of elevated atmospheric CO2 is causing surface ocean pH to decline, a process known as ocean acidification (OA). To date, few studies have assessed the physiological impacts of OA on early life-history stages of intertidal organisms, which transition from habitats with fluctuating pH (intertidal zone) to relatively stable (pelagic zone) pH environments. We used the intertidal crab Petrolisthes cinctipes to determine whether metabolic responses to year 2300 predictions for OA vary among early developmental stages and to examine whether the effects were more pronounced in larval stages developing in the open ocean. Oxygen consumption rate, total protein, dry mass, total lipids and C/N were determined in late-stage embryos, zoea I larvae and newly settled juveniles reared in ambient pH (7.93±0.06) or low pH (7.58±0.06). After short-term exposure to low pH, embryos displayed 11% and 6% lower metabolism and dry mass, respectively, which may have an associated bioenergetic cost of delayed development to hatching. However, metabolic responses appeared to vary among broods, suggesting significant parental effects among the offspring of six females, possibly a consequence of maternal state during egg deposition and genetic differences among broods. Larval and juvenile metabolism were not affected by acute exposure to elevated CO2. Larvae contained 7% less nitrogen and C/N was 6% higher in individuals reared at pH 7.58 for 6 days, representing a possible switch from lipid to protein metabolism under low pH; the metabolic switch appears to fully cover the energetic cost of responding to elevated CO2. Juvenile dry mass was unaffected after 33 days exposure to low pH seawater. Increased tolerance to low pH in zoea I larvae and juvenile stages may be a consequence of enhanced acid–base regulatory mechanisms, allowing greater compensation of extracellular pH changes and thus preventing decreases in metabolism after exposure to elevated PCO2. The observed variation in responses of P. cinctipes to decreased pH in the present study suggests the potential for this species to adapt to future declines in near-shore pH.
Effect of stress on female-specific ornamentation
Authors: Weiss Stacey L. , Mulligan Emily E. , Wilson Dawn , Kabelik David
Published: March 2013

Signal honesty is theorized to be maintained by condition-dependent trait expression. However, the mechanisms mediating the condition-dependence of sexually selected traits are often unknown. New work suggests that elevated glucocorticoid levels during physiological stress may play a role in maintaining signal honesty. Here, we experimentally examine the effect of both chronic and acute stress on the expression of the condition-dependent ornamentation of female striped plateau lizards, Sceloporus virgatus. Females were stressed either chronically via corticosterone implants or relatively acutely via autotomy, were sham manipulated or were left unmanipulated. Both stressors resulted in elevations in corticosterone within physiologically relevant levels, though the implants resulted in significantly higher levels than did autotomy. Corticosterone-implanted females were less likely to produce a clutch of eggs, but those individuals that did reproduce had similar reproductive output to females from other treatment groups. Compared to females in other groups, the corticosterone-implanted females tended to develop smaller ornaments that had less UV and orange-to-red wavelength reflectance relative to medium wavelength reflectance. The sex steroid hormones testosterone and estradiol were correlated to corticosterone levels, but did not appear to underlie the effect on ornament expression; of the steroids measured, only corticosterone levels were negatively related to ornament size and coloration. Thus, the condition-dependent ornamentation of female lizards is sensitive to chronic elevations in stress hormones, supporting their importance in the maintenance of signal honesty.
Defense through sensory inactivation: sea hare ink reduces sensory and motor responses of spiny lobsters to food odors
Authors: Love-Chezem Tiffany , Aggio Juan F. , Derby Charles D.
Published: March 2013

Antipredator defenses are ubiquitous and diverse. Ink secretion of sea hares (Aplysia) is an antipredator defense acting through the chemical senses of predators by different mechanisms. The most common mechanism is ink acting as an unpalatable repellent. Less common is ink secretion acting as a decoy (phagomimic) that misdirects predators' attacks. In this study, we tested another possible mechanism – sensory inactivation – in which ink inactivates the predator's reception of food odors associated with would-be prey. We tested this hypothesis using spiny lobsters, Panulirus argus, as model predators. Ink secretion is composed of two glandular products, one being opaline, a viscous substance containing concentrations of hundreds of millimolar of total free amino acids. Opaline sticks to antennules, mouthparts and other chemosensory appendages of lobsters, physically blocking access of food odors to the predator's chemosensors, or over-stimulating (short term) and adapting (long term) the chemosensors. We tested the sensory inactivation hypotheses by treating the antennules with opaline and mimics of its physical and/or chemical properties. We compared the effects of these treatments on responses to a food odor for chemoreceptor neurons in isolated antennules, as a measure of effect on chemosensory input, and for antennular motor responses of intact lobsters, as a measure of effect on chemically driven motor behavior. Our results indicate that opaline reduces the output of chemosensors by physically blocking reception of and response to food odors, and this has an impact on motor responses of lobsters. This is the first experimental demonstration of inactivation of peripheral sensors as an antipredatory defense.
The physiological response of the marine platyhelminthMacrostomum lignanoto different environmental oxygen concentrations
Authors: Rivera-Ingraham Georgina A. , Bickmeyer Ulf , Abele Doris
Published: March 2013

