Control of aversion by glycine-gated GluN1/GluN3A NMDA receptors in the adult medial habenula.

The unconventional N-methyl-d-aspartate (NMDA) receptor subunits GluN3A and GluN3B can, when associated with the other glycine-binding subunit GluN1, generate excitatory conductances purely activated by glycine. However, functional GluN1/GluN3 receptors have not been identified in native adult tissues. We discovered that GluN1/GluN3A receptors are operational in neurons of the mouse adult medial habenula (MHb), an epithalamic area controlling aversive physiological states. In the absence of glycinergic neuronal specializations in the MHb, glial cells tuned neuronal activity via GluN1/GluN3A receptors. Reducing GluN1/GluN3A receptor levels in the MHb prevented place-aversion conditioning. Our study extends the physiological and behavioral implications of glycine by demonstrating its control of negatively valued emotional associations via excitatory glycinergic NMDA receptors.

Inward versus reward: white matter pathways in extraversion.

The trait of extraversion is one of the longest-standing domains that captures the social dimension of personality and can potentially explain the covariation of a wide variety of behaviors. To date, there is a growing recognition that human behavior should be specified not only through the psychological mechanisms underlying each trait but also through their underlying neurobehavioral systems. While imaging studies have revealed important initial insights into the structural and functional neural correlates of extraversion, current knowledge about the relationships between extraversion and brain structures is still rather limited, especially with regard to the relationship between extraversion and white matter (WM). In this study, we aimed to investigate WM microstructure in extraversion in greater depth. Thirty-five healthy volunteers (21 women; mean age 35) underwent magnetic resonance imaging, as a part of a larger project aimed at investigating the longitudinal effect of motor training. WM integrity was assessed using the diffusion tensor imaging technique combining multiple diffusion tensor measures. Extraversion was assessed by the Eysenck Personality Questionnaire-Revised. Voxelwise correlation analyses between fractional anisotropy, axial diffusivities, and radial diffusivities maps and extraversion score showed decreased connectivity in the right inferior fronto-occipital fasciculus and forceps major among individuals who had high extraversion ratings. In conclusion, individual differences in extraversion may reflect differential organization of the WM tracts connecting frontal cortex, temporal, and occipital areas, which are related to socioemotional and control functions.

Atomic force microscopy analysis of extracellular vesicles.

Extracellular vesicles (EVs) are small vesicles ensuring transport of molecules between cells and throughout the body. EVs contain cell type-specific signatures and have been proposed as biomarkers in a variety of diseases. Their small size (<1 µm) and biological and physical functions make them obvious candidates for therapeutic agents in immune therapy, vaccination, regenerative medicine and drug delivery. However, due to the complexity and heterogeneity of their origin and composition, the actual mechanism through which these vesicles exert their functions is still unknown and represents a great biomedical challenge. Moreover, because of their small dimensions, the quantification, size distribution and biophysical characterization of these particles are challenging and still subject to controversy. Here, we address the advantage of atomic force microscopy (AFM), for the characterization of isolated EVs. We review AFM imaging of EVs immobilized on different substrates (mica, glass) to identify the influence of isolation and deposition methods on the size distribution, morphology and mechanical properties of EVs.

Grasping with a soft glove: intrinsic impedance control in pneumatic actuators.

The interaction of a robotic manipulator with unknown soft objects represents a significant challenge for traditional robotic platforms because of the difficulty in controlling the grasping force between a soft object and a stiff manipulator. Soft robotic actuators inspired by elephant trunks, octopus limbs and muscular hydrostats are suggestive of ways to overcome this fundamental difficulty. In particular, the large intrinsic compliance of soft manipulators such as 'pneu-nets'-pneumatically actuated elastomeric structures-makes them ideal for applications that require interactions with an uncertain mechanical and geometrical environment. Using a simple theoretical model, we show how the geometric and material nonlinearities inherent in the passive mechanical response of such devices can be used to grasp soft objects using force control, and stiff objects using position control, without any need for active sensing or feedback control. Our study is suggestive of a general principle for designing actuators with autonomous intrinsic impedance control.

