132 research outputs found
BOOM: Broadcast Optimizations for On-chip Meshes
Future many-core chips will require an on-chip network that can support broadcasts and multicasts at