Respiration rate of meiofauna is difficult to measure, and the response to variations in the environmental oxygen concentrations has so far been mainly addressed through behavioral investigation. We investigated the effect of different oxygen concentrations on the physiology of the marine platyhelminth Macrostomum lignano. Respiration was measured using batches of 20 animals in a glass microtiter plate equipped with optical oxygen sensor spots. At higher oxygen saturations (>12kPa), animals showed a clear oxyconforming behavior. However, below this values, the flatworms kept respiration rates constant at 0.064±0.001 nmol O2 l-1 h-1 ind-1 down to 3 kPa PO2, and this rate was increased in 30% in animals that were reoxygenated after enduring a period of 1.5h in anoxia. Physiological changes related to tissue oxygenation were assessed using live imaging techniques with different fluorophores in animals maintained in normoxic (21 kPa), hyperoxic (40 kPa), near anoxic (≈0 kPa) conditions and subjected to anoxia-reoxygenation. Ageladine-A and BCECF both indicated that pHi under near anoxia increases by about 0.07 to 0.10 units. Mitochondrial membrane potential, Δψm, was higher in anoxic and hyperoxic compared to normoxic conditions (JC1). Staining with ROS sensitive dyes, DHE for detection of superoxide anion (O2•-) formation and C-H2DFFDA for other ROS species aside from O2•- (H2O2, HOO• and ONOO-), both showed increased ROS formation following anoxia reoxygenation treatment. Animals exposed to hyperoxic, normoxic and anoxic treatments displayed no significant differences in O2•- formation, whereas mitochondrial ROS formation as detected by C-H2DFFDA was higher after hyperoxic exposure and lowest under near anoxia compared to the normoxic control group. M. lignano seems to be a species tolerant to a wide range of oxygen concentrations (being able to maintain aerobic metabolism from extremely low PO2 and up to hyperoxic conditions) which is an essential prerequisite for successfully dealing with the drastic environmental oxygen variations that occur within intertidal sediments.
Environmental salinity modulates the effects of elevated CO2 levels on juvenile hard shell clams, Mercenaria mercenaria
Authors: Dickinson Gary H. , Matoo Omera B. , Tourek Robert T. , Sokolova Inna M. , Beniash Elia
Published: March 2013

Ocean acidification due to increasing atmospheric CO2 concentrations results in a decrease in seawater pH and shifts in the carbonate chemistry that can negatively affect marine organisms. Marine bivalves such as the hard shell clams Mercenaria mercenaria serve as ecosystem engineers in estuaries and coastal zones of the western Atlantic and, as for many marine calcifiers, are sensitive to the impacts of ocean acidification. In estuaries, the effects of ocean acidification can be exacerbated by low buffering capacity of brackish waters, acidic inputs from freshwaters and land, and/or the negative effects of salinity on organisms’ physiology. We determined the interactive effects of 21 weeks of exposure to different levels of CO2 (~395, 800 and 1500 µatm corresponding to pH of 8.2, 8.1 and 7.7 respectively) and salinity (32 vs. 16) on biomineralization, shell properties and energy metabolism of juveniles of the hard shell clam M. mercenaria. Low salinity had profound effects on survival, energy metabolism and biomineralization of hard shell clams and modulated their responses to elevated PCO2. Negative effects of low salinity in juvenile clams were mostly due to the strongly elevated basal energy demand indicating energy deficiency that led to reduced growth, elevated mortality and impaired shell maintenance (evidenced by the extensive damage to the periostracum). The effects of elevated PCO2 on physiology and biomineralization of hard shell clams were more complex. Elevated PCO2 (~800-1500 µatm) had no significant effects on standard metabolic rates (indicative of the basal energy demand), but affected growth and shell mechanical properties in juvenile clams. Moderate hypercapnia (~800 µatm PCO2) increased shell and tissue growth and reduced mortality of juvenile clams in high salinity exposures; however, these effects were abolished under the low salinity conditions or at high PCO2 (~1500 µatm). Mechanical properties of the shell (measured as microhardness and fracture toughness of the shells) were negatively affected by elevated CO2 alone or in combination with low salinity, which may have important implications for protection against predators or environmental stressors. Our data indicate that environmental salinity can strongly modulate responses to ocean acidification in hard shell clams and thus should be taken into account when predicting the effects of ocean acidification on estuarine bivalves.
Immune response to an endotoxin challenge involves multiple immune parameters and is consistent among the annual-cycle stages of a free-living temperate zone bird
Authors: Hegemann Arne , Matson Kevin D. , Versteegh Maaike A. , Villegas Auxiliadora , Tieleman B. Irene
Published: March 2013

