Descripción: The effective action for quantum fields on a d-dimensional spacetime can be computed using a non-local expansion in powers of the curvature. We show explicitly that, for conformal fields and up to quadratic order in the curvature, the non-local effective action is equivalent to the d + 1 action for classical gravity in AdSd+1 restricted to a (d - 1)-brane. This generalizes previous results about quantum corrections to the Newtonian potential and provides an alternative method for making local a non-local effective action. The equivalence can be easily understood by comparing the Kallen-Lehmann decomposition of the classical propagator with the spectral representation of the non-local form factors in the quantum effective action. © 2001 Published by Elsevier Science B.V.

Descripción: Fil:Eguia, M.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Descripción: We investigate the renormalization group approach to nonequilibrium field theory. We show that it is possible to derive nontrivial renormalization group flow from iterative coarse graining of a closed-time-path action. This renormalization group is different from the usual in quantum field theory textbooks, in that it describes nontrivial noise and dissipation. We work out a specific example where the variation of the closed-time-path action leads to the so-called Kardar-Parisi-Zhang equation, and show that the renormalization group obtained by coarse graining this action, agrees with the dynamical renormalization group derived by directly coarse graining the equations of motion. © 2002 The American Physical Society.

Descripción: Electrical transmission among neurons has been considered a mechanism to synchronize neuronal activity, and rectification provides a mechanism to confine the flow of signals among the connected neurons. The question is how this type of transmission operates within complex neuronal networks. In the leech, the neurons located in position 151 of the midbody ganglion map are connected to virtually every motoneuron via rectifying electrical synapses that pass negative current to the motoneurons. These are nonspiking neurons, and here we have labeled them NS neurons. The goal of this investigation has been to assess their role in regulating motor activity and how rectifying electrical synapses contribute to the function of motor networks. The coupling between NS neurons and motoneurons was voltage sensitive: it increased as motoneurons were depolarized. In addition, excitation of motoneurons evoked hyperpolarizing synaptic responses in NS neurons, the amplitude of which depended on the membrane potential of the latter and on the motoneuron firing frequency. This hyperpolarization was mediated by chemical transmission through an interneuronal layer that spanned the nerve cord. These interactions established a feedback loop between NS and motoneurons that was regulated by the membrane potential of NS. This mechanism was responsible for the uncoupling between otherwise electrically coupled motoneurons. In this way, the NS neurons can act as "electrical neuromodulators," modifying the interaction of other neurons, depending on the activity of the system as a whole.

Descripción: Transmission at the mouse neuromuscular junction normally relies on P/Q-type channels, but became jointly dependent on both N-and R-type Ca2+ channels when the P/Q-type channel α1A subunit was deleted. R-type channels lay close to Ca2+ sensors for exocytosis and IK(Ca) channel activation, like the P/Q-type channels they replaced. In contrast, N-type channels were less well localized, but abundant enough to influence secretion strongly, particularly when action potentials were prolonged. Our data suggested that active zone structures may select among multiple Ca2+ channels in the hierarchy P/Q>R>N. The α1A-/- neuromuscular junction displayed several other differences from wild-type: lowered quantal content but greater ability to withstand reductions in the Ca2+/Mg2+ ratio, and little or no paired-pulse facilitation, the latter findings possibly reflecting compensatory mechanisms at individual release sites. Changes in presynaptic function were also associated with a significant reduction in the size of postsynaptic acetylcholine receptor clusters.

Descripción: Testicular macrophages as well as endothelial cells, which are intimately associated with Leydig cells, constitute a potential source of paracrine nitric oxide (NO) in the testis. In the present study, we investigated the effect of NO donors on MA-10 murine Leydig tumor cell line and rat Leydig cell steroidogenesis. We show that NO donors inhibit human CG- induced steroidogenesis in both type of cells. We also studied NO mechanism of action. Contrary to what is observed in many other systems, NO inhibitory effect on Leydig cell steroidogenesis is not mediated by cyclic GMP (cGMP) because NO fails to increase cGMP production, and cGMP analogs do not reproduce NO effect. NO does not modify the production of cAMP, the main second messenger that mediates gonadotropin action. When we studied NO effect over the steroidogenic pathway in MA-10 cells, we found that NO was inhibiting the conversion of cholesterol to pregnenolone. Taken together these results show an inhibitory effect of NO donors on Leydig cell steroidogenesis, and suggest that NO can be directly inhibiting cholesterol side-chain cleavage enzyme (cytochrome P450(scc)) as it does with other heme proteins, including different cytochromes P459.

