Desmin is essential for the structure and function of the sinoatrial node:implications for increased arrhythmogenesis

Our objective was to investigate the effect of desmin depletion on the structure and function of the sinoatrial pacemaker complex (SANcl) and its implication in arrhythmogenesis. Analysis of mice and humans (SANcl) indicated that the sinoatrial node exhibits high amounts of desmin, desmoplakin, N-cadherin, and β-catenin in structures we call “lateral intercalated disks” connecting myocytes side by side. Examination of the SANcl from an arrhythmogenic cardiomyopathy model, desmin-deficient (Des-/-) mouse, by immunofluorescence, ultrastructural, and Western blot analysis showed that the number of these lateral intercalated disks was diminished. Also, electrophysiological recordings of the isolated compact sinoatrial node revealed increased pacemaker systolic potential and higher diastolic depolarization rate compared with wild-type mice. Prolonged interatrial conduction expressed as a longer P wave duration was also observed in Des-/mice. Upregulation of mRNA levels of both T-type Ca2+ current channels, Cav3.1 and Cav3.2, in the Des-/- myocardium (1.8- and 2.3-fold, respectively) and a 1.9-fold reduction of funny hyperpolarization-activated cyclic nucleotide-gated K+ channel 1 could underlie these functional differences. To investigate arrhythmogenicity, electrocardiographic analysis of Des-deficient mice revealed a major increase in supraventricular and ventricular ectopic beats compared with wild-type mice. Heart rate variability analysis indicated a sympathetic predominance in Des-/- mice, which may further contribute to arrhythmogenicity. In conclusion, our results indicate that desmin elimination leads to structural and functional abnormalities of the SANcl. These alterations may be enhanced by the sympathetic component of the cardiac autonomic nervous system, which is predominant in the desmin-deficient heart, thus leading to increased arrhythmogenesis

Wormhole IP over (Connectionless) ATM

ABSTRACT: In the eighties, high throughput and low latency requirements in multiprocessor interconnection networks led to wormhole routing. Today, the same techniques are applicable to routing internet packets over ATM hardware athigh speed. Just like virtual channels in wormhole routing carry packets segmented into flits, a number of hardware-managed VC’s in ATM can carry IP packets segmented into cells according to AAL-5; each VC is dedicated to one packet for the duration of that packet, and is afterwards reassigned to another packet, in hardware. This idea was introduced by Barnett [Barn97] and was named connectionless ATM. We modify the Barnett proposal to make it applicable to existing ATMequipment: we propose a single-input, single-output Wormhole IP Router, that functions as a VP/VC translation filter between ATM subnetworks; fast IP routing lookups can be as in [GuLK98]. Based on actual internet traces, we show by simulation that a few tens of hardware-managed VC’s per outgoing VP suffice for all but 10 −4 or less of the packets. We ana-lyze the hardware cost of a wormhole IP routing filter, and show that it can be built at low cost: 10 off-the-shelf chips will do for 622 Mb/s operation; using pipelining, oper-ation is feasible even at 10 Gb/s, today

Wormhole IP over (Connectionless) ATM

Abstract− − High speed switches and routers internally operate using fixed-size cells or segments; variable-size packets are segmented and later reassembled. Connectionless ATMwas proposed to quickly carry IP packets segmented into cells (AAL5) using a number of hardware-managed ATM VC’s. We show that this is analogous to wormhole routing. We modify this architecture to make it applicable to existing ATM equipment: we propose a low-cost, singleinput, single-output Wormhole IP Router that functions as a VP/VC translation filter between ATM subnetworks. When compared to IP routers, the proposed architecture features simpler hardware and lower latency. When compared to software-based IP-over-ATM techniques, the new architecture avoids the overheads of a large number of labels, or the delays of establishing new flows in software after the first few packets have suffered considerable latencies. We simulated a wormhole IP routing filter, showing that a few tens of hardware-managed VC’s per outgoing VP usually suffice. We built and successfully tested a prototype, operating at 2 × 155 Mbps, using one FPGA and DRAM. Simple analysis shows that operation at 10 Gbps and beyond is feasible today. Index Terms− − IP over ATM, connectionless ATM, wormhole routing, gigabit router, wormhole IP, routing filter. 1

PPARβ/δ at the crossroads of energy metabolism, mitochondrial quality control and redox balance

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ), member of the PPAR subfamily of nuclear receptors, is highly expressed in tissues with high rates of oxidative metabolism, such as the heart, skeletal muscle and liver. PPARβ/δ exerts its transcriptional control by direct binding on specific response elements on target genes promoters with the help of cofactors resulting in transactivation or transrepression of multiple genes involved in energy metabolism, mitochondrial biogenesis, or antioxidant defense. Several pre-clinical studies have shown that reduced PPARβ/δ expression in the heart is associated with diminished cardiac performance, impaired contractility and relaxation and even decreased survival in cardiomyopathies with distinct aetiologies while ligand-mediated activation or overexpression of PPARβ/δ has been shown to be protective in the setting of ischemia/reperfusion injury and several types of cardiomyopathies (dilated, hypertrophic or diabetic). PPARβ/δ stimulates fatty acid and glucose uptake as well as fatty acid oxidation but does not control triglyceride synthesis. In parallel, PPARβ/δ upregulates PGC1α, which is the critical regulator of mitochondrial biogenesis, and is also associatedwith mediators of mitochondrial fusion/fission and components of mitochondrial respiration. In addition, PPARβ/δ has been linked to multiple antioxidant defense mechanisms in the heart, including SOD1 and 2, Catalase, ALDH2 or NF-κB related pathways. Overall, this review summarizes the research data on the role of PPARβ/δ in the regulation of cardiac energy metabolism, antioxidant defense systems and mitochondrial quality control. Those data suggest the potential of PPARβ/δ activation as a therapeutic target for patients with cardiometabolic disorders

The <i>Han:SPRD</i> Rat: A Preclinical Model of Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) stands as the most prevalent hereditary renal disorder in humans, ultimately culminating in end-stage kidney disease. Animal models carrying mutations associated with polycystic kidney disease have played an important role in the advancement of ADPKD research. The Han:SPRD rat model, carrying an R823W mutation in the Anks6 gene, is characterized by cyst formation and kidney enlargement. The mutated protein, named Samcystin, is localized in cilia of tubular epithelial cells and seems to be involved in cystogenesis. The homozygous Anks6 mutation leads to end-stage renal disease and death, making it a critical factor in kidney development and function. This review explores the utility of the Han:SPRD rat model, highlighting its phenotypic similarity to human ADPKD. Specifically, we discuss its role in preclinical trials and its importance for investigating the pathogenesis of the disease and developing new therapeutic approaches