Trade-offs between immune function and other physiological and behavioral processes are central in ecoimmunology, but one important problem is how to distinguish a reallocation of resources away from the immune system from a reallocation or redistribution within the immune system. While variation in baseline values of individual immune parameters is well established, studies in wild animals on multiple parameters during an immune response are lacking. It also remains to be tested if and how immune responses correlate with baseline values that vary e.g. over the course of an annual cycle. We studied immunological responses to an endotoxin challenge in skylarks (Alauda arvensis), a partial migrant bird breeding in temperate zones. We compared birds injected with the endotoxin LPS with un-injected controls, characterizing immunological responses with leukocyte profiles, titres of lytic enzymes and natural antibodies, and concentrations of haptoglobin and heat shock proteins. We did this in five annual-cycle stages to test if the response varied throughout the year. The endotoxin challenge affected 6 of 10 measured parameters. Lysis titers and proportions of heterophils increased; haptoglobin concentrations and proportions of lymphocytes, basophils and eosinophils decreased. The variable effects on different immune components demonstrate the complexity of an immune response. We found no evidence that the response differed between annual-cycle stages. The response was independent of baseline measures taken directly upon capture in the field, indicating that birds were facing no immunological ceiling when mounting an immune response. Values of five parameters collected under field conditions were significantly related to values taken under standardised lab conditions. We conclude that multiple parts of the immune system are modulated during an immunological response and that responses are not re-organised throughout the annual cycle.
Flight performance of western sandpipers Calidris mauri remains uncompromised when mounting an acute phase immune response
Authors: Nebel Silke , Buehler Deborah M. , MacMillan Alexander , Guglielmo Christopher G.
Published: March 2013

Migratory birds have been implicated in the spread of some zoonotic diseases, but how well infected individuals can fly remains poorly understood. We used western sandpipers Calidris mauri to experimentally test whether flight is affected when long-distance migrants are mounting an immune response and whether migrants maintain immune defences during a flight in a wind tunnel. We measured five indicators of innate immunity in ‘flown-healthy’ birds (flying in a wind tunnel without mounting an immune response),’flown-sick’ birds (flying while mounting an acute phase response, which is part of induced innate immunity), and a non-flying control group. Voluntary flight duration did not differ between ‘flown-healthy’ and ‘flown-sick’ birds, indicating that mounting an acute phase response to simulated infection did not hamper an individual’s ability to fly for up to three hours. However, in comparison to ‘not flown’ birds bacterial killing ability of plasma was significantly reduced after flight in ‘flown-sick’ birds. In ‘flown-healthy’ birds, voluntary flight duration was positively correlated with bacterial killing ability and baseline haptoglobin concentration of the blood plasma measured 1 - 3 weeks before experimental flights, suggesting that high quality birds had strong immune systems and greater flight capacity. Our findings indicate that flight performance is not diminished by prior immune challenge, but that flight while mounting an acute phase response negatively affects other aspects of immune function. These findings have important implications for our understanding of the transmission of avian diseases, as they suggest that birds can still migrate while fighting an infection.
Input Sourcing and Multinational Production
Authors: Garetto Stefania
Published: March 2013

I propose a general equilibrium framework where firms decide whether to outsource or integrate input manufacturing, domestically or abroad. By outsourcing, firms may benefit from suppliers' technologies, but pay mark-up prices. By sourcing intrafirm, they save on mark-ups and pay possibly lower foreign wages. Multinational corporations arise when firms integrate production abroad. The model predicts that intrafirm imports are positively correlated with the mean and variance of the firms' productivity distribution and with the degree of input differentiation. I use the model to quantify the US welfare gains from intrafirm trade, which amount to about 0.23 percent of consumption per-capita. (JEL D21, F12, F23, F41, L11, L24)
Importing Skill-Biased Technology
Authors: Burstein Ariel , Cravino Javier , Vogel Jonathan
Published: March 2013

The production of capital equipment is concentrated among a small group of countries, and many countries import a large share of their equipment. If capital-skill complementarity is an important feature of technology, international trade may have important effects on the skill premium through its impact on equipment accumulation. In this paper we propose a tractable framework for evaluating this effect, provide simple analytic expressions linking observable changes in import shares by sector to changes in real wages of skilled and unskilled workers (and, therefore, the skill premium), and quantify the importance of this effect for a large set of countries. (JEL E22, F11, F16, J24, L64)
Correlation between miRNA-targeted-gene promoter methylation and miRNA regulation of target genes
Authors: Taguchi Y-h
Published: March 2013

BackgroundmiRNA regulation of target genes and promoter methylation are known to be the primary mechanisms underlying the epigenetic regulation of gene expression. However, how these two processes cooperatively regulate gene expression has not been extensively studied. 

