Nonlinear signaling on biological networks: the role of stochasticity and spectral clustering

Signal transduction within biological cells is governed by networks of interacting proteins. Communication between these proteins is mediated by signaling molecules which bind to receptors and induce stochastic transitions between different conformational states. Signaling is typically a cooperative process which requires the occurrence of multiple binding events so that reaction rates have a nonlinear dependence on the amount of signaling molecule. It is this nonlinearity that endows biological signaling networks with robust switch-like properties which are critical to their biological function. In this study, we investigate how the properties of these signaling systems depend on the network architecture. Our main result is that these nonlinear networks exhibit bistability where the network activity can switch between states that correspond to a low and high activity level. We show that this bistable regime emerges at a critical coupling strength that is determined by the spectral structure of the network. In particular, the set of nodes that correspond to large components of the leading eigenvector of the adjacency matrix determines the onset of bistability. Above this transition, the eigenvectors of the adjacency matrix determine a hierarchy of clusters, defined by its spectral properties, which are activated sequentially with increasing network activity. We argue further that the onset of bistability occurs either continuously or discontinuously depending upon whether the leading eigenvector is localized or delocalized. Finally, we show that at low network coupling stochastic transitions to the active branch are also driven by the set of nodes that contribute more strongly to the leading eigenvector.Comment: 30 pages, 12 figure

Pharmacology and clinical potential of vortioxetine in the treatment of major depressive disorder

Vortioxetine is a new multimodal action antidepressant with two types of action: serotonin transporter (SERT) blockade and a strong affinity for several serotoninergic receptors. It is an antagonist of the 5-HT3 and 5-HT7 receptors, a partial agonist of 5-HT1B, and an agonist of 5-HT1A. Its combined action on SERT and four subtypes of serotoninergic receptors increases the extracellular concentration of serotonin, dopamine, and noradrenaline. Twelve clinical trials have been carried out, nine of which had positive results versus placebo. When active comparators were included in the study design, no significant differences were found except in one study in which the efficacy of vortioxetine was superior to the comparator (agomelatine) in depression resistant to selective serotonin reuptake inhibitors (SSRI)/serotonin-norepinephrine reuptake inhibitors (SNRI) treatment. Tolerability studies indicate that the drug does not cause any important problems on blood tests, vital signs, or on electrocardiography. The lack of weight gain and induction of metabolic syndrome and the lack of significant changes in the QTc are especially important. The incidence rate of sexual dysfunction is low and similar to placebo in various trials. Similarly, cognitive function remains intact with vortioxetine

A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder

The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ⩾30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) – placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD

Ziprasidone versus Olanzapine in the weight gain associated with the treatment of schizophrenia: A six-month double-blind randomized parallel group study

ABSTRACT -Background and Objectives: Previous data from safety analysis indicate that olanzapine can result in substantial weight gain, while no change has been observed with ziprasidone. Obesity may be a threat to health and cause subjects to discontinue their antipsychotic medication. To further evaluate the differential effects of ziprasidone and olanzapine on weight gain, a study was carried out having body weight as the primary efficacy endpoint. Methods: A six-month randomized, double-blind, parallel study was carried out in male and female subjects aged 18-70 years with a primary diagnosis of schizophrenia (DSM-IV-TR) and a clinical condition requiring treatment initiation with a new antipsychotic, ziprasidone or olanzapine 1:1, to assess treatment-related weight changes. Fifty patients were included. Efficacy outcomes were assessed at baseline and at weeks 1, 4, 12, 18 and 24. The primary efficacy endpoint was the percent change from baseline in body weight at week 24. Safety was also assessed. Results: At week 24, there was a significantly greater increase in body weight (7.5%, p &lt; 0.0001) in patients treated with olanzapine than in those treated with ziprasidone and EFFECTS OF ZIPRASIDONE VERSUS OLANZAPINE IN WEIGHT GAIN 24

Methodology to improve the model of series inductance in CMOS integrated inductors

This paper presents a systematic optimization methodology to achieve an accurate estimation of series inductance of inductors implemented in standard CMOS technologies. Proposed method is based on an optimization procedure which aims to obtain adjustment factors associated to main physical inductor characteristics, allowing to estimate more accurate series inductance values that can be used in design stage. Experimental measurements of diverse square inductor geometries are shown and compared with previous approaches in order to demonstrate and validate presented approach.National Council of Science and Technology of México (CONACYT) TEC2013-45638-C3-3-RSpanish Ministry of Economy and Competitiveness TEC2013-45638-C3-3-REuropean Regional Development Fund TEC2013-45638-C3-3-RConsejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía P12-TIC-148

