The 4q subtelomere harboring the FSHD locus is specifically anchored with peripheral heterochromatin unlike most human telomeres

This paper investigates the nuclear localization of human telomeres and, specifically, the 4q35 subtelomere mutated in facioscapulohumeral dystrophy (FSHD). FSHD is a common muscular dystrophy that has been linked to contraction of D4Z4 tandem repeats, widely postulated to affect distant gene expression. Most human telomeres, such as 17q and 17p, avoid the nuclear periphery to reside within the internal, euchromatic compartment. In contrast, 4q35 localizes at the peripheral heterochromatin with 4p more internal, generating a reproducible chromosome orientation that we relate to gene expression profiles. Studies of hybrid and translocation cell lines indicate this localization is inherent to the distal tip of 4q. Investigation of heterozygous FSHD myoblasts demonstrated no significant displacement of the mutant allele from the nuclear periphery. However, consistent association of the pathogenic D4Z4 locus with the heterochromatic compartment supports a potential role in regulating the heterochromatic state and makes a telomere positioning effect more likely. Furthermore, D4Z4 repeats on other chromosomes also frequently organize with the heterochromatic compartment at the nuclear or nucleolar periphery, demonstrating a commonality among chromosomes harboring this subtelomere repeat family

A Hubble Space Telescope Imaging Survey of Nearby Active Glactic Nuclei

We obtained 500-second F606W WFPC2 images of 256 of the nearest (z<0.035) Seyfert 1,Seyfert 2, and starburst galaxies. Less than 10% show tidal features or multiple nuclei. The incidence of inner starburst rings is about 10% in both classes of Sy galaxies. In contrast, galaxies with H II region emission line spectra appear substantially more irregular because of their much higher specific rates of star formation. An unresolved central continuum source in our HST images is a virtually perfect indicator of a Sy1 spectrum. 52% of these Sy1 point sources are saturated in our images; we use their wings to estimate their magnitudes. The converse is not however true, as over a third of Sy's with direct spectroscopic evidence for broad Balmer wings show no nuclear point source. Like the Sy2's, they have central surface brightnesses consistent with those expected for the bulges of normal galaxies. The frequency of bars in Sy1's and 2's and non-Sys are the same. The Sy2 galaxies are significantly more likely to show nuclear dust absorption, especially in lanes and patches which are irregular or reach close to the nucleus. The difference cannot be explained by different average redshifts or selection techniques. This is confirmed by our morphology classifications, which show that Sy1 nuclei reside in earlier type galaxies than Sy2 nuclei. This intrinsic difference in host galaxy properties may undermine the strong unification hypothesis for Sy galaxies that they appear different due to the orientation of their central engine. The excess galactic dust we see in Sy2's may cause substantial absorption which obscures their hypothesized broad emission-line regions and central nonstellar continua. This galactic dust could produce much of the absorption in Sy2 nuclei which had instead been attributed to a thick dusty accretion torus.Comment: The text of the paper is 23 pages (ms.tex), there are 8 tables, and 9 figures. Figures 1, 2, and 3 are the image gallery (45 pages) and are NOT included here. They can be ftp'ed from ftp.astro.ucla.edu. Log in as anonymous and give your e-mail address as the password. The images are in the /pub/submit/vg/AGNgallery . Figures 4-9 are in eps format and are included here and can be printed using the lpr command in unix system

L’impact d’un campus clinique régional en milieu urbain : les perceptions des parties prenantes de la collectivité