MethodsGene expression and promoter methylation profiles of 271 distinct human cell lines were obtained from gene expression omnibus. P-values that describe both miRNA-targeted-gene promoter methylaion and miRNA regulation of target genes were computed using the MiRaGE method proposed recently by the author.

Results Significant changes in promoter methylation were associated with miRNA targeting. It was also found that miRNA-targeted-gene promoter hypomethylation was related to differential target gene expression; the genes with miRNA-targeted-gene promoter hypomethylation were downregulated during cell senescence and upregulated during cellular differentiation. Promoter hypomethylation was especially enhanced for genes targeted by miR-548 miRNAs, which are non-conserved, primate-specific miRNAs that are typically expressed at lower levels than the frequently investigated conserved miRNAs.

ConclusionsIt was found that promoter methylation was affected by miRNA targeting. Furthermore, miRNA-targeted-gene promoter hypomethylation is suggested to facilitate gene regulation by miRNAs that are not strongly expressed (e.g., miR-548 miRNAs).
Synthesis of complex oxygenated heterocycles
Authors: Nicolas Lionel , Butkevich Alexey N. , Guérinot Amandine , Corbu Andrei , Reymond Sébastien , Cossy Janine
Published: March 2013

Versatile and chemoselective preparation of substituted oxygenated heterocycles is described. Highly diastereoselective metal-catalyzed syntheses of trans-2,6- and cis-2,6-disubstituted tetrahydropyrans (THPs) are presented, along with an easy one-pot access to various ring size benzoannulated spiroketals.
Parsing the Phonological Loop: Activation Timing in the Dorsal Speech Stream Determines Accuracy in Speech Reproduction
Authors: Herman Alexander B. , Houde John F. , Vinogradov Sophia , Nagarajan Srikantan S.
Published: March 2013

Despite significant research and important clinical correlates, direct neural evidence for a phonological loop linking speech perception, short-term memory and production remains elusive. To investigate these processes, we acquired whole-head magnetoencephalographic (MEG) recordings from human subjects performing a variable-length syllable sequence reproduction task. The MEG sensor data were source localized using a time–frequency optimized spatially adaptive filter, and we examined the time courses of cortical oscillatory power and the correlations of oscillatory power with behavior between onset of the audio stimulus and the overt speech response. We found dissociations between time courses of behaviorally relevant activations in a network of regions falling primarily within the dorsal speech stream. In particular, verbal working memory load modulated high gamma power in both Sylvian–parietal–temporal and Broca's areas. The time courses of the correlations between high gamma power and subject performance clearly alternated between these two regions throughout the task. Our results provide the first evidence of a reverberating input–output buffer system in the dorsal stream underlying speech sensorimotor integration, consistent with recent phonological loop, competitive queuing, and speech–motor control models. These findings also shed new light on potential sources of speech dysfunction in aphasia and neuropsychiatric disorders, identifying anatomically and behaviorally dissociable activation time windows critical for successful speech reproduction.
Simultaneous Monitoring of Presynaptic Transmitter Release and Postsynaptic Receptor Trafficking Reveals an Enhancement of Presynaptic Activity in Metabotropic Glutamate Receptor-Mediated Long-Term Depression
Authors: Xu Wei , Tse Yiu Chung , Dobie Frederick A. , Baudry Michel , Craig Ann Marie , Wong Tak Pan , Wang Yu Tian
Published: March 2013

Although the contribution of postsynaptic mechanisms to long-term synaptic plasticity has been studied extensively, understanding the contribution of presynaptic modifications to this process lags behind, primarily because of a lack of techniques with which to directly and quantifiably measure neurotransmitter release from synaptic terminals. Here, we developed a method to measure presynaptic activity through the biotinylation of vesicular transporters in vesicles fused with presynaptic membranes during neurotransmitter release. This method allowed us for the first time to selectively quantify the spontaneous or evoked release of glutamate or GABA at their respective synapses. Using this method to investigate presynaptic changes during the expression of group I metabotropic glutamate receptor (mGluR1/5)-mediated long-term depression (LTD) in cultured rat hippocampal neurons, we discovered that this form of LTD was associated with increased presynaptic release of glutamate, despite reduced miniature EPSCs measured with whole-cell recording. Moreover, we found that specific blockade of AMPA receptor (AMPAR) endocytosis with a membrane-permeable GluR2-derived peptide not only prevented the expression of LTD but also eliminated LTD-associated increase in presynaptic release. Thus, our work not only demonstrates that mGluR1/5-mediated LTD is associated with increased endocytosis of postsynaptic AMPARs but also reveals an unexpected homeostatic/compensatory increase in presynaptic release. In addition, this study indicates that biotinylation of vesicular transporters in live cultured neurons is a valuable tool for studying presynaptic function.
Variability of Human Corticospinal Excitability Tracks the State of Action Preparation
Authors: Klein-Flügge Miriam C. , Nobbs David , Pitcher Julia B. , Bestmann Sven
Published: March 2013

