Utility of genetics for risk stratification in pediatric hypertrophic cardiomyopathy.

Children with hypertrophic cardiomyopathy (HCM) experience sudden cardiac death (SCD) and other life-threatening events. We assessed if affected gene and variant burden predict outcomes. Patients <18 years old with primary HCM with a pathogenic variant or variant of uncertain significance in cardiomyopathy genes were included. Association of gene and variant number and type with freedom from major adverse cardiac events (MACE), that is, ICD insertion, myectomy, aborted SCD, transplantation or death, was assessed by Cox regression. A total of 98 of 155 gene-tested patients carried a non-benign variant. The primary affected gene was MYH7 in 35% (MYH7+) and MYBPC3 in 49% (MYBPC3+). MYH7+ patients had earlier disease onset and higher risk of MACE (hazard ratio 2.7, 95% CI 1.3-5.7). Risk of MACE was also higher in patients with multiple variants (n = 16) (HR 2.5, CI: 1.1-5.9) compared to a propensity score-matched single variant subset, after adjustment for primary gene, and in patients with de novo (n = 18) vs inherited variants (HR 5.7, CI: 2.6-12.7). Affected gene (eg, MYH7), higher variant burden and de novo variant status are independently associated with earlier onset and higher frequency of adverse outcomes in pediatric HCM, highlighting the importance of genetic risk stratification in HCM.

Apomorphine reduces subthalamic neuronal entropy in parkinsonian patients.

Dopamine depletion in Parkinson's disease (PD) alters the neuronal activity in basal ganglia circuits. Characterizing these changes in network activity is an important step in understanding the disease and how therapies mitigate symptoms. Non-linear analysis methods can complement the traditional description of neuronal firing characteristics. Here we examine the entropy of subthalamic neurons in PD patients undergoing stereotactic surgery for deep brain stimulation (DBS). The activity of 8 neurons was recorded prior to, during, and following systemic administration of the dopamine agonist apomorphine at clinically effective doses. Apomorphine induced a decrease in entropy measured in the inter-spike intervals of sub-thalamic neurons in 6 of the 8 neurons. This is the first report that anti-parkinsonian drugs affect non-linear features of neuronal firing in the basal ganglia of parkinsonian patients.

Proteomics characterization of abundant Golgi membrane proteins.

A mass spectrometric analysis of proteins partitioning into Triton X-114 from purified hepatic Golgi apparatus (84% purity by morphometry, 122-fold enrichment over the homogenate for the Golgi marker galactosyl transferase) led to the unambiguous identification of 81 proteins including a novel Golgi-associated protein of 34 kDa (GPP34). The membrane protein complement was resolved by SDS-polyacrylamide gel electrophoresis and subjected to a hierarchical approach using delayed extraction matrix-assisted laser desorption ionization mass spectrometry characterization by peptide mass fingerprinting, tandem mass spectrometry to generate sequence tags, and Edman sequencing of proteins. Major membrane proteins corresponded to known Golgi residents, a Golgi lectin, anterograde cargo, and an abundance of trafficking proteins including KDEL receptors, p24 family members, SNAREs, Rabs, a single ARF-guanine nucleotide exchange factor, and two SCAMPs. Analytical fractionation and gold immunolabeling of proteins in the purified Golgi fraction were used to assess the intra-Golgi and total cellular distribution of GPP34, two SNAREs, SCAMPs, and the trafficking proteins GBF1, BAP31, and alpha(2)P24 identified by the proteomics approach as well as the endoplasmic reticulum contaminant calnexin. Although GPP34 has never previously been identified as a protein, the localization of GPP34 to the Golgi complex, the conservation of GPP34 from yeast to humans, and the cytosolically exposed location of GPP34 predict a role for a novel coat protein in Golgi trafficking.

Terabit optical local area networks for multiprocessing systems.

The design of a scalable optical local area network formultiprocessing systems is described. Each workstation has aparallel-fiber-ribbon optical link to a centralized complementarymetal-oxide silicon (CMOS) switch core, implemented on a singlecompact printed circuit board (PCB). When the Motorola Optobusfiber technology is used, each workstation has a data bandwidth of 6.4Gbits/s to the core. A centralized switch core interconnecting 32workstations supports a 204-Gbit/s aggregate data bandwidth. Theswitch core is based on a conventional broadcast-and-selectarchitecture, implemented with parallel CMOS integrated circuits(IC's). The switch core scales well; by incorporation of theCMOS optoelectronic IC's with optical input-output, the electricalcore can be reduced to a single-chip optoelectronic IC with terabitcapacities. A prototype of an optoelectronic switch core has been fabricated and is described. The appeal of the architectureincludes its reliance on commercially available parallel-fibertechnology, its reliance on the well-developed markets of local areanetworks and networks of workstations, and its smooth scalability from the electrical to optical domains as technology matures.