Cache coherence strategies in a many-core processor

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2009.Cataloged from PDF version of thesis.Includes bibliographical references (p. 53-55).Caches are frequently employed in memory systems, exploiting memory locality to gain advantages in high-speed performance and low latency. However, as computer processor core counts increase, maintaining coherence between caches becomes increasingly difficult. Current methods of cache coherence work well in small-scale multi-core processors, however, the viability of cache coherence as processors scale to thousands of cores remains an open question. A novel many-core execution-driven performance simulator, called Graphite and implemented by the Carbon group, has been utilized to study a variety of cache coherency strategies of processors up to 256 cores. Results suggest that cache coherence may be possible in future many-core processors, but that software developers will have to exercise great care to match their algorithms to the target architecture to avoid sub-optimal performance.by Christopher P. Celio.M.Eng

Graphite: A Distributed Parallel Simulator for Multicores

This paper introduces the open-source Graphite distributed parallel multicore simulator infrastructure. Graphite is designed from the ground up for exploration of future multicore processors containing dozens, hundreds, or even thousands of cores. It provides high performance for fast design space exploration and software development for future processors. Several techniques are used to achieve this performance including: direct execution, multi-machine distribution, analytical modeling, and lax synchronization. Graphite is capable of accelerating simulations by leveraging several machines. It can distribute simulation of an off-the-shelf threaded application across a cluster of commodity Linux machines with no modification to the source code. It does this by providing a single, shared address space and consistent single-process image across machines. Graphite is designed to be a simulation framework, allowing different component models to be easily replaced to either model different architectures or tradeoff accuracy for performance. We evaluate Graphite from a number of perspectives and demonstrate that it can simulate target architectures containing over 1000 cores on ten 8-core servers. Performance scales well as more machines are added with near linear speedup in many cases. Simulation slowdown is as low as 41x versus native execution for some applications. The Graphite infrastructure and existing models will be released as open-source software to allow the community to simulate their own architectures and extend and improve the framework

Contractile Function during Angiotensin-II Activation:Increased Nox2 Activity Modulates Cardiac Calcium Handling via Phospholamban Phosphorylation

AbstractBackgroundRenin-angiotensin system activation is a feature of many cardiovascular conditions. Activity of myocardial reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2 or Nox2) is enhanced by angiotensin II (Ang II) and contributes to increased hypertrophy, fibrosis, and adverse remodeling. Recent studies found that Nox2-mediated reactive oxygen species production modulates physiological cardiomyocyte function.ObjectivesThis study sought to investigate the effects of cardiomyocyte Nox2 on contractile function during increased Ang II activation.MethodsWe generated a cardiomyocyte-targeted Nox2-transgenic mouse model and studied the effects of in vivo and ex vivo Ang II stimulation, as well as chronic aortic banding.ResultsChronic subpressor Ang II infusion induced greater cardiac hypertrophy in transgenic than wild-type mice but unexpectedly enhanced contractile function. Acute Ang II treatment also enhanced contractile function in transgenic hearts in vivo and transgenic cardiomyocytes ex vivo. Ang II–stimulated Nox2 activity increased sarcoplasmic reticulum (SR) Ca2+ uptake in transgenic mice, increased the Ca2+ transient and contractile amplitude, and accelerated cardiomyocyte contraction and relaxation. Elevated Nox2 activity increased phospholamban phosphorylation in both hearts and cardiomyocytes, related to inhibition of protein phosphatase 1 activity. In a model of aortic banding–induced chronic pressure overload, heart function was similarly depressed in transgenic and wild-type mice.ConclusionsWe identified a novel mechanism in which Nox2 modulates cardiomyocyte SR Ca2+ uptake and contractile function through redox-regulated changes in phospholamban phosphorylation. This mechanism can drive increased contractility in the short term in disease states characterized by enhanced renin-angiotensin system activation

Calcium-binding protein immunoreactivity in Gudden's tegmental nuclei and the hippocampal formation: differential co-localization in neurons projecting to the mammillary bodies

The principal projections to the mammillary bodies arise from just two sites, Gudden’s tegmental nuclei (dorsal and ventral nuclei) and the hippocampal formation (subiculum and pre/postsubiculum). The present study sought to compare the neurochemical properties of these mammillary body inputs in the rat, with a focus on calcium-binding proteins. Neuronal calretinin (CR) immunoreactivity was sparse in Gudden’s tegmental nuclei and showed no co-localization with neurons projecting to the mammillary bodies. In contrast, many of the ventral tegmental nucleus of Gudden cell that project to the mammillary bodies were parvalbumin (PV)-positive whereas a smaller number of mammillary inputs stained for calbindin (CB). Only a few mammillary body projection cells in the dorsal tegmental nucleus of Gudden co-localized with PV and none co-localized with CB. A very different pattern was found in the hippocampal formation. Here, a large proportion of postsubiculum cells that project to the mammillary bodies co-localized with CR, but not CB or PV. While many neurons in the dorsal and ventral subiculum projected to the mammillary bodies, these cells did not co-localize with the immunofluorescence of any of the three tested proteins. These findings highlight marked differences between hippocampal and tegmental inputs to the rat mammillary bodies as well as differences between the medial and lateral mammillary systems. These findings also indicate some conserved neurochemical properties in Gudden’s tegmental nuclei across rodents and primates