Task-evoked trial-by-trial variability is a ubiquitous property of neural responses, yet its functional role remains largely unclear. Recent work in nonhuman primates shows that the temporal structure of neural variability in several brain regions is task-related. For example, trial-by-trial variability in premotor cortex tracks motor preparation with increasingly consistent firing rates and thus a decline in variability before movement onset. However, whether noninvasive measures of the variability of population activity available from humans can similarly track the preparation of actions remains unknown. We tested this by using single-pulse transcranial magnetic stimulation (TMS) over primary motor cortex (M1) to measure corticospinal excitability (CSE) at different times during action preparation. First, we established the basic properties of intrinsic CSE variability at rest. Then, during the task, responses (left or right button presses) were either directly instructed (forced choice) or resulted from a value decision (choice). Before movement onset, we observed a temporally specific task-related decline in CSE variability contralateral to the responding hand. This decline was stronger in fast-response compared with slow-response trials, consistent with data in nonhuman primates. For the nonresponding hand, CSE variability also decreased, but only in choice trials, and earlier compared with the responding hand, possibly reflecting choice-specific suppression of unselected actions. These findings suggest that human CSE variability measured by TMS over M1 tracks the state of motor preparation, and may reflect the optimization of preparatory population activity. This provides novel avenues in humans to assess the dynamics of action preparation but also more complex processes, such as choice-to-action transformations.
Interhemispheric Functional Connectivity following Prenatal or Perinatal Brain Injury Predicts Receptive Language Outcome
Authors: Dick Anthony Steven , Raja Beharelle Anjali , Solodkin Ana , Small Steven L.
Published: March 2013

Early brain injury alters both structural and functional connectivity between the cerebral hemispheres. Despite increasing knowledge on the individual hemispheric contributions to recovery from such injury, we know very little about how their interactions affect this process. In the present study, we related interhemispheric structural and functional connectivity to receptive language outcome following early left hemisphere stroke. We used functional magnetic resonance imaging to study 14 people with neonatal brain injury, and 25 age-matched controls during passive story comprehension. With respect to structural connectivity, we found that increased volume of the corpus callosum predicted good receptive language outcome, but that this is not specific to people with injury. In contrast, we found that increased posterior superior temporal gyrus interhemispheric functional connectivity during story comprehension predicted better receptive language performance in people with early brain injury, but worse performance in typical controls. This suggests that interhemispheric functional connectivity is one potential compensatory mechanism following early injury. Further, this pattern of results suggests refinement of the prevailing notion that better language outcome following early left hemisphere injury relies on the contribution of the contralesional hemisphere (i.e., the “right-hemisphere-take-over” theory). This pattern of results was also regionally specific; connectivity of the angular gyrus predicted poorer performance in both groups, independent of brain injury. These results present a complex picture of recovery, and in some cases, such recovery relies on increased cooperation between the injured hemisphere and homologous regions in the contralesional hemisphere, but in other cases, the opposite appears to hold.
Axonal Translation of β-Catenin Regulates Synaptic Vesicle Dynamics
Authors: Taylor Anne Marion , Wu Jason , Tai Hwan-Ching , Schuman Erin M.
Published: March 2013

Many presynaptic transcripts have been observed in axons, yet their role in synapse development remains unknown. Using visually and pharmacologically isolated presynaptic terminals from dissociated rat hippocampal neurons, we found that ribosomes and β-catenin mRNA preferentially localize to recently formed boutons. Locally translated β-catenin accumulates at presynaptic terminals, where it regulates synaptic vesicle release dynamics. Thus, local translation of β-catenin is a newly described mechanism for axons to independently functionalize nerve terminals at great distances from cellular somata.
A Novel Growth-Promoting Pathway Formed by GDNF-Overexpressing Schwann Cells Promotes Propriospinal Axonal Regeneration, Synapse Formation, and Partial Recovery of Function after Spinal Cord Injury
Authors: Deng Ling-Xiao , Deng Ping , Ruan Yiwen , Xu Zao Cheng , Liu Nai-Kui , Wen Xuejun , Smith George M. , Xu Xiao-Ming
Published: March 2013

