Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Neuronal circuitry for pain processing in the dorsal horn

Neurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organization and circuitry of this complex region

Effects of anandamide in migraine: data from an animal model

Systemic nitroglycerin (NTG) produces spontaneous-like migraine attacks in migraine sufferers and induces a condition of hyperalgesia in the rat 4 h after its administration. Endocannabinoid system seems to be involved in the modulation of NTG-induced hyperalgesia, and probably, in the pathophysiological mechanisms of migraine. In this study, the analgesic effect of anandamide (AEA) was evaluated by means of the formalin test, performed in baseline conditions and following NTG-induced hyperalgesia in male Sprague–Dawley rats. AEA was administered 30 min before the formalin injection. In addition, the effect of AEA (administered 30 min before NTG injection) was investigated on NTG-induced Fos expression and evaluated 4 h following NTG injection. AEA induced a significant decrease in the nociceptive behavior during both phases of the formalin test in the animals treated with vehicle, while it abolished NTG-induced hyperalgesia during the phase II. Pre-treatment with AEA significantly reduced the NTG-induced neuronal activation in nucleus trigeminalis caudalis, confirming the results obtained in our previous study, and in area postrema, while the same treatment induced an increase of Fos expression in paraventricular and supraoptic nuclei of the hypothalamus, parabrachial nucleus, and periaqueductal grey. The study confirms that a dysfunction of the endocannabinoid system may contribute to the development of migraine attacks and that a pharmacological modulation of CB receptors can be useful for the treatment of migraine pain

Basement membrane components are key players in specialized extracellular matrices

More than three decades ago, basement membranes (BMs) were described as membrane-like structures capable of isolating a cell from and connecting a cell to its environment. Since this time, it has been revealed that BMs are specialized extracellular matrices (sECMs) with unique components that support important functions including differentiation, proliferation, migration, and chemotaxis of cells during development. The composition of these sECM is as unique as the tissues to which they are localized, opening the possibility that such matrices can fulfill distinct functions. Changes in BM composition play significant roles in facilitating the development of various diseases. Furthermore, tissues have to provide sECM for their stem cells during development and for their adult life. Here, we briefly review the latest research on these unique sECM and their components with a special emphasis on embryonic and adult stem cells and their niches

Tryptophan depletion selectively reduces CSF 5-HT metabolites in healthy young men: results from single lumbar puncture sampling technique

Plasma tryptophan (Trp) depletion is a commonly used tool for determining the role of brain serotonin (5-HT) function in a variety of psychiatric disorders. This study measured the cerebrospinal fluid (CSF) monoamine metabolite response to Trp depletion and control testing in five healthy subjects utilizing a single lumbar puncture. Testing was done in a placebo-controlled, double-blind, randomized, cross-over design. Plasma-free and total Trp levels and behavioural ratings were obtained prior to and 5 h after ingestion of each amino-acid drink. CSF was obtained by performing a standard lumbar puncture 7 h after ingestion of the drink. Compared to control testing, Trp depletion caused a significant decrease of CSF 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.03), but not of homovanillic acid or 3-methoxy-4-hydroxy-phenylglycol. Behavioural ratings were minimally affected in all subjects. This confirms that plasma Trp depletion reduces central nervous system measures of 5-HT function and suggests that the single lumbar puncture technique may be sufficient to detect the extent of CSF 5-HIAA changes during Trp depletion studies