Background: Regional medical campuses (RMC) have shown promise in addressing physician shortages. RMCs have been positively evaluated in rural/remote communities, however, it is unclear whether this model will be as beneficial in underserved urban areas. This study evaluated the impact of a RMC on a midsized urban city (Windsor, Ontario). We compare our results with a similar study conducted in a remote community in British Columbia (BC). Methods: A broad array of community stakeholders representing different sectors were consulted using a semi-structured interview format replicated from the BC Northern Medical Program (NMP) study. Thematic analysis based on the resulting rich data was conducted within a grounded theory context. Results: Twenty-three participants (52% male) representing healthcare, education, business, community and government/politico sectors were consulted. Their views regarding the Windsor Regional Medical Campus (WRMC) aligned around several themes: improved healthcare, enhanced community reputation, stimulated economic/community development, expanded training opportunities and an engaged community regarding the WRMC. These results were compared to the main findings of the NMP study with both similarities (e.g. increased community pride) and differences (e.g. resource concerns) discussed. Conclusion: Community stakeholders provided strong support for the WRMC through their perceptions of its positive impact on this urban region. These findings are consistent with similar RMC studies in rural/remote areas. Those interested in developing a RMC might benefit from considering these findings.Contexte&nbsp;: Les campus cliniques régionaux (CCR) se sont révélés prometteurs pour remédier à la pénurie de médecins. Les CCR ont été évalués positivement dans les collectivités rurales/éloignées, mais il n’est pas certain que ce modèle soit aussi bénéfique dans les zones urbaines mal desservies. La présente étude évalue l’impact d’un CCR dans une ville de taille moyenne (Windsor, Ontario). Nous comparons nos résultats avec ceux d’une étude similaire menée dans une collectivité éloignée en Colombie-Britannique (BC). Méthode&nbsp;: Un large éventail de parties prenantes de la collectivité représentant différents secteurs a été consulté par le biais d’entrevues semi-structurées calquées sur celles de l’étude du BC Northern Medical Program (NMP). L’analyse thématique des riches données obtenues a été faite selon l’approche de la Grounded Theory (théorie ancrée). Résultats&nbsp;: Vingt-trois participants (52&nbsp;% d’hommes) des secteurs de la santé, de l’éducation, des affaires, de la vie communautaire, du gouvernement ou encore du monde politique ont été consultés. Leurs opinions concernant le campus clinique régional de Windsor (WRMC) s’articulaient autour de plusieurs thèmes&nbsp;: l’amélioration des soins de santé, le renforcement de la réputation de la collectivité, la stimulation du développement économique et communautaire, l’élargissement des possibilités de formation et l’engagement de la communauté envers le WRMC. Les résultats ont été comparés aux principales conclusions de l’étude du NMP, en analysant aussi bien les similitudes (par exemple, fierté accrue de la collectivité) que les différences (par exemple, les préoccupations en matière de ressources). Conclusion&nbsp;: Percevant l’impact positif qu’a eu le WRMC dans la région urbaine, les acteurs de la collectivité témoignent d’un ferme appui à son égard. Ces résultats sont conformes aux études similaires portant sur des CCR dans les zones rurales/éloignées. Les résultats de l’étude seraient utiles à tous ceux qui souhaitant mettre sur pied un CCR

SIRT1-dependent myoprotective effects of resveratrol on muscle injury induced by compression

© 2015 Sin, Yung, Yip, Chan, Wong, Tam and Siu. Our current understanding on the molecular mechanisms by which sustained compression induces skeletal muscle injury is very limited. This study aimed to test the hypothesis that activation of SIRT1 by the natural antioxidant resveratrol could deactivate apoptotic and catabolic signaling in skeletal muscle exposed to moderate compression. Two cycles of 6-h constant pressure at 100 mmHg was applied to the tibialis region of right, but not left hindlimbs of Sprague Dawley rats pre-treated with DMSO (vehicle control) or resveratrol with/without sirtinol. Skeletal muscle tissues lying underneath and spatially corresponding to the compressed sites were collected for analyses. Resveratrol prevented the compression-induced manifestations of pathohistological damages including elevations of the number of interstitial nuclei and area of interstitial space and ameliorated oxidative damages measured as 4-hydroxy-2-nonenal (4HNE) and nitrotyrosine in skeletal muscle. In parallel, resveratrol augmented the expression level and activity of SIRT1 and phosphorylation levels of Foxo3a and Akt while suppressed the increases in protein abundances of p53, Bax, MAFbx, and ubiquitin, enzymatic activities of caspase 3 and 20S proteasome, and apoptotic DNA fragmentation in the compressed muscle. These favorable myoprotective effects of resveratrol were diminished upon pharmacological blockade of SIRT1 by using sirtinol. These novel data support the hypothesis that the anti-apoptotic and anti-catabolic effects of resveratrol on compression injury in skeletal muscle required the action of SIRT1.Link_to_subscribed_fulltex

S100A8 and S100A9 Are Associated with Doxorubicin-Induced Cardiotoxicity in the Heart of Diabetic Mice

© 2016 Pei, Tam, Sin, Wang, Yung, Chan, Wong, Ying, Lai and Siu. Cardiomyopathy is a clinical problem that occurs in the hearts of type 2 diabetic patients as well as cancer patients undergoing doxorubicin chemotherapy. The number of diabetic cancer patients is increasing but surprisingly the cardiac damaging effects of doxorubicin, a commonly used chemotherapeutic drug, on diabetic hearts have not been well-examined. As the signaling mechanisms of the doxorubicin-induced cardiomyopathy in type 2 diabetic heart are largely unknown, this study examined the molecular signaling pathways that are responsible for the doxorubicin-induced cardiotoxicity in type 2 diabetic hearts. Male 14- to 18-week-old db/db mice were used as the type 2 diabetic model, and age-matched non-diabetic db/+ mice served as controls. The db/+ non-diabetic and db/db diabetic mice were randomly assigned to the following groups: db/+CON, db/+DOX-5d, db/+DOX-7d, db/dbCON, db/dbDOX-5d, and db/dbDOX-7d. Mice assigned to doxorubicin (DOX) group were exposed to an intraperitoneal (i.p.) injection of DOX at a dose of 15 mg/kg to induce cardiomyopathy. Mice in control (CON) groups were i.p. injected with the same volume of saline instead of DOX. Mice were euthanized by overdose of ketamine and xylazine 5 or 7 days after the DOX injection. Microarray analysis was adopted to examine the changes of the whole transcriptional profile in response to doxorubicin exposure in diabetic hearts. Ventricular fractional shortening was examined as an indicator of cardiac function by transthoracic echocardiography. The presence of diabetic cardiomyopathy in db/db mice was evident by the reduction of fractional shortening. There was a further impairment of cardiac contractile function 7 days after the DOX administration in db/db diabetic mice. According to our microarray analysis, we identified a panel of regulatory genes associated with cardiac remodeling, inflammatory response, oxidative stress, and metabolism in the DOX-induced cardiac injury in diabetic heart. The microarray results of selected genes were confirmed by real time PCR. Notably, S100A8 and S100A9 were found to have a unique specific expression pattern that was coincident with the DOX-induced cardiomyopathy in diabetic hearts. Correspondingly, NF-κB expression in diabetic hearts was increased together with the elevation of S100A8/9 and activation of p38 MAPK signaling after DOX administration, which induced cardiac inflammation as demonstrated by the elevation of cardiac IL-6 level. These findings provide novel pre-clinical information for revealing the S100A8/A9-associated molecular signaling pathways that mediate the doxorubicin-induced cardiotoxicity in diabetic hearts.Link_to_subscribed_fulltex

Enhancement of outflow facility in the murine eye by targeting selected tight-junctions of Schlemm's canal endothelia

The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm’s canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system

Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease

Fabry disease is an X-linked lysosomal storage disorder caused by loss of alpha-galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of glycosphingolipids in multiple cells and tissues. FLT190, an investigational gene therapy, is currently being evaluated in a Phase 1/2 clinical trial in patients with Fabry disease (NCT04040049). FLT190 consists of a potent, synthetic capsid (AAVS3) containing an expression cassette with a codon-optimized human GLA cDNA under the control of a liver-specific promoter FRE1 (AAV2/S3-FRE1-GLAco). For mouse studies FLT190 genome was pseudotyped with AAV8 for efficient transduction. Preclinical studies in a murine model of Fabry disease (Gla-deficient mice), and non-human primates (NHPs) showed dose-dependent increases in plasma α-Gal A with steady-state observed 2 weeks following a single intravenous dose. In Fabry mice, AAV8-FLT190 treatment resulted in clearance of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in plasma, urine, kidney, and heart; electron microscopy analyses confirmed reductions in storage inclusion bodies in kidney and heart. In NHPs, α-Gal A expression was consistent with the levels of hGLA mRNA in liver, and no FLT190-related toxicities or adverse events were observed. Taken together, these studies demonstrate preclinical proof-of-concept of liver-directed gene therapy with FLT190 for the treatment of Fabry disease