Descending propriospinal neurons (DPSN) are known to establish functional relays for supraspinal signals, and they display a greater growth response after injury than do the long projecting axons. However, their regenerative response is still deficient due to their failure to depart from growth supportive cellular transplants back into the host spinal cord, which contains numerous impediments to axon growth. Here we report the construction of a continuous growth-promoting pathway in adult rats, formed by grafted Schwann cells overexpressing glial cell line-derived neurotrophic factor (GDNF). We demonstrate that such a growth-promoting pathway, extending from the axonal cut ends to the site of innervation in the distal spinal cord, promoted regeneration of DPSN axons through and beyond the lesion gap of a spinal cord hemisection. Within the distal host spinal cord, regenerated DPSN axons formed synapses with host neurons leading to the restoration of action potentials and partial recovery of function.
Schwann Cell LRP1 Regulates Remak Bundle Ultrastructure and Axonal Interactions to Prevent Neuropathic Pain
Authors: Orita Sumihisa , Henry Kenneth , Mantuano Elisabetta , Yamauchi Kazuyo , De Corato Alice , Ishikawa Tetsuhiro , Feltri M. Laura , Wrabetz Lawrence , Gaultier Alban , Pollack Melanie , Ellisman Mark , Takahashi Kazuhisa , Gonias Steven L. , Campana W. Marie
Published: March 2013

Trophic support and myelination of axons by Schwann cells in the PNS are essential for normal nerve function. Herein, we show that deletion of the LDL receptor-related protein-1 (LRP1) gene in Schwann cells (scLRP1−/−) induces abnormalities in axon myelination and in ensheathment of axons by nonmyelinating Schwann cells in Remak bundles. These anatomical changes in the PNS were associated with mechanical allodynia, even in the absence of nerve injury. In response to crush injury, sciatic nerves in scLRP1−/−mice showed accelerated degeneration and Schwann cell death. Remyelinated axons were evident 20 d after crush injury in control mice, yet were largely absent in scLRP1−/−mice. In the partial nerve ligation model, scLRP1−/−mice demonstrated significantly increased and sustained mechanical allodynia and loss of motor function. Evidence for central sensitization in pain processing included increased p38MAPK activation and activation of microglia in the spinal cord. These studies identify LRP1 as an essential mediator of normal Schwann cell–axonal interactions and as a pivotal regulator of the Schwann cell response to PNS injuryin vivo. Mice in which LRP1 is deficient in Schwann cells represent a model for studying how abnormalities in Schwann cell physiology may facilitate and sustain chronic pain.
Nitric Oxide Synthesis and cGMP Production Is Important for Neurite Growth and Synapse Remodeling after Axotomy
Authors: Cooke Ria M. , Mistry Rajendra , Challiss R.A. John , Straub Volko A.
Published: March 2013

Nitric oxide (NO) is an important signaling molecule with a variety of functions in the CNS, including a potential role in modulating neuronal growth and synapse formation. In the present study, we used tractable, identified neurons in the CNS of the pond snailLymnaea stagnalisto study the role of endogenous NO signaling in neuronal growth and synaptic remodeling after nerve injury. Axonal damage ofL. stagnalisneurons B1 and B2 induces extensive central growth of neurites that is accompanied by changes in existing electrical connections, the transient formation of novel electrical connections, and the formation of a novel excitatory chemical synapse from B2 to B1 neurons. Partial chronic inhibition of endogenous NO synthesis reduces neurite growth in NO-synthase-expressing B2, but has only minor effects on NOS-negative B1 neurons. Chronic application of an NO donor while inhibiting endogenous NO synthesis rescues neurite extension in B2 neurons and boosts growth of B1 neurons. Blocking soluble guanylate cyclase activity completely suppresses neurite extension and synaptic remodeling after nerve crush, demonstrating the importance of cGMP in these processes. Interestingly, inhibition of cGMP-dependent protein kinase only suppresses chemical synapse formation without effects on neuronal growth and electrical synapse remodeling. We conclude that NO signaling via cGMP is an important modulator of both neurite growth and synaptic remodeling after nerve crush. However, differential effects of cGMP-dependent protein kinase inhibition on neurite growth and synaptic remodeling suggest that these effects are mediated by separate signaling pathways.
The Countermanding Task Revisited: Fast Stimulus Detection Is a Key Determinant of Psychophysical Performance
Authors: Salinas Emilio , Stanford Terrence R.
Published: March 2013

The countermanding task is a standard method for assessing cognitive/inhibitory control over action and for investigating its neural correlates. In it, the subject plans a movement and either executes it, if no further instruction is given, or attempts to prevent it, if a stop signal is shown. Through various experimental manipulations, many studies have sought to characterize the inhibitory mechanisms thought to be at work in the task, typically using an inferred, model-dependent metric called the stop-signal reaction time. This approach has consistently overlooked the impact of perceptual evaluation on performance. Through analytical work and computer simulations, here we show that psychophysical performance in the task can be easily understood as the result of an ongoing motor plan that is modified (decelerated) by the outcome of a rapid sensory detection process. Notably, no specific assumptions about hypothetical inhibitory mechanisms are needed. This modeling framework achieves four things: (1) it replicates and reconciles behavioral results in numerous variants of the countermanding task; (2) it provides a new, objective metric for characterizing task performance that is more effective than the stop-signal reaction time; (3) it shows that the time window over which detection of a high-visibility stimulus effectively occurs is extremely short (∼20 ms); and (4) it indicates that modulating neuronal latencies and the buildup rates of developing motor plans are two key neural mechanisms for controlling action. The results suggest that manipulations of the countermanding task often cause changes in perceptual detection processes, and not necessarily in inhibition.
Retinoic Acid Deficiency Impairs the Vestibular Function
Authors: Romand Raymond , Krezel Wojciech , Beraneck Mathieu , Cammas Laura , Fraulob Valérie , Messaddeq Nadia , Kessler Pascal , Hashino Eri , Dollé Pascal
Published: March 2013