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

A Highly Productive Implementation of an Out-of-Order Processor Generator

General-purpose serial-thread performance gains have become more difficult for industry to realize due to the slowing down of process improvements. In this new regime of poor process scaling, continued performance improvement relies on a number of small-scale micro- architectural enhancements. However, software simulator-based models, which computer architecture research has largely relied upon, may not be well-suited for evaluating ideas at the necessary fidelity.To facilitate architecture research during this fallow period of Moore’s Law, we propose using processor simulators built from synthesizable processor designs. This thesis describes the design of a synthesizable, industry-competitive processor built on recent advancements in open-source hardware: we leverage the new open-source RISC-V instruction set architecture, the new Chisel hardware construction language, and the Rocket-chip processor generator.Our processor generator is called BOOM, and it designed for use in education, research, and industry. Like most contemporary high-performance cores, BOOM is superscalar (able to execute multiple instructions per cycle) and out-of-order (able to execute instructions as their dependencies are resolved and not restricted to their program order).The BOOM generator was implemented using the Chisel hardware construction language, allowing for the rapid implementation of parameterized designs. The Chisel description generates synthesizable implementations of BOOM that can target both FPGAs and ASIC tool-flows. The BOOM effort culminated in a test chip that was fabricated in the TSMC 28 nm HPM process (high performance mobile) using the foundry-provided standard-cell library and memory compiler.This thesis highlights two aspects of the BOOM design: its industry-competitive branch prediction and its configurable execution datapath. The remainder of the thesis discusses the BOOM tape-out, which was performed by two graduate students and demonstrated the ability to quickly adapt the design to the physical design issues that arose

Urban-agricultural water appropriation: the Hyderabad, India case

With the urbanisation drive comes steady growth in urban water demand. Although in the past this new demand could often be met by tapping unclaimed water sources, this option is increasingly untenable in many regions where little if any unclaimed water remains. The result is that urban water capture, and the appropriation of associated physical and institutional infrastructure, now often implies conflict with other existing uses and users. While the urbanisation process has been studied in great depth, the processes and, critically, impacts of urban water capture and appropriation are not well researched or understood. This paper undertakes a critical examination of the specific case of Hyderabad, one of India's fastest growing cities, to shed light more generally on the process of water capture by cities and the resultant impacts on pre-existing claims, particularly agriculture. It does this by examining the history and institutional response to Hyderabad's urban-rural water contest; how the results of that contest are reflected in surface and groundwater hydrology; and the eventual impacts on agriculture. The findings show that the magnitude, and sometimes even direction, of impact from urban water transfer vary in space and time and depend on location-specific rainfall patterns, the nature of existing water infrastructure and institutions, and farmers' adaptive capacities and options, notably recourse to groundwater. Broader consideration of the specific findings provides insights into policy mechanisms to reduce the possible negative impacts from the global, and seemingly inexorable, flow of water to the world's growing cities

Urban-agricultural water appropriation: the Hyderabad, India case

With the urbanisation drive comes steady growth in urban water demand. Although in the past this new demand could often be met by tapping unclaimed water sources, this option is increasingly untenable in many regions where little if any unclaimed water remains. The result is that urban water capture, and the appropriation of associated physical and institutional infrastructure, now often implies conflict with other existing uses and users. While the urbanisation process has been studied in great depth, the processes and, critically, impacts of urban water capture and appropriation are not well researched or understood. This paper undertakes a critical examination of the specific case of Hyderabad, one of India's fastest growing cities, to shed light more generally on the process of water capture by cities and the resultant impacts on pre-existing claims, particularly agriculture. It does this by examining the history and institutional response to Hyderabad's urban-rural water contest; how the results of that contest are reflected in surface and groundwater hydrology; and the eventual impacts on agriculture. The findings show that the magnitude, and sometimes even direction, of impact from urban water transfer vary in space and time and depend on location-specific rainfall patterns, the nature of existing water infrastructure and institutions, and farmers' adaptive capacities and options, notably recourse to groundwater. Broader consideration of the specific findings provides insights into policy mechanisms to reduce the possible negative impacts from the global, and seemingly inexorable, flow of water to the world's growing cities