Rationale: Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is critical for cardiac development and function. However, it is not clear how these two kinase-domains function to maintain cardiac performance. Objective: To determine the molecular functions of the two kinase-domains of SPEG. Methods and Results: A proteomics approach identified sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) as a protein interacting with the second kinase-domain but not the first kinase-domain of SPEG. Furthermore, the second kinase-domain of SPEG could phosphorylate Thr 484 on SERCA2a, promote its oligomerization and increase calcium re-uptake into the sarcoplasmic/endoplasmic reticulum in culture cells and primary neonatal rat cardiomyocytes. Phosphorylation of SERCA2a by SPEG enhanced its calcium transporting activity without affecting its ATPase activity. Depletion of Speg in neonatal rat cardiomyocytes inhibited SERCA2a Thr 484 phosphorylation and SR calcium re-uptake. Moreover, over-expression of SERCA2a Thr484Ala mutant protein also slowed SR calcium re-uptake in neonatal rat cardiomyocytes. In contrast, domain-mapping and phosphorylation analysis revealed that the first kinase-domain of SPEG interacted and phosphorylated its recently-identified substrate junctophilin-2 (JPH2). An inducible heart-specific Speg knockout mouse model was generated to further study this SPEG-SERCA2a signal nexus in vivo. Inducible deletion of Speg decreased SERCA2a Thr 484 phosphorylation and its oliogomerization in the heart. Importantly, inducible deletion of Speg inhibited SERCA2a calcium transporting activity and impaired calcium re-uptake into the SR in cardiomyocytes, which preceded morphological and functional alterations of the heart and eventually led to heart failure in adult mice. Conclusion: Our data demonstrate that the two kinase-domains of SPEG may play distinct roles to regulate cardiac function. The second kinase-domain of SPEG is a critical regulator for SERCA2a. Our findings suggest that SPEG may serve as a new target to modulate SERCA2a activation for treatment of heart diseases with impaired calcium homeostasis.
The authors investigated whether genetic and environmental factors influence risk for sagittal craniosynostosis. Cases were ascertained from craniofacial clinics in the Baltimore-Washington metropolitan region. Controls were recruited from the Johns Hopkins newborn nursery and a large pediatric practice in Baltimore County. Forty-two probands with isolated, nonsyndromic sagittal craniosynostosis born in the mid-Atlantic region were included in this analysis. Controls are infants born in Maryland without any known birth defects (n = 182). Odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated. Cases were genotyped at several loci implicated in malformation syndromes including craniosynostosis. There were no elevated risks for craniosynostosis related to maternal or paternal smoking or maternal vitamin usage. Case mothers consumed less alcohol (OR = 0.38, 95% CI = 0.17-0.85) and had less education than control mothers ( < 0.001). All cases that were sequenced were negative for mutations at the following genes: exon IIIa 755C->G, (exons IIIa and IIIc,), exon IIIa, and exon 1. These findings suggest that whereas TWIST and the genes are important for syndromic craniosynostosis, they are unlikely to be involved in isolated sagittal craniosynostosis. Parental education and alcohol consumption were associated with sagittal craniosynostosis in this study.
Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10−6
Uniprocessor simulators track resource utilization cycle by cycle to estimate performance. Multiprocessor simulators, however, must account for synchronization events that increase the cost of every cycle simulated and shared resource contention that increases the total number of cycles simulated. These effects cause multiprocessor simulation times to scale superlinearly with the number of cores.Composable performance regression (CPR) fundamentally addresses these intractable multiprocessor simulation times, estimating multiprocessor performance with a combination of uniprocessor, contention, and penalty models. The uniprocessor model predicts baseline performance of each core while the contention models predict interfering accesses from other cores. Uniprocessor and contention model outputs are composed by a penalty model to produce the final multiprocessor performance estimate. Trained with a production quality simulator, CPR is accurate with median errors of 6.63, 4.83 percent for dual-, quad-core multiprocessors. Furthermore, composable regression is scalable, requiring 0.33x the simulations required by prior regression strategies.
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