The retinaldehyde dehydrogenase 3 (Raldh3) gene encodes a major retinoic acid synthesizing enzyme and is highly expressed in the inner ear during embryogenesis. We found that mice deficient inRaldh3bear severe impairment in vestibular functions. These mutant mice exhibited spontaneous circling/tilted behaviors and performed poorly in several vestibular–motor function tests. In addition, video-oculography revealed a complete loss of the maculo-ocular reflex and a significant reduction in the horizontal angular vestibulo-ocular reflex, indicating that detection of both linear acceleration and angular rotation were compromised in the mutants. Consistent with these behavioral and functional deficiencies, morphological anomalies, characterized by a smaller vestibular organ with thinner semicircular canals and a significant reduction in the number of otoconia in the saccule and the utricle, were consistently observed in theRaldh3mutants. The loss of otoconia in the mutants may be attributed, at least in part, to significantly reduced expression ofOtop1, which encodes a protein known to be involved in calcium regulation in the otolithic organs. Our data thus reveal a previously unrecognized role ofRaldh3in structural and functional development of the vestibular end organs.
Uncertainty Increases Pain: Evidence for a Novel Mechanism of Pain Modulation Involving the Periaqueductal Gray
Authors: Yoshida Wako , Seymour Ben , Koltzenburg Martin , Dolan Raymond J.
Published: March 2013

Predictions about sensory input exert a dominant effect on what we perceive, and this is particularly true for the experience of pain. However, it remains unclear what component of prediction, from an information-theoretic perspective, controls this effect. We used a vicarious pain observation paradigm to study how the underlying statistics of predictive information modulate experience. Subjects observed judgments that a group of people made to a painful thermal stimulus, before receiving the same stimulus themselves. We show that the mean observed rating exerted a strong assimilative effect on subjective pain. In addition, we show that observed uncertainty had a specific and potent hyperalgesic effect. Using computational functional magnetic resonance imaging, we found that this effect correlated with activity in the periaqueductal gray. Our results provide evidence for a novel form of cognitive hyperalgesia relating to perceptual uncertainty, induced here by vicarious observation, with control mediated by the brainstem pain modulatory system.
The Cellular Code for Mammalian Thermosensation
Authors: Pogorzala Leah A. , Mishra Santosh K. , Hoon Mark A.
Published: March 2013

Mammalian somatosenory neurons respond to thermal stimuli and allow animals to reliably discriminate hot from cold and to select their preferred environments. Previously, we generated mice that are completely insensitive to temperatures from noxious cold to painful heat (−5 to 55°C) by ablating several different classes of nociceptor early in development. In the present study, we have adopted a selective ablation strategy in adult mice to study this phenotype and have demonstrated that separate populations of molecularly defined neurons respond to hot and cold. TRPV1-expressing neurons are responsible for all behavioral responses to temperatures between 40 and 50°C, whereas TRPM8 neurons are required for cold aversion. We also show that more extreme cold and heat activate additional populations of nociceptors, including cells expressing Mrgprd. Therefore, although eliminating Mrgprd neurons alone does not affect behavioral responses to temperature, when combined with ablation of TRPV1 or TRPM8 cells, it significantly decreases responses to extreme heat and cold, respectively. Ablation of TRPM8 neurons distorts responses to preferred temperatures, suggesting that the pleasant thermal sensation of warmth may in fact just reflect reduced aversive input from TRPM8 and TRPV1 neurons. As predicted by this hypothesis, mice lacking both classes of thermosensor exhibited neither aversive nor attractive responses to temperatures between 10 and 50°C. Our results provide a simple cellular basis for mammalian thermosensation whereby two molecularly defined classes of sensory neurons detect and encode both attractive and aversive cues.
Purkinje Cell Ataxin-1 Modulates Climbing Fiber Synaptic Input in Developing and Adult Mouse Cerebellum
Authors: Ebner Blake A. , Ingram Melissa A. , Barnes Justin A. , Duvick Lisa A. , Frisch Jill L. , Clark H. Brent , Zoghbi Huda Y. , Ebner Timothy J. , Orr Harry T.
Published: March 2013

