Manual / Issue 4 / Blue

Manual, a journal about art and its making. Blue.The fourth issue. Indigo blue, ultramarine blue, cobalt blue, cerulean blue, zaffre blue, indanthrone blue, phthalo blue, cyan blue, Han blue, French blue, Berlin blue, Prussian blue, Venetian blue, Dresden blue, Tiffany blue, Lanvin blue, Majorelle blue, International Klein Blue, Facebook blue. The names given to different shades of blue speak of plants, minerals, and modern chemistry; exoticism, global trade, and national pride; capitalist branding and pure invention. The fourth issue of Manual is a meditation on blue. From precious substance to controllable algorithm to the wide blue yonder, join us as we leap into the blue. Softcover, 64 pages. Published 2015 by the RISD Museum. Proceeds from RISD Museum publications support the work of the museum. Manual 4 (Blue) contributors include Lawrence Berman, A. Will Brown, Linda Catano, Spencer Fitch, Jessica Helfand, Kate Irvin, Oda van Maanen, Dominic Molon, Maggie Nelson, Ingrid A. Neuman, Margot Nishimura, Karen B. Schloss, Anna Strickland, Louis van Tilborgh, and Elizabeth A. Williams.https://digitalcommons.risd.edu/risdmuseum_journals/1003/thumbnail.jp

MASH Explorer: A Universal Software Environment for Top-Down Proteomics

Top-down mass spectrometry (MS)-based proteomics enable a comprehensive analysis of proteoforms with molecular specificity to achieve a proteome-wide understanding of protein functions. However, the lack of a universal software for top-down proteomics is becoming increasingly recognized as a major barrier, especially for newcomers. Here, we have developed MASH Explorer, a universal, comprehensive, and user-friendly software environment for top-down proteomics. MASH Explorer integrates multiple spectral deconvolution and database search algorithms into a single, universal platform which can process top-down proteomics data from various vendor formats, for the first time. It addresses the urgent need in the rapidly growing top-down proteomics community and is freely available to all users worldwide. With the critical need and tremendous support from the community, we envision that this MASH Explorer software package will play an integral role in advancing top-down proteomics to realize its full potential for biomedical research

A Mouse Model of the Human Fragile X Syndrome I304N Mutation

The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA–binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5′UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1) in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N) in the second FMRP KH-type RNA–binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1–null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder

Angiotensin-converting enzyme 2 over-expression in the central nervous system reduces angiotensin-II-mediated cardiac hypertrophy.

Angiotensin-converting enzyme type 2 (ACE2) has been shown to be an important member of the renin angiotensin system. Previously, we observed that central ACE2 reduces the development of hypertension following chronic angiotensin II (Ang-II) infusion in syn-hACE2 transgenic (SA) mice, in which the human ACE2 transgene is selectively targeted to neurons. To study the physiological consequences of central ACE2 over-expression on cardiac function and cardiac hypertrophy, SA and non-transgenic (NT) mice were infused with Ang-II (600 ng/kg/min, sc) for 14 days, and cardiac function was assessed by echocardiography. Blood pressure (BP), hemodynamic parameters, left ventricle (LV) mass/tibia length, relative ventricle wall thickness (2PW/LVD), cardiomyocyte diameters and collagen deposition were similar (P>0.05) between NT and SA mice during saline infusion. After a 2-week infusion, BP was elevated in NT but not in SA mice. Although ejection fraction and fractional shortening were not altered, Ang-II infusion increased 2PW/LVD compared to saline infusion in NT mice. Interestingly, the 2PW/LVD and LV mass/tibia ratios were significantly lower in SA compared to NT mice at the end of infusion. Moreover, Ang-II infusion significantly increased arterial collagen deposition and cardiomyocytes diameter in NT mice but not in transgenic animals (P<0.05). More importantly, ACE2 over expression significantly reduced the Ang-II-mediated increase in urine norepinephrine levels in SA compared to NT mice. The protective effect of ACE2 appears to involve reductions in Ang-II-mediated hypertension and sympathetic nerve activity

TNF-alpha blockade decreases oxidative stress in the paraventricular nucleus and attenuates sympathoexcitation in heart failure rats

Oxidative stress plays an important role in the pathophysiology of cardiovascular disease. Recent evidence suggests that cytokines induce oxidative stress and contribute to cardiac dysfunction. In this study, we investigated whether increased circulating and tissue levels of tumor necrosis factor (TNF)-alpha in congestive heart failure (CHF) modulate the expression of NAD(P)H oxidase subunits, Nox2 and its isoforms, in the paraventricular nucleus (PVN) of the hypothalamus and contribute to exaggerated sympathetic drive in CHF. Heart failure was induced in Sprague-Dawly rats by coronary artery ligation and was confirmed using echocardiography. Pentoxifylline (PTX) was used to block the production of cytokines for a period of 5 wk. CHF induced a significant increase in the production of reactive oxygen species (ROS) in the left ventricle (LV) and in the PVN. The mRNA and protein expression of TNF-alpha, Nox1, Nox2, and Nox4 was significantly increased in the LV and PVN of CHF rats. CHF also decreased ejection fraction, increased Tei index, and increased circulating catecholamines (epinephrine and norepinephrine) and renal sympathetic activity (RSNA). In contrast, treatment with PTX in CHF rats completely blocked oxidative stress and decreased the production of TNF-alpha and Nox2 isoforms both in the LV and PVN. PTX treatment also decreased catecholamines and RSNA and prevented further decrease in cardiac function. In summary, TNF-alpha blockade attenuates ROS and sympathoexcitation in CHF. This study unveils new mechanisms by which cytokines play a role in the pathogenesis of CHF, thus underscoring the importance of targeting cytokines in heart failure

Cardiac hemodynamic parameters for NT and SA mice.

<p>The data is expressed as mean ± SEM (n = 6). All measurements were performed on 3 different cardiac cycles and the values averaged. BP: blood pressure; HR: heart rate; IVS: interventricular septum; LVID: left ventricle internal diameter; LVPW: left ventricle posterior wall thickness; LV Vol: left ventricle end volume; %EF: ejection fraction; %FS: <i>P</i> value (<0.05).</p>*<p>compared to NT in the same treatment and</p>#<p>compared to saline in the same genotype.</p

ACE2 over expression in the brain reduces Ang II-induced collagen deposition in aortas and coronary arteries.

<p>Mice were anesthetized and hearts were processed for Masson's Trichrome staining at the end of 2 weeks Ang II or saline infusion. The average trichrome staining densities were quantified by using Image-Pro Plus software. Brain-targeted ACE2 over expression significantly reduces collagen deposition in coronary arteries (<b>A, B</b>) and aortas (<b>C, D</b>) following 2 weeks of Ang II infusion. N = 5/group. Statistical significance: *<i>P</i><0.05 vs. NT with the same treatment; ^#<i>P</i><0.05 vs. saline with the same genotype.</p