Descripción: The molecular mechanisms governing the pathogenesis of ACTH-secreting pituitary adenomas are still obscure. Furthermore, the pharmacological treatment of these tumors is limited. In this study, we report that bone morphogenetic protein-4 (BMP-4) is expressed in the corticotrophs of human normal adenohypophysis and its expression is reduced in corticotrophinomas obtained from Cushing's patients compared with the normal pituitary. BMP-4 treatment of AtT-20 mouse corticotrophinoma cells has an inhibitory effect on ACTH secretion and cell proliferation. AtT-20 cells stably transfected with a dominant-negative form of the BMP-4 signal cotransducer Smad-4 or the BMP-4 inhibitor noggin have increased tumorigenicity in nude mice, showing that BMP-4 has an inhibitory role on corticotroph tumorigenesis in vivo. Because the activation of the retinoic acid receptor has an inhibitory action on Cushing's disease progression, we analyzed the putative interaction of these two pathways. Indeed, retinoic acid induces both BMP-4 transcription and expression and its antiproliferative action is blocked in Smad-4dn- and noggin-transfected Att-20 cells that do not respond to BMP-4. Therefore, retinoic acid induces BMP-4, which participates in the antiproliferative effects of retinoic acid. This new mechanism is a potential target for therapeutic approaches for Cushing's disease. Copyright © 2006 by The Endocrine Society.

Descripción: Although the negative regulation of gene expression by insulin has been widely studied, the transcription factors responsible for the insulin effect are still unknown. The purpose of this work was to explore the molecular mechanisms involved in the insulin repression of the 5-aminolevulinate synthase (ALAS) gene. Deletion analysis of the 5′-regulatory region allowed us to identify an insulin-responsive region located at -459 to -354 bp. This fragment contains a highly homologous insulin-responsive (IRE) sequence. By transient transfection assays, we determined that hepatic nuclear factor 3 (HNF3) and nuclear factor 1 (NF1) are necessary for an appropriate expression of the ALAS gene. Insulin overrides the HNF3β or HNF3β plus NF1-mediated stimulation of ALAS transcriptional activity. Electrophoretic mobility shift assay and Southwestern blotting indicate that HNF3 binds to the ALAS promoter. Mutational analysis of this region revealed that IRE disruption abrogates insulin action, whereas mutation of the HNF3 element maintains hormone responsiveness. This dissociation between HNF3 binding and insulin action suggests that HNF3β is not the sole physiologic mediator of insulin-induced transcriptional repression. Furthermore, Southwestern blotting assay shows that at least two polypeptides other than HNF3β can bind to ALAS promoter and that this binding is dependent on the integrity of the IRE. We propose a model in which insulin exerts its negative effect through the disturbance of HNF3β binding or transactivation potential, probably due to specific phosphorylation of this transcription factor by Akt. In this regard, results obtained from transfection experiments using kinase inhibitors support this hypothesis. Due to this event, NF1 would lose accessibility to the promoter. The posttranslational modification of HNF3 would allow the binding of a protein complex that recognizes the core IRE. These results provide a potential mechanism for the insulin-mediated repression of IRE-containing promoters.

Descripción: 1. The effects of the voltage-dependent calcium channel (VDCC) blockers ω-agatoxin IVA (ω-AgaIVA), ω-conotoxin GVIA (ω-CgTx), ω-conotoxin MVIIC (ω-MVIIC) and ω-conotoxin MVIID (ω-MVIID) were evaluated on transmitter release in the mouse diaphragm preparation. The effects of ω-AgaIVA and ω-MVIIC were also evaluated on the perineurial calcium and calcium-dependent potassium currents, I(ca), and I(K(Ca)), respectively, in the mouse levator auris preparation. 2. The P- and Q-type VDCC blocker ω-AgaIVA (100 nM) and P- Q- and N-type channel blockers ω-MVIIC (1 μM) and ω-MVIID (3 μM) strongly reduced transmitter release (> 80-90% blockade) whereas the selective N-type channel blocker ω-CgTx (5 μM) was ineffective. 3. The process of release was much more sensitive to ω-MVIIC (IC50 = 39 nM) than to ω-MVIID (IC50 = 1.4 μM). After almost completely blocking transmitter release (quantal content ~0.3% of its control value) with 3 μM ω-MVIIC, elevating the external [Ca2+] from 2 to 10 mM induced an increase of ~20 fold on the quantal content of the endplate potential (e.p.p.) (from 0.2 ± 0.04 to 4.8 ± 1.4). 4. Nerve-evoked transmitter release in a low Ca2+-high Mg2+ medium (low release probability, quantal content = 2 ± 0.1) had the same sensitivity to ω-AgaIVA (IC50 = 16.8 nM) as that in normal saline solutions. In addition, K+-evoked transmitter release was also highly sensitive to the action of this toxin (IC50 = 11.5 nM; 100 nM > 95% blockade). The action of ω-AgaIVA on transmitter release could be reversed by toxin washout if the experiments were carried out at 31-33°C. Conversely, the effect of ω-AgaIVA persisted even after two hours of toxin washout at room temperature. 5. Both the calcium and calcium-dependent potassium presynaptic currents, I(ca), and I(K(Ca)), respectively, were highly sensitive to low concentrations (10-30 nM) of ω-AgaIVA. The I(ca), and the I(K(Ca)) were also strongly reduced by 1 μM ω-MVIIC. The most marked difference between the action of these two toxins was the long incubation times required to achieve maximal effects with ω-MVIIC. 6. In summary these results provide more evidence that synaptic transmission at the mammalian neuromuscular junction is mediated by Ca2+ entry through P- and/or Q-type calcium channels.

