Carrier-induced ferromagnetism in p-Zn1-xMnxTe

We present a systematic study of the ferromagnetic transition induced by the holes in nitrogen doped Zn1-xMnxTe epitaxial layers, with particular emphasis on the values of the Curie-Weiss temperature as a function of the carrier and spin concentrations. The data are obtained from thorough analyses of the results of magnetization, magnetoresistance and spin-dependent Hall effect measurements. The experimental findings compare favorably, without adjustable parameters, with the prediction of the Rudermann-Kittel-Kasuya-Yosida (RKKY) model or its continuous-medium limit, that is, the Zener model, provided that the presence of the competing antiferromagnetic spin-spin superexchange interaction is taken into account, and the complex structure of the valence band is properly incorporated into the calculation of the spin susceptibility of the hole liquid. In general terms, the findings demonstrate how the interplay between the ferromagnetic RKKY interaction, carrier localization, and intrinsic antiferromagnetic superexchange affects the ordering temperature and the saturation value of magnetization in magnetically and electrostatically disordered systems.Comment: 14 pages, 10 figure

The role of cytokines in modulating learning and memory and brain plasticity

Cytokines are proteins secreted in the central nervous system by neurons, microglia, astrocytes and infiltrating peripheral immune cells under physiological and pathological conditions. Over the last 20 years, a growing number of reports have investigated the effects of these molecules on brain plasticity. In this review, we describe how the key cytokines interleukin 1β, interleukin 6 and tumour necrosis factor α were found to support long-term plasticity and learning and memory processes in physiological conditions. In contrast, during inflammation where cytokines levels are elevated such as in models of brain injury or infection, depression or neurodegeneration, the effects of cytokines are mostly detrimental to memory mechanisms, associated behaviours and homeostatic plasticity

Functionalized carbon nanotubes: From intracellular uptake and cell-related toxicity to systemic brain delivery

AbstractCarbon nanotubes (CNTs) have long been regarded as promising carriers in biomedicine. Due to their high surface area and unique needle-like structure, CNTs are uniquely equipped to carry therapeutic molecules across biological membranes and, therefore, have been widely researched for use in theranostic applications. The attractive properties of the CNTs entice also their use in the brain environment. Cutting edge brain-specific therapies, capable of circumventing the physical and biochemical blockage of the blood-brain barrier, could be a precious tool to tackle brain disorders. With an increasing number of applications and expanding production, the effects of direct and indirect exposure to CNTs on cellular and molecular levels and more globally the general health, must be carefully assessed and limited.In this chapter, we review the most recent trends on the development and application of CNT-based nanotechnologies, with a particular focus on the carrier properties, cell internalisation and processing, and mechanisms involved in cell toxicity. Novel approaches for CNT-based systemic therapeutic brain delivery following intravenous administration are also reviewed. Moreover, we highlight fundamental questions that should be addressed in future research involving CNTs, aiming at achieving its safe introduction into the clinics

Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.

Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S-nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release

Magnetically Decorated Multiwalled Carbon Nanotubes as Dual MRI and SPECT Contrast Agents

Carbon nanotubes (CNTs) have been proposed as one of the most promising nanomaterials to be used in biomedicine for their applications in drug/gene delivery as well as biomedical imaging. The present study developed radio-labeled iron oxide decorated multi-walled CNTs (MWNT) as dual magnetic resonance (MR) and single photon emission computed tomography (SPECT) imaging agents. Hybrids containing different amounts of iron oxide were synthesized by in situ generation. Physicochemical characterisations revealed the presence of superparamagnetic iron oxide nanoparticles (SPION) granted the magnetic properties of the hybrids. Further comprehensive examinations including high resolution transmission electron microscopy (HRTEM), fast Fourier transform simulations (FFT), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) assured the conformation of prepared SPION as γ-Fe(2)O(3). High r(2) relaxivities were obtained in both phantom and in vivo MRI compared to the clinically approved SPION Endorem(®). The hybrids were successfully radio-labeled with technetium-99m through a functionalized bisphosphonate and enabled SPECT/CT imaging and γ-scintigraphy to quantitatively analyze the biodistribution in mice. No abnormality was found by histological examination and the presence of SPION and MWNT were identified by Perls stain and Neutral Red stain, respectively. TEM images of liver and spleen tissues showed the co-localization of SPION and MWNT within the same intracellular vesicles, indicating the in vivo stability of the hybrids after intravenous injection. The results demonstrated the capability of the present SPION-MWNT hybrids as dual MRI and SPECT contrast agents for in vivo use

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

This is the final version of the article. Available from American Society for Clinical Investigation via the DOI in this record.The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR–selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.ABT, AC, and PMS received funding from a Wellcome Trust Collaborative Award (201529/Z/16/Z). ABT, SJB, AJB, and TMH were funded through a Medical Research Council programme leader grant provided by the MRC Toxicology Unit. CCF, LMB, AJM, and HES were funded by the Eli Lilly Company. JMB received funding through a Lilly Research Award Program (LRAP) grant (Eli Lilly). RP received funding from the Marie Curie grant “Extrabrain” (European Commission). AC is a senior principal research fellow and PMS a principal research fellow of the National Health and Medical Research Council of Australia. Tissue samples were from Randy Woltjer at the Oregon Alzheimer’s Disease Center. The Oregon Alzheimer’s Disease Center is supported by NIH grant P30AG008017

Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction.

G protein-coupled receptors (GPCRs) are known to initiate a plethora of signaling pathways in vitro. However, it is unclear which of these pathways are engaged to mediate physiological responses. Here, we examine the distinct roles of Gq/11-dependent signaling and receptor phosphorylation-dependent signaling in bronchial airway contraction and lung function regulated through the M3-muscarinic acetylcholine receptor (M3-mAChR). By using a genetically engineered mouse expressing a G protein-biased M3-mAChR mutant, we reveal the first evidence, to our knowledge, of a role for M3-mAChR phosphorylation in bronchial smooth muscle contraction in health and in a disease state with relevance to human asthma. Furthermore, this mouse model can be used to distinguish the physiological responses that are regulated by M3-mAChR phosphorylation (which include control of lung function) from those responses that are downstream of G protein signaling. In this way, we present an approach by which to predict the physiological/therapeutic outcome of M3-mAChR-biased ligands with important implications for drug discovery.This study is funded by the Medical Research Council (MRC) through funding of program leaders provided by the MRC Toxicology Unit (to A.B.T.)

Inhibition of neuroinflammatory nitric oxide signalling supresses protein glycation and recovers neuronal dysfunction in prion disease

Background: Several neurodegenerative diseases associated with protein misfolding (Alzheimer’s, Parkinson’s disease) exhibit oxidative and nitrergic stress following initiation of neuroinflammatory pathways. Associated nitric oxide (NO)-mediated post-translational modifications impact upon protein functions that can exacerbate pathology. Non-enzymatic and irreversible glycation signalling has been implicated as an underlying pathway that promotes protein misfolding, but the direct interactions between both pathways are poorly understood.Methods: Here we investigated the potential therapeutic effects of supressing neurotoxic NO signalling during early progression of prion disease. Tg37 mice aged 3-4 weeks were inoculated by intracerebral injection with either 1% brain homogenate of Rocky Mountain Laboratory (RML) scrapie prion protein or control normal brain homogenate (NBH). Hippocampal gene and protein expression levels of oxidative and nitrergic stress markers were analysed and electrophysiological characterisations of pyramidal neurons were performed in 6-10 weeks old RML and NBH mice. Mice were injected with a NO synthase (NOS) inhibitor and the time course of disease markers was compared to controls. Electrophysiology, immunoblotting and immunocytochemistry studies were performed to identify the effects of NOS inhibition on neurophysiology, glycation, prion protein misfolding and cell death. Statistical analyses employed two-tailed unpaired Student’s t-test, one-way or two-way ANOVA as required and data were considered significant with P<0.05.Results: Increased neuroinflammatory signalling was observed in mice between 6 and 10 weeks post inoculation (w.p.i.) with scrapie prion protein which was characterised by enhanced nitrergic stress and associated with a decline in hippocampal neuronal function by 9 w.p.i.. Daily in vivo administration of the NOS inhibitor L-NAME between 6 and 9 w.p.i. at 20 mg/kg abolished the functional degeneration of hippocampal neurons in prion mice. We further found that this intervention in diseased mice ameliorated 3-nitrotyrosination of triose-phosphate isomerase, an enzyme involved in the formation of disease-associated glycation signalling. Furthermore, L-NAME application reduced the expression of the receptor for advanced glycation end products and the accumulation of hippocampal prion misfolding.Conclusions: Our data suggest that alleviating nitrergic stress during early phases of neurodegeneration reduces neurotoxic post-translational NO signalling and glycation-assisted prion misfolding in the hippocampus, a mechanism which might be applicable to other protein misfolding neurodegenerative conditions