Calibration of Correlation Radiometers Using Pseudo-Random Noise Signals

The calibration of correlation radiometers, and particularly aperture synthesis interferometric radiometers, is a critical issue to ensure their performance. Current calibration techniques are based on the measurement of the cross-correlation of receivers’ outputs when injecting noise from a common noise source requiring a very stable distribution network. For large interferometric radiometers this centralized noise injection approach is very complex from the point of view of mass, volume and phase/amplitude equalization. Distributed noise injection techniques have been proposed as a feasible alternative, but are unable to correct for the so-called “baseline errors” associated with the particular pair of receivers forming the baseline. In this work it is proposed the use of centralized Pseudo-Random Noise (PRN) signals to calibrate correlation radiometers. PRNs are sequences of symbols with a long repetition period that have a flat spectrum over a bandwidth which is determined by the symbol rate. Since their spectrum resembles that of thermal noise, they can be used to calibrate correlation radiometers. At the same time, since these sequences are deterministic, new calibration schemes can be envisaged, such as the correlation of each receiver’s output with a baseband local replica of the PRN sequence, as well as new distribution schemes of calibration signals. This work analyzes the general requirements and performance of using PRN sequences for the calibration of microwave correlation radiometers, and particularizes the study to a potential implementation in a large aperture synthesis radiometer using an optical distribution network

Allelic and genotypic associations of DRD2 Taq I A polymorphism with heroin dependence in Spanish subjects: a case control study

Background: Conflicting associations with heroin dependence have been found involving the A1 allele of dopamine D2 receptor gene ( DRD2) TaqI A polymorphism. Methods: We compared two samples of unrelated Spanish individuals, all of European origin: 281 methadone-maintained heroin-dependent patients ( 207 males and 74 females) who frequently used non-opioid substances, and 145 control subjects ( 98 males and 47 females). Results: The A1-A1 genotype was detected in 7.1% of patients and 1.4% of controls ( P = 0.011, odds ratio = 5.48, 95% CI 1.26-23.78). Although the A1 allele was not associated with heroin dependence in the entire sample, the frequency of A1 allele was higher in male patients than in male controls ( 24.4% vs. 16.3%, P = 0.024, odds ratio = 1.65, 95% CI 1.07-2.57). A logistic regression analysis showed an interaction between DRD2 alleles and gender ( odds ratio = 1.77, 95% CI 1.15-2.70). Conclusion: Our results indicate that, in Spanish individuals, genotypes of the DRD2 TaqI A polymorphism contribute to variations in the risk of heroin dependence, while single alleles contribute only in males

Stress tensor fluctuations in de Sitter spacetime

The two-point function of the stress tensor operator of a quantum field in de Sitter spacetime is calculated for an arbitrary number of dimensions. We assume the field to be in the Bunch-Davies vacuum, and formulate our calculation in terms of de Sitter-invariant bitensors. Explicit results for free minimally coupled scalar fields with arbitrary mass are provided. We find long-range stress tensor correlations for sufficiently light fields (with mass m much smaller than the Hubble scale H), namely, the two-point function decays at large separations like an inverse power of the physical distance with an exponent proportional to m^2/H^2. In contrast, we show that for the massless case it decays at large separations like the fourth power of the physical distance. There is thus a discontinuity in the massless limit. As a byproduct of our work, we present a novel and simple geometric interpretation of de Sitter-invariant bitensors for pairs of points which cannot be connected by geodesics.Comment: 35 pages, 4 figure

Engineering Polar Oxynitrides: Hexagonal Perovskite BaWON2

Non-centrosymmetric polar compounds have important technological properties. Reported perovskite oxy- nitrides show centrosymmetric structures, and for some of them high permittivities have been observed and ascribed to local dipoles induced by partial order of nitride and oxide. Reported here is the first hexagonal perovskite oxynitride BaWON2, which shows a polar 6H polytype. Synchrotron X-ray and neutron powder diffraction, and annular bright-field in scan- ning transmission electron microscopy indicate that it crystal- izes in the non-centrosymmetric space group P63mc, with a total order of nitride and oxide at two distinct coordination environments in cubic and hexagonal packed BaX3 layers. A synergetic second-order Jahn-Teller effect, supported by first principle calculations, anion order, and electrostatic repulsions between W6+ cations, induce large distortions at two inequiva- lent face-sharing octahedra that lead to long-range ordered dipoles and spontaneous polarization along the c axis. The new oxynitride is a semiconductor with a band gap of 1.1 eV and a large permittivity