Presynaptic NMDA receptors: Roles and rules.

NMDA receptors (NMDARs) are glutamate-gated ion channels widely expressed in the central nervous system (CNS) and endowed with unique biophysical, pharmacological and signaling properties. These receptors are best known for their critical roles in synaptic plasticity and their implications in a variety of neurological and psychiatric disorders. Since their discovery three decades ago, NMDARs have been thoroughly studied as components of postsynaptic excitatory potentials. Early on, however, both anatomical and physiological evidence pointed out to the existence of NMDARs away from the postsynaptic density. Some were found to be extrasynaptic, while others seemed to be specifically present at presynaptic (i.e. axonal) elements. Although presynaptic NMDARs (preNMDARs) were at first thought to be exceptional, there is now strong evidence that these receptors are relatively widespread in the CNS and regulate synaptic strength in specific sets of synapses. In this review, we compile our current knowledge on preNMDARs, presenting their anatomical distribution, developmental regulation, subunit composition, activation mechanisms as well as their downstream effects on synapse function. Contentious issues that animate the field are also discussed. Finally, particular emphasis is put on the molecular and cellular diversity of preNMDARs which translates into a variety of effects, both short- and long-term, on synaptic efficacy. Overshadowed by their postsynaptic counterparts, preNMDARs are progressively emerging as important regulators of neuronal signaling.

A proprioceptive neuromechanical theory of crawling.

The locomotion of many soft-bodied animals is driven by the propagation of rhythmic waves of contraction and extension along the body. These waves are classically attributed to globally synchronized periodic patterns in the nervous system embodied in a central pattern generator (CPG). However, in many primitive organisms such as earthworms and insect larvae, the evidence for a CPG is weak, or even non-existent. We propose a neuromechanical model for rhythmically coordinated crawling that obviates the need for a CPG, by locally coupling the local neuro-muscular dynamics in the body to the mechanics of the body as it interacts frictionally with the substrate. We analyse our model using a combination of analytical and numerical methods to determine the parameter regimes where coordinated crawling is possible and compare our results with experimental data. Our theory naturally suggests mechanisms for how these movements might arise in developing organisms and how they are maintained in adults, and also suggests a robust design principle for engineered motility in soft systems.

Intermittent locomotion as an optimal control strategy.

Birds, fish and other animals routinely use unsteady effects to save energy by alternating between phases of active propulsion and passive coasting. Here, we construct a minimal model for such behaviour that can be couched as an optimal control problem via an analogy to travelling with a rechargeable battery. An analytical solution of the optimal control problem proves that intermittent locomotion has lower energy requirements relative to steady-state strategies. Additional realistic hypotheses, such as the assumption that metabolic cost at a given power should be minimal (the fixed gear hypothesis), a nonlinear dependence of the energy storage rate on propulsion and/or a preferred average speed, allow us to generalize the model and demonstrate the flexibility of intermittent locomotion with implications for biological and artificial systems.

Disclosing and overcoming the trade-off between noise and scanning speed in atomic force microscopy.

Traditional dynamic modalities for atomic force microscopy imaging suffer from a stringent trade-off between fast scanning speed, weak interaction forces and accurate topography reconstruction. Finding an effective compromise between these aspects is often challenging, especially for soft biological samples for which stringent requirements hold when imaged in vivo. In this paper the main causes of this undesired trade-off in standard systems are analyzed and the exploitation of the intrinsic dynamics of the cantilever through a nonlinear control strategy is proposed as a method to overcome this limitation. A direct application to imaging of biological samples is reported to validate the results and show the effectiveness of the proposed technique.

Two cases of neonatal adrenal hemorrhage presenting with persistent jaundice.

The adrenal hemorrhage is a relatively rare event in newborns but must be considered in the presence of a persistent unexplained jaundice, especially in presence of predisposing factors. Serial ultrasonography is the modality of choice for initial diagnosis and follow-up of neonatal adrenal hemorrhage. We report two cases of neonatal adrenal hemorrhage presenting with persistent jaundice. The causes of the neonatal adrenal hemorrhages were a difficult vaginal delivery in macrosomic infant and a neonatal infection.

Balancing on tightropes and slacklines.

Balancing on a tightrope or a slackline is an example of a neuromechanical task where the whole body both drives and responds to the dynamics of the external environment, often on multiple timescales. Motivated by a range of neurophysiological observations, here we formulate a minimal model for this system and use optimal control theory to design a strategy for maintaining an upright position. Our analysis of the open and closed-loop dynamics shows the existence of an optimal rope sag where balancing requires minimal effort, consistent with qualitative observations and suggestive of strategies for optimizing balancing performance while standing and walking. Our consideration of the effects of nonlinearities, potential parameter coupling and delays on the overall performance shows that although these factors change the results quantitatively, the existence of an optimal strategy persists.

Long-term memory deficits in Huntington's disease are associated with reduced CBP histone acetylase activity.

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by an expanded CAG/polyglutamine repeat in the coding region of the huntingtin (htt) gene. Although HD is classically considered a motor disorder, there is now considerable evidence that early cognitive deficits appear in patients before the onset of motor disturbances. Here we demonstrate early impairment of long-term spatial and recognition memory in heterozygous HD knock-in mutant mice (Hdh(Q7/Q111)), a genetically accurate HD mouse model. Cognitive deficits are associated with reduced hippocampal expression of CREB-binding protein (CBP) and diminished levels of histone H3 acetylation. In agreement with reduced CBP, the expression of CREB/CBP target genes related to memory, such c-fos, Arc and Nr4a2, was significantly reduced in the hippocampus of Hdh(Q7/Q111) mice compared with wild-type mice. Finally, and consistent with a role of CBP in cognitive impairment in Hdh(Q7/Q111) mice, administration of the histone deacetylase inhibitor trichostatin A rescues recognition memory deficits and transcription of selective CREB/CBP target genes in Hdh(Q7/Q111) mice. These findings demonstrate an important role for CBP in cognitive dysfunction in HD and suggest the use of histone deacetylase inhibitors as a novel therapeutic strategy for the treatment of memory deficits in this disease.

[Biological roles of trace elements in the brain with special focus on Zn and Fe]. / Rôles biologiques des éléments traces dans le cerveau--exemples du Zn et du Fe.

INTRODUCTION: Many metals like iron (Fe), copper (Cu) or zinc (Zn) fulfil various essential biological functions and are thus vital for all living organisms. For instance, they play important roles in nervous tissue, participating in a wide range of processes such as neurotransmitter synthesis, myelination or synaptic transmission. STATE OF THE ART: As in other tissues, brain cells tightly control the concentration of metals but any excess or deficit can lead to deleterious responses and alter cognitive functions. Of note, certain metals such as Zn, Fe or Cu accumulate in specific brain structures over lifespan and several neurodegenerative diseases are associated with a dysregulation of the homeostatic mechanisms controlling the concentration of these cations. CONCLUSION AND PERSPECTIVES: This review will address some of the cellular and molecular processes controlling the entry and distribution of selected metals (mainly Zn and Fe) in the brain, as well as their roles in synaptic transmission, in the pathogenesis of some neurologic diseases such as Parkinson's disease and Alzheimer's disease, and their impact on cognitive functions.

Zinc at glutamatergic synapses.

It has long been known that the mammalian forebrain contains a subset of glutamatergic neurons that sequester zinc in their synaptic vesicles. This zinc may be released into the synaptic cleft upon neuronal activity. Extracellular zinc has the potential to interact with and modulate many different synaptic targets, including glutamate receptors and transporters. Among these targets, NMDA receptors appear particularly interesting because certain NMDA receptor subtypes (those containing the NR2A subunit) contain allosteric sites exquisitely sensitive to extracellular zinc. The existence of these high-affinity zinc binding sites raises the possibility that zinc may act both in a phasic and tonic mode. Changes in zinc concentration and subcellular zinc distribution have also been described in several pathological conditions linked to glutamatergic transmission dysfunctions. However, despite intense investigation, the functional significance of vesicular zinc remains largely a mystery. In this review, we present the anatomy and the physiology of the glutamatergic zinc-containing synapse. Particular emphasis is put on the molecular and cellular mechanisms underlying the putative roles of zinc as a messenger involved in excitatory synaptic transmission and plasticity. We also highlight the many controversial issues and unanswered questions. Finally, we present and compare two widely used zinc chelators, CaEDTA and tricine, and show why tricine should be preferred to CaEDTA when studying fast transient zinc elevations as may occur during synaptic activity.

Modelling and analysis of autonomous micro-cantilever oscillations.

Tapping mode atomic force microscopy provides good resolution in imaging applications, but it still requires a time-consuming initial configuration and features quite low scanning velocity. In this paper we present a new dynamic mode in which the cantilever gets excited by a feedback loop containing a saturation function. The proposed scheme is then analysed in the frequency domain and simulated against the standard set-up, showing good performance and elimination of some of the known drawbacks. Preliminary results in experiments confirm the effectiveness of this operating mode.

Clinical use of Heliox in asthma and COPD.

Heliox is a low density gas mixture of helium and oxygen commonly used in deep diving (> 6 ATM). This mixture has been also used for clinical purposes, particularly in the critical care setting. Due to of its physical proprieties, Heliox breathing reduces air flow resistances within the bronchial tree; in patients with obstructive lung diseases Heliox may also reduce the work of breathing and improve pulmonary gas exchange efficiency. Beneficial effects have been documented in severe asthma attacks and in patients with chronic obstructive pulmonary disease. A reduction in WOB during mechanical ventilation and an increase in exercise endurance capacity have also been described in COPD. Heliox has been also used in the treatment of upper airways obstruction, bronchiolitis and bronchopulmonary dysplasia. Despite the encouraging results, Heliox use in routine practice remains controversial because of technical implications and high costs.

Water and sodium imbalance in COPD patients.

Water retention and hyponatraemia are typically observed in the final stages of Chronic Obstructive Pulmonary Disease (COPD) and the onset of edema is a poor prognostic factor. For several years the pathogenesis of edema in COPD patients was attributed to heart impairment because of pulmonary hypertension, but the evidence that cardiac output is often adequate for the metabolic demands has suggested, since 1960, that the pathogenesis of edema in these patients would be correlated with gas exchange impairment and in particular with carbon dioxide (CO2) retention. The gas exchange impairment induces, in these patients several hormonal abnormalities: renin (Rn), angiotensin II (AnII), aldosterone (Ald), atrial natriuretic peptide (ANP), vasopressin (ADH) and endothelial factors are some of the factors involved. The systemic response to hypercapnia has the effect of reducing the renal blood flow and, as a result, increasing water and sodium retention with the final effect of edema and hyponatraemia. The aim of this brief review is to highlight the current knowledge on renal/hormonal abnormalities in COPD and their therapeutic implications.

Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors.

Pemetrexed disodium (ALIMTA), "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck. Pemetrexed inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. As a single agent, pemetrexed exhibits a moderate toxicity profile at a dose of 500 mg/m(2) by 10-minute infusion once every 21 days with myelosuppression being the dose-limiting toxicity. Folic acid added to the diet in preclinical studies reduced toxicities while maintaining antitumor activity. Based on this observation and clinical toxicities, folic acid and vitamin B(12) dietary supplementation has been recently introduced into all ongoing trials. Studies combining pemetrexed with other active chemotherapeutic agents demonstrate that these combination therapies may become important treatment regimens in a variety of cancer types. Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate.