Fifty Years of ISCA: A data-driven retrospective on key trends

Computer Architecture, broadly, involves optimizing hardware and software for current and future processing systems. Although there are several other top venues to publish Computer Architecture research, including ASPLOS, HPCA, and MICRO, ISCA (the International Symposium on Computer Architecture) is one of the oldest, longest running, and most prestigious venues for publishing Computer Architecture research. Since 1973, except for 1975, ISCA has been organized annually. Accordingly, this year will be the 50th year of ISCA. Thus, we set out to analyze the past 50 years of ISCA to understand who and what has been driving and innovating computing systems thus far. Our analysis identifies several interesting trends that reflect how ISCA, and Computer Architecture in general, has grown and evolved in the past 50 years, including minicomputers, general-purpose uniprocessor CPUs, multiprocessor and multi-core CPUs, general-purpose GPUs, and accelerators.Comment: 17 pages, 11 figure

Configurable isolation: building high availability systems with commodity multi-core processors

High availability is an increasingly important requirement for enterprise systems, often valued more than performance. Systems designed for high availability typically use redundant hardware for error detection and continued uptime in the event of a failure. Chip multiprocessors with an abundance of identical resources like cores, cache and interconnection networks would appear to be ideal building blocks for implementing high availability solutions on chip. However, doing so poses significant challenges with respect to error containment and faulty component replacement. Increasing silicon and transient fault rates with future technology scaling exacerbate the problem. This paper proposes a novel, costeffective, architecture for high availability systems built from future multi-core processors. We propose a new chip multiprocessor architecture that provides configurable isolation for fault containment and component retirement, based upon cost-effective modifications to commodity designs. The design is evaluated for a state-of-the-art industrial fault model and the proposed architecture is shown to provide effective fault isolation and graceful degradation even when the failure rate is high

The utility of laboratory testing for pediatric patients undergoing isotretinoin treatment

Isotretinoin, the most effective treatment for severe cystic acne, involves laboratory monitoring. In this retrospective case series of 130 pediatric patients taking isotretinoin, there were significant increases in cholesterol (143.9 mg/dl to 155.3 mg/dl), triglycerides (81.8 mg/dl to 115.2 mg/dl), and low-density lipoprotein (82.0 mg/dl to 98.1 mg/dl), and a decrease in high-density lipoprotein (50.0 mg/dl to 44.7 mg/dl) from baseline to follow-up (p \u3c .05); there were no significant changes in liver enzymes. None of the patients had clinical sequelae (triglyceride-induced pancreatitis, retinoid-induced hepatotoxicity) related to their abnormal lab values. These findings question the utility of laboratory monitoring for prevention of severe clinical sequelae in pediatric patients, and suggest testing based on individualized risk factors may be more appropriate

Synthesis and Biological Evaluation of N-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1

We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship (SAR) exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic (PK) and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid (CSF) glycine biomarker model in both rodents and non-human primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC)

Synthesis and Biological Evaluation of <i>N</i>‑((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter‑1

We previously disclosed the discovery of rationally designed <i>N</i>-((1-(4-(propylsulfonyl)­piperazin-1-yl)­cycloalkyl)­methyl)­benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues <b>10</b> and <b>11</b>. We describe herein further structure–activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent <i>in vitro</i> GlyT-1 potency and selectivity, favorable ADME and <i>in vitro</i> pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-<b>67</b> exhibited robust <i>in vivo</i> activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-<b>67</b> significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC)