Cell type-specific regulation of choline acetyltransferase gene expression - Role of the neuron-restrictive silencer element and cholinergic-specific enhancer

This study demonstrates the presence of positive and negative regulatory elements within a 2336-base pair-long region of the rat choline acetyltransferase (ChAT) gene promoter that cooperate to direct cell type-specific expression in cholinergic cells. A 21-base pair-long neuron-restrictive silencer element (NRSE) was identified in the proximal part of this region. This element was recognized by the neuron-restrictive silencer factor (NRSF), previously shown to regulate expression of other neuron-specific genes. The ChAT NRSE was inactive in both cholinergic and non-cholinergic neuronal cells, but repressed expression from a heterologous promoter in non-neuronal cells. Specific deletion of this element allowed ChAT gene promoter activity in non-neuronal cells, and overexpression of NRSF repressed ChAT gene promoter activity in cholinergic cells. The distal part of the ChAT gene promoter showed cholinergic-specific enhancing activity, which stimulated promoter activity in cholinergic cells, but was inactive in non-cholinergic neuronal and non-neuronal cells. This enhancer region suppressed the activity of the ChAT NRSE in cholinergic cells, even after NRSF overexpression. Thus, at least two kinds of regulatory elements cooperate to direct ChAT gene expression to cholinergic neurons, namely a neuron-restrictive silencer element and a cholinergic-specific enhancer

Event generation with SHERPA 1.1

In this paper the current release of the Monte Carlo event generator Sherpa, version 1.1, is presented. Sherpa is a general-purpose tool for the simulation of particle collisions at high-energy colliders. It contains a very flexible tree-level matrix-element generator for the calculation of hard scattering processes within the Standard Model and various new physics models. The emission of additional QCD partons off the initial and final states is described through a parton-shower model. To consistently combine multi-parton matrix elements with the QCD parton cascades the approach of Catani, Krauss, Kuhn and Webber is employed. A simple model of multiple interactions is used to account for underlying events in hadron--hadron collisions. The fragmentation of partons into primary hadrons is described using a phenomenological cluster-hadronisation model. A comprehensive library for simulating tau-lepton and hadron decays is provided. Where available form-factor models and matrix elements are used, allowing for the inclusion of spin correlations; effects of virtual and real QED corrections are included using the approach of Yennie, Frautschi and Suura.Comment: 47 pages, 21 figure

In Utero Drug Exposure Impact on Infant Health

Drug use during pregnancy has many impacts on the baby’s and mother’s health. Prenatal drug use affects a child’s development during his or her life. When exposed to in utero drug use the baby tends to have a lower birth weight, preterm birth, and intrauterine growth restrictions compared to a baby not exposed to drugs. The number of infants being born with withdrawal to drugs is increasing. This is an important problem because the number of fetuses exposed in utero to drugs is increasing. Research shows that exposure does pose a risk to the fetus and birth outcomes. Finding and implementing interventions to support expecting mothers struggling with drug use is a challenge for medical professionals.https://corescholar.libraries.wright.edu/lake_research_symposium_abstracts/1003/thumbnail.jp

Local dynamics of topological magnetic defects in the itinerant helimagnet FeGe

Chiral magnetic interactions induce complex spin textures including helical and conical spin waves, as well as particle-like objects such as magnetic skyrmions and merons. These spin textures are the basis for innovative device paradigms and give rise to exotic topological phenomena, thus being of interest for both applied and fundamental sciences. Present key questions address the dynamics of the spin system and emergent topological defects. Here we analyze the micromagnetic dynamics in the helimagnetic phase of FeGe. By combining magnetic force microscopy, single-spin magnetometry, and Landau-Lifschitz-Gilbert simulations we show that the nanoscale dynamics are governed by the depinning and subsequent motion of magnetic edge dislocations. The motion of these topologically stable objects triggers perturbations that can propagate over mesoscopic length scales. The observation of stochastic instabilities in the micromagnetic structure provides new insight to the spatio-temporal dynamics of itinerant helimagnets and topological defects, and discloses novel challenges regarding their technological usage

IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients

Insulin-like growth factors (IGFs) are essential for skeletal muscle development, regeneration, and hypertrophy. Although autocrine actions of IGF-II are known to initiate myoblast differentiation, the regulatory elements and upstream signaling pathways for myogenic expression of IGF-II remain elusive. Here, we report the regulation of IGF-II transcription by mTOR, as well as by amino acid sufficiency, through the IGF-II promoter 3 and a downstream enhancer during C2C12 myoblast differentiation. Furthermore, we present evidence that IGF production, and not IGF signaling, is the primary target for mTOR's function in the initiation of differentiation. Moreover, myogenic signaling by mTOR is independent of its kinase activity and mediated by the PI3K–Akt pathway. Our findings represent the first identification of a signaling pathway that regulates IGF-II expression in myogenesis and implicate the mTOR–IGF axis as a molecular link between nutritional levels and skeletal muscle development

Body composition and cartilage biomarkers are affected by diet in growing large breed dogs

The purpose of this study was to describe cartilage and bone biochemical markers and body composition in growing large breed dogs and to determine if these masurements are affected by diets of similar caloric density but differing composition

A 0535+26 in the August/September 2005 outburst observed by RXTE and INTEGRAL

In this Letter we present results from INTEGRAL and RXTE observations of the spectral and timing behavior of the High Mass X-ray Binary A 0535+26 during its August/September 2005 normal (type I) outburst with an average flux F(5-100keV)~400mCrab. The search for cyclotron resonance scattering features (fundamental and harmonic) is one major focus of the paper. Our analysis is based on data from INTEGRAL and RXTE Target of Opportunity Observations performed during the outburst. The pulse period is determined. X-ray pulse profiles in different energy ranges are analyzed. The broad band INTEGRAL and RXTE pulse phase averaged X-ray spectra are studied. The evolution of the fundamental cyclotron line at different luminosities is analyzed. The pulse period P is measured to be 103.39315(5)s at MJD 53614.5137. Two absorption features are detected in the phase averaged spectra at E_1~45keV and E_2~100keV. These can be interpreted as the fundamental cyclotron resonance scattering feature and its first harmonic and therefore the magnetic field can be estimated to be B~4x10^12G.Comment: 4 pages, 5 figures, accepted for publication in A&A Letter

A 12-month phase 3 study of pasireotide in cushing's disease

BACKGROUND: Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. METHODS: In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 ??g (82 patients) or 900 ??g (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 ??g twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. RESULTS: Twelve of the 82 patients in the 600-??g group and 21 of the 80 patients in the 900-??g group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. CONCLUSIONS: The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.) Copyright © 2012 Massachusetts Medical Society