Descripción: Context. Recent observational and theoretical works have suggested that the Tully-Fisher relation might be generalised to include dispersion-dominated systems by combining the rotation and dispersion velocity in the definition of the kinematical indicator. Mergers and interactions have been pointed out as responsible of driving turbulent and disordered gas kinematics, which could generate Tully-Fisher relation outliers. Aims. We investigated the gas kinematics of galaxies by using a simulated sample that includes gas-disc-dominated as well as spheroid-dominated systems. We paid particular attention to the scatter evolution of the Tully-Fisher relation. We also determined the gas-phase velocity indicator, which traces the potential well of the galaxy better. Methods. Cosmological hydrodynamical simulations that include a multiphase model and physically motivated supernova feedback were performed to follow the evolution of galaxies as they are assembled. We analysed the gas kinematics of the surviving gas discs to estimate all velocity indicators. Results. Both the baryonic and stellar Tully-Fisher relations for gas-disc-dominated systems are tight while, as more dispersion-dominated systems are included, the scatter increases. We found a clear correlation between σ/V rot and morphology, with dispersion-dominated systems exhibiting higher values (>0.7). Mergers and interactions can affect the rotation curves directly or indirectly, inducing a scatter in the Tully-Fisher relation larger than the simulated evolution since z ~ 3. Kinematical indicators, which combine rotation velocity and dispersion velocity, can reduce the scatter in the baryonic and the stellar mass-velocity relations. In particular, s 1.0 = (V rot 2 + σ 2) 0.5 seems to be the best tracer of the circular velocity at larger radii. Our findings also show that the lowest scatter in both relations is obtained if the velocity indicators are measured at the maximum of the rotation curve. Conclusions. In agreement with previous works, we found that the gas kinematics of galaxies is significantly regulated by mergers and interactions, which play a key role in inducing gas accretion, outflows and starbursts. The joint action of these processes within a hierarchical ΛCDM Universe generates a mean simulated Tully-Fisher relation in good agreement with observations since z ~ 3 but with a scatter depending on morphology. The rotation velocity estimated at the maximum of the gas rotation curve is found to be the best proxy for the potential well regardless of morphology. ©2012 ESO.

Descripción: In the mammalian auditory system, the synapse between efferent olivocochlear (OC) neurons and sensory cochlear hair cells is cholinergic, fast, and inhibitory. This efferent synapse is mediated by the nicotinic α9α10 receptor coupled to the activation of SK2 Ca 2+-activated K+ channels that hyperpolarize the cell. So far, the ion channels that support and/or modulate neurotransmitter release from the OC terminals remain unknown. To identify these channels, we used an isolated mouse cochlear preparation and monitored transmitter release from the efferent synaptic terminals in inner hair cells (IHCs) voltage clamped in the whole-cell recording configuration. Acetylcholine (ACh) release was evoked by electrically stimulating the efferent fibers that make axosomatic contacts with IHCs before the onset of hearing. Using the specific antagonists for P/Q- and N-type voltage-gated calcium channels (VGCCs), ω-agatoxin IVA and ω-conotoxin GVIA, respectively, we show that Ca2+ entering through both types of VGCCs support the release process at this synapse. Interestingly, we found that Ca2+ entering through the dihydropiridine-sensitive L-type VGCCs exerts a negative control on transmitter release. Moreover, using immunostaining techniques combined with electrophysiology and pharmacology, we show that BK Ca2+-activated K+ channels are transiently expressed at the OC efferent terminals contacting IHCs and that their activity modulates the release process at this synapse. The effects of dihydropiridines combined with iberiotoxin, a specific BK channel antagonist, strongly suggest that L-type VGCCs negatively regulate the release of ACh by fueling BK channels that are known to curtail the duration of the terminal action potential in several types of neurons. Copyright © 2010 the authors.

