Quality of Service and System Design

Quality of Service (QoS) of the implementation of an application can be defined as a function of the properties of the application and its implementation as observed by the user and/or the environment. Typical application and implementation properties include latency, throughput, jitter, and the level of resolution. Many of the current and pending most popular applications, such as multimedia, wireless sensing and communications, security and PEBBs, have intrinsic relevant QoS components. Recently, quality of service attracted a great of deal of attention in a number of research and development communities, and in particular, in the network and multimedia literature. However, until now synthesis and CAD research did not addressed how to design systems with quantitative QoS requirements. Our goal in this paper is to outline foundations and framework in which QoS system design trade-offs and optimization can be addressed. We first identify and state in synthesis-usable way two currently most popular approaches to Quality of Service treatment: Q-RAM and DScurve (demand/service). We discuss advantages and limitations of the two approaches. Next, we show how these two approaches can be combined in a new more comprehensive QoS framework. We also explain and illustrate using examples interaction between QoS and synthesis and compilation tasks. We conclude by identifying and discussing the future directions related to synthesis of QoS-sensitive systems

Long-Term Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Golden Retriever Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n =4) and were compared with age-matched, untreated GRMD controls (n =3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large-animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients

Long-term Restoration of Cardiac Dystrophin Expression in Golden Retriever Muscular Dystrophy Following rAAV6-mediated Exon Skipping

Although restoration of dystrophin expression via exon skipping in both cardiac and skeletal muscle has been successfully demonstrated in the mdx mouse, restoration of cardiac dystrophin expression in large animal models of Duchenne muscular dystrophy (DMD) has proven to be a challenge. In large animals, investigators have focused on using intravenous injection of antisense oligonucleotides (AO) to mediate exon skipping. In this study, we sought to optimize restoration of cardiac dystrophin expression in the golden retriever muscular dystrophy (GRMD) model using percutaneous transendocardial delivery of recombinant AAV6 (rAAV6) to deliver a modified U7 small nuclear RNA (snRNA) carrying antisense sequence to target the exon splicing enhancers of exons 6 and 8 and correct the disrupted reading frame. We demonstrate restoration of cardiac dystrophin expression at 13 months confirmed by reverse transcription-PCR (RT-PCR) and immunoblot as well as membrane localization by immunohistochemistry. This was accompanied by improved cardiac function as assessed by cardiac magnetic resonance imaging (MRI). Percutaneous transendocardial delivery of rAAV6 expressing a modified U7 exon skipping construct is a safe, effective method for restoration of dystrophin expression and improvement of cardiac function in the GRMD canine and may be easily translatable to human DMD patients

60-GHz LNA Using a Hybrid Transmission Line and Conductive Path to Ground Technique in Silicon

A monolithic 60 GHz low-noise amplifier (LNA) using a passive noise suppression technique and an enhanced hybrid transmission line structure, fabricated in a 0.12 mum SiGe BiCMOS process is presented. This design provides the entire circuit with a conductive path to ground the P-substrate. Near active device regions, noise injection and crosstalk paths are shunted to ground. Measurements of the single-stage LNA show peak performance at 59 GHz exhibiting a gain of 14.5 dB, a NF of 4.1 dB, a + 1.5 dBm output compression point, while consuming 4.5 mA from a 1.8 v supply. Across the entire V-band (57 - 64 GHz), the LNA provides a minimum gain of 12 dB with an average noise figure of 5 dB. This LNA has the highest known figure of merit reported for a 60 GHz application

A Comparative Study of <i>N</i>-glycolylneuraminic Acid (Neu5Gc) and Cytotoxic T Cell (CT) Carbohydrate Expression in Normal and Dystrophin-Deficient Dog and Human Skeletal Muscle

<div><p>The expression of <i>N</i>-glycolylneuraminic acid (Neu5Gc) and the cytotoxic T cell (CT) carbohydrate can impact the severity of muscular dystrophy arising from the loss of dystrophin in mdx mice. Here, we describe the expression of these two glycans in skeletal muscles of dogs and humans with or without dystrophin-deficiency. Neu5Gc expression was highly reduced (>95%) in muscle from normal golden retriever crosses (GR, n = 3) and from golden retriever with muscular dystrophy (GRMD, n = 5) dogs at multiple ages (3, 6 and 13 months) when compared to mouse muscle, however, overall sialic acid expression in GR and GRMD muscles remained high at all ages. Neu5Gc was expressed on only a minority of GRMD satellite cells, CD8⁺ T lymphocytes and macrophages. Human muscle from normal (no evident disease, n = 3), Becker (BMD, n = 3) and Duchenne (DMD, n = 3) muscular dystrophy individuals had absent to very low Neu5Gc staining, but some punctate intracellular muscle staining was present in BMD and DMD muscles. The CT carbohydrate was localized to the neuromuscular junction in GR muscle, while GRMD muscles had increased expression on a subset of myofibers and macrophages. In humans, the CT carbohydrate was ectopically expressed on the sarcolemmal membrane of some BMD muscles, but not normal human or DMD muscles. These data are consistent with the notion that altered Neu5Gc and CT carbohydrate expression may modify disease severity resulting from dystrophin deficiency in dogs and humans.</p></div

Quantification of Neu5Ac and Neu5Gc levels in normal and dystrophin-deficient mouse and dog muscles.

<p>Tibialis anterior (TA) and soleus (Sol) muscles were analyzed from 11 wild type (WT) mice, TA and gastrocnemius (GS) muscles were analyzed from 8 mdx mice, and vastus lateralis (VL) and cranial sartorius (CS) muscles were analyzed from 2 golden retriever (GR) and 5 golden retriever muscular dystrophy (GRMD) dogs. Average Neu5Gc as a percentage of total sialic acid is shown. Errors are standard deviation (SD). ***P<0.001, for all dog vs. mouse muscle comparisons.</p

Co-localization of Neu5Gc staining with markers for endosomes and Golgi in BMD and DMD muscle.

<p>(A) BMD muscle co-stained for Neu5Gc (green) and clathrin (red), a marker of endosomes. Merged image on right shows overlap of Neu5Gc and clathrin expression in yellow. Arrow marks several examples of co-staining. (B) DMD muscle co-stained for Neu5Gc (green) with LAMP1, a lysosomal marker, 58K Golgi, a Golgi marker, or calnexin, and endoplasmic reticulum marker, all in red, and DAPI (blue). Arrow marks region of coincident staining (yellow) for Neu5Gc and 58K Golgi. Bar is 50 µm for all panels in A and B.</p