Suppression of peripheral pain by blockade of voltage-gated calcium 2.2 channels in nociceptors induces RANKL and impairs recovery from inflammatory arthritis in a mouse model

Objective: A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies the inflammation and joint deformation. Patients with RA rate pain relief with highest priority, however, few studies have addressed the efficacy and safety of therapies directed specifically towards pain pathways. The conotoxin MVIIA (Prialt/Ziconotide) is used in humans to alleviate persistent pain syndromes because it specifically blocks the CaV 2.2 voltage-gated calcium channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals. The purpose of this study was to investigate whether block of CaV 2.2 can suppress arthritic pain, and to examine the progression of induced arthritis during persistent CaV 2.2 blockade. Methods: Transgenic mice (Tg-MVIIA) expressing a membrane-tethered form of the {Omega}-conotoxin MVIIA, under the control of a nociceptor-specific gene, were employed. These mice were subjected to unilateral induction of joint inflammation using the Antigen- and Collagen-Induced Arthritis (ACIA) model. Results: We observed that CaV 2.2-blockade mediated by t-MVIIA effectively suppressed arthritis-induced pain; however, in contrast to their wild-type littermates, which ultimately regained use of their injured joint as inflammation subsides, Tg-MVIIA mice showed continued inflammation with an up-regulation of the osteoclast activator RANKL and concomitant joint and bone destruction. Conclusion: Altogether, our results indicate that alleviation of peripheral pain by blockade of CaV 2.2- mediated calcium influx and signaling in nociceptor sensory neurons, impairs recovery from induced arthritis and point to the potentially devastating effects of using CaV 2.2 channel blockers as analgesics during inflammation

Habenular expression of rare missense variants of the β4 nicotinic receptor subunit alters nicotine consumption

The CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the {alpha}5, {alpha}3, and {beta}4 nicotinic acetylcholine receptor (nAChR) subunits, has been linked to nicotine dependence. The habenulo-interpeduncular (Hb-IPN) tract is particularly enriched in {alpha}3{beta}4 nAChRs. We recently showed that modulation of these receptors in the medial habenula (MHb) in mice altered nicotine consumption. Given that {beta}4 is rate-limiting for receptor activity and that single nucleotide polymorphisms (SNPs) in CHRNB4 have been linked to altered risk of nicotine dependence in humans, we were interested in determining the contribution of allelic variants of {beta}4 to nicotine receptor activity in the MHb. We screened for missense SNPs that had allele frequencies >0.0005 and introduced the corresponding substitutions in Chrnb4. Fourteen variants were analyzed by co-expression with {alpha}3. We found that {beta}4A90I and {beta}4T374I variants, previously shown to associate with reduced risk of smoking, and an additional variant {beta}4D447Y, significantly increased nicotine-evoked current amplitudes, while {beta}4R348C, the mutation most frequently encountered in sporadic amyotrophic lateral sclerosis (sALS), showed reduced nicotine currents. We employed lentiviruses to express {beta}4 or {beta}4 variants in the MHb. Immunoprecipitation studies confirmed that {beta}4 lentiviral-mediated expression leads to specific upregulation of {alpha}3{beta}4 but not {beta}2 nAChRs in the Mhb. Mice injected with the {beta}4-containing virus showed pronounced aversion to nicotine as previously observed in transgenic Tabac mice overexpressing Chrnb4 at endogenous sites including the MHb. Habenular expression of the {beta}4 gain-of-function allele T374I also resulted in strong aversion, while transduction with the {beta}4 loss-of function allele R348C failed to induce nicotine aversion. Altogether, these data confirm the critical role of habenular {beta}4 in nicotine consumption, and identify specific SNPs in CHRNB4 that modify nicotine-elicited currents and alter nicotine consumption in mice

On Bootstrap Percolation in Living Neural Networks

Recent experimental studies of living neural networks reveal that their global activation induced by electrical stimulation can be explained using the concept of bootstrap percolation on a directed random network. The experiment consists in activating externally an initial random fraction of the neurons and observe the process of firing until its equilibrium. The final portion of neurons that are active depends in a non linear way on the initial fraction. The main result of this paper is a theorem which enables us to find the asymptotic of final proportion of the fired neurons in the case of random directed graphs with given node degrees as the model for interacting network. This gives a rigorous mathematical proof of a phenomena observed by physicists in neural networks

Interferências no agrossistema e riscos ambientais de culturas transgênicas tolerantes a herbicidas e protegidas contra insetos.

A engenharia genética possibilitou o desenvolvimento de cultivares transgênicas, cuja área plantada em 18 países atinge 67,7 milhões de hectares, principalmente de cultivares tolerantes a herbicidas e protegidas contra insetos-praga. Mesmo após rigorosa avaliação de riscos, o plantio dessas cultivares tem despertado preocupação com impactos ambientais, como escape gênico e efeitos na biodiversidade. Considerando o milho e a soja, o risco de fluxo gênico horizontal é remoto pela inexistência de espécies silvestres compatíveis, existindo esse risco para algodão em certas regiões do Brasil. O escape gênico para lavouras convencionais pode ocorrer, mas pode ser evitado por isolamento dos cultivos. Outra preocupação é o impacto de cultivares expressando proteínas inseticidas, mas os diversos estudos disponíveis indicam riscos desprezíveis desse cultivo. A redução no uso de defensivos em cultivos transgênicos favorece a biodiversidade, mas o uso prolongado do glifosato ou de cultivares Bt pode favorecer a evolução de resistência e a poluição ambiental, riscos inerentes a qualquer tipo de cultivo. Dos estudos avaliados, verifica-se que os cultivos transgênicos causam alterações no agrossistema, mas estas não diferem em natureza e magnitude daquelas dos cultivos convencionais. Para garantir sua segurança, medidas preventivas e o monitoramento são preconizados para os cultivos transgênicos

Biophysical characterization of interactions involving importin-alpha during nuclear import

Proteins containing the classical nuclear localization sequences (NLSs) are imported into the nucleus by the importin-alpha/beta heterodimer. Importin-alpha contains the NLS binding site, whereas importin-beta mediates the translocation through the nuclear pore. We characterized the interactions involving importin-alpha during nuclear import using a combination of biophysical techniques (biosensor, crystallography, sedimentation equilibrium, electrophoresis, and circular dichroism). Importin-alpha is shown to exist in a monomeric autoinhibited state (association with NLSs undetectable by biosensor). Association with importin-beta (stoichiometry, 1:1; K-D = 1.1 x 10(-8) m) increases the affinity for NLSs; the importin-alpha/beta complex binds representative monopartite NLS (simian virus 40 large T-antigen) and bipartite NLS (nucleoplasmin) with affinities (K-D = 3.5 x 10(-8) m and 4.8 x 10(-8) m, respectively) comparable with those of a truncated importin-alpha lacking the autoinhibitory domain (T-antigen NLS, K-D = 1.7 x 10(-8) m; nucleoplasmin NLS, K-D = 1.4 x 10(-8) m). The autoinhibitory domain (as a separate peptide) binds the truncated importin-alpha, and the crystal structure of the complex resembles the structure of full-length importin-alpha. Our results support the model of regulation of nuclear import mediated by the intrasteric autoregulatory sequence of importin-alpha and provide a quantitative description of the binding and regulatory steps during nuclear import

Spin Waves in Canted Phases: An Application to Doped Manganites

We present the effective lagrangian for low energy and momentum spin waves in canted phases at next to leading order in the derivative expansion. The symmetry breaking pattern SU(2) --> 1 of the internal spin group and that of the crystallographic space group imply that there is one ferromagnetic and one antiferromagnetic spin wave. The interaction of the spin waves with the charge carriers is also discussed for canted, ferromagnetic and antiferromagnetic phases. All this together allows us to write the doping dependence of the dispersion relation parameters for doped manganites. We point out that the spin waves posses distinctive characteristics which may allow us to experimentally differentiate canted phases from phase separation regions in doped manganites.Comment: 34 pages, latex file, 1 eps included figure. Minor changes, published versio

Métrica Induzida da Correntropia Complexa Comparada ao NESTA no Problema de Amostragem Compressiva / Induced Complex Correntropy Metric Compared to NESTA on the Compressive Sampling Problem

Esse artigo compara ao algoritmo de Nesterov (NESTA) o desempenho da métrica induzida da correntropia complexa (Complex Correntropy Induced Metric - CCIM) enquanto uma aproximação de l0 num problema de amostragem compressiva. As simulações mostram que a CCIM é capaz de reconstruir um vetor esparso complexo usando menos medidas do que o NEST

Phase separation and suppression of critical dynamics at quantum transitions of itinerant magnets: MnSi and (Sr1−x_{1-x}Cax_{x})RuO3_{3}

Quantum phase transitions (QPTs) have been studied extensively in correlated electron systems. Characterization of magnetism at QPTs has, however, been limited by the volume-integrated feature of neutron and magnetization measurements and by pressure uncertainties in NMR studies using powderized specimens. Overcoming these limitations, we performed muon spin relaxation ($\mu$SR) measurements which have a unique sensitivity to volume fractions of magnetically ordered and paramagnetic regions, and studied QPTs from itinerant heli/ferro magnet to paramagnet in MnSi (single-crystal; varying pressure) and (Sr$_{1-x}$Ca$_{x}$)RuO$_{3}$ (ceramic specimens; varying $x$). Our results provide the first clear evidence that both cases are associated with spontaneous phase separation and suppression of dynamic critical behavior, revealed a slow but dynamic character of the ``partial order'' diffuse spin correlations in MnSi above the critical pressure, and, combined with other known results in heavy-fermion and cuprate systems, suggest a possibility that a majority of QPTs involve first-order transitions and/or phase separation.Comment: 11 pages, 4 figures, 21 authors, to appear in Nature Physic