Descripción: In the mature cochlea, inner hair cells (IHCs) transduce acoustic signals into receptor potentials, communicating to the brain by synaptic contacts with afferent fibers. Before the onset of hearing, a transient efferent innervation is found on IHCs, mediated by a nicotinic cholinergic receptor that may contain both α9 and α10 subunits. Calcium influx through that receptor activates calcium-dependent (SK2-containing) potassium channels. This inhibitory synapse is thought to disappear after the onset of hearing [after postnatal day 12 (P12)]. We documented this developmental transition using whole-cell recordings from IHCs in apical turns of the rat organ of Corti. Acetylcholine elicited ionic currents in 88-100% of IHCs between P3 and P14, but in only 1 of 11 IHCs at P16-P22. Potassium depolarization of efferent terminals caused IPSCs in 67% of IHCs at P3, in 100% at P7-P9, in 93% at P10-P12, but in only 40% at P13-P14 and in none of the IHCs tested between P16 and P22. Earlier work had shown by in situ hybridization that α9 mRNA is expressed in adult IHCs but that α10 mRNA disappears after the onset of hearing. In the present study, antibodies to α10 and to the associated calcium-dependent (SK2) potassium channel showed a similar developmental loss. The correlated expression of these gene products with functional innervation suggests that Alpha10 and SK2, but not Alpha9, are regulated by synaptic activity. Furthermore, this developmental knock-out of α10, but not α9, supports the hypothesis that functional nicotinic acetylcholine receptors in hair cells are heteromers containing both these subunits.

Descripción: Most animals rely on olfaction to find sexual partners, food or a habitat. The olfactory system faces the challenge of extracting meaningful information from a noisy odorous environment. In most moth species, males respond to sex pheromone emitted by females in an environment with abundant plant volatiles. Plant odours could either facilitate the localization of females (females calling on host plants), mask the female pheromone or they could be neutral without any effect on the pheromone. Here we studied how mixtures of a behaviourally-attractive floral odour, heptanal, and the sex pheromone are encoded at different levels of the olfactory pathway in males of the noctuid moth Agrotis ipsilon. In addition, we asked how interactions between the two odorants change as a function of the males' mating status. We investigated mixture detection in both the pheromone-specific and in the general odorant pathway. We used a) recordings from individual sensilla to study responses of olfactory receptor neurons, b) in vivo calcium imaging with a bath-applied dye to characterize the global input response in the primary olfactory centre, the antennal lobe and c) intracellular recordings of antennal lobe output neurons, projection neurons, in virgin and newly-mated males. Our results show that heptanal reduces pheromone sensitivity at the peripheral and central olfactory level independently of the mating status. Contrarily, heptanal-responding olfactory receptor neurons are not influenced by pheromone in a mixture, although some post-mating modulation occurs at the input of the sexually isomorphic ordinary glomeruli, where general odours are processed within the antennal lobe. The results are discussed in the context of mate localization. © 2012 Deisig et al.

Descripción: Alternative splicing affects more than 90% of human genes. Coupling between transcription and splicing has become crucial in the complex network underlying alternative splicing regulation. Because chromatin is the real template for nuclear transcription, changes in its structure, but also in the "reading" and "writing" of the histone code, could modulate splicing choices. Here, we discuss the evidence supporting these ideas, from the first proposal of chromatin affecting alternative splicing, performed 20 years ago, to the latest findings including genome-wide evidence that nucleosomes are preferentially positioned in exons. We focus on two recent reports from our laboratories that add new evidence to this field. The first report shows that a physiological stimulus such as neuron depolarization promotes intragenic histone acetylation (H3K9ac) and chromatin relaxation, causing the skipping of exon 18 of the neural cell adhesion molecule gene. In the second report, we show how specific histone modifications can be created at targeted gene regions as a way to affect alternative splicing: Using small interfering RNAs (siRNAs), we increased the levels of H3K9me2 and H3K27me3 in the proximity of alternative exon 33 of the human fibronectin gene, favoring its inclusion into mature messenger RNA (mRNA) through a mechanism that recalls RNAmediated transcriptional gene silencing. © 2010 Cold Spring Harbor Laboratory Press.