Previous studies indicate that while transgenic mice with ATXN1[30Q]-D776-induced disease share pathological features caused by ATXN1[82Q] having an expanded polyglutamine tract, they fail to manifest the age-related progressive neurodegeneration seen in spinocerebellar ataxia type 1. The shared features include morphological alterations in climbing fiber (CF) innervation of Purkinje cells (PCs). To further investigate the ability of ataxin-1 (ATXN1) to impact CF/PC innervation, this study used morphological and functional approaches to examine CF/PC innervation during postnatal development in ATXN1[30Q]-D776 and ATXN1[82Q] cerebella. Notably, ATXN1[30Q]-D776 induced morphological alterations consistent with the development of the innervation of PCs by CFs being compromised, including a reduction of CF translocation along the PC dendritic tree, and decreased pruning of CF terminals from the PC soma. As previously shown for ATXN1[82Q], ATXN1[30Q]-D776 must enter the nucleus of PCs to induce these alterations. Experiments usingconditional ATXN1[30Q]-D776mice demonstrate that both the levels and specific timing of mutant ATXN1 expression are critical for alteration of the CF–PC synapse. Together these observations suggest that ATXN1, expressed exclusively in PCs, alters expression of a gene(s) in the postsynaptic PC that are critical for its innervation by CFs. To investigate whether ATXN1[30Q]-D776 curbs the progressive disease inATXN1[82Q]-S776mice, we crossedATXN1[30Q]-D776andATXN1[82Q]-S776mice and found that double transgenic mice developed progressive PC atrophy. Thus, the results also show that to develop progressive cerebellar degeneration requires expressing ATXN1 with an expanded polyglutamine tract.
The α Crystallin Domain of Small Heat Shock Protein b8 (Hspb8) Acts as Survival and Differentiation Factor in Adult Hippocampal Neurogenesis
Authors: Ramírez-Rodríguez Gerardo , Babu Harish , Klempin Friederike , Krylyshkina Olga , Baekelandt Veerle , Gijsbers Rik , Debyser Zeger , Overall Rupert W. , Nicola Zeina , Fabel Klaus , Kempermann Gerd
Published: March 2013

Adult hippocampal neurogenesis is to a large degree controlled at the level of cell survival, and a number of potential mediators of this effect have been postulated. Here, we investigated the small heat shock protein Hspb8, which, because of its pleiotropic prosurvival effects in other systems, was considered a particularly promising candidate factor. Hspb8 is, for example, found in plaques of Alzheimer disease but exerts neuroprotective effects. We found that expression of Hspb8 increased during differentiationin vitroand was particularly associated with later stages (48–96 h) of differentiation. Gain-of-function and loss-of-function experiments supported the hypothesis that Hspb8 regulates cell survival of new neuronsin vitro. In the dentate gyrus of adult micein vivo, lentiviral overexpression of Hspb8 doubled the surviving cells and concomitantly promoted differentiation and net neurogenesis without affecting precursor cell proliferation. We also discovered that the truncated form of the crystallin domain of Hspb8 was sufficient to affect cell survival and neuronal differentiationin vitroandin vivo. Precursor cell experimentsin vitrorevealed that Hspb8 increases the phosphorylation of Akt and suggested that the prosurvival effect can be produced by a cell-autonomous mechanism. Analysis of hippocampal Hspb8 expression in mice of 69 strains of the recombinant inbred set BXD revealed thatHspb8is acis-acting gene whose expression was associated with clusters of transcript enriched in genes linked to growth factor signaling and apoptosis. Our results strongly suggest that Hspb8 and its α-crystallin domain might act as pleiotropic prosurvival factor in the adult hippocampus.
Storage protein profile and amino acid content in wild rice Oryza glumaepatula
Authors: Santos Karina Freire D'eça Nogueira , Silveira Ricardo Diógenes Dias , Martin-Didonet Claudia Cristina Garcia , Brondani Claudio
Published: March 2013

- The objective of this work was to determine the total protein profile and the contents of the four major protein fractions (albumin, globulin, prolamin and glutelin) and of the amino acids in the endosperm of the rice wild species Oryza glumaepatula. The experiment was performed with 29 accessions of this species, collected from 13 Brazilian locations, and two commercial cultivars. Protein samples were prepared using dried, polished, and ground grains to obtain homogeneous, dry flour used in the preparation of extracts. Oryza glumaepatula accessions were identified with the highest levels of total protein, albumin and glutelin protein fractions, and amino acids (with the exception of tryptophan) in comparison to the two analized rice cultivars. The albumin and glutelin profiles in SDS-Page were distinct between rice cultivars and O. glumaepatula. This wild species has the potential to increase the nutritional quality of rice storage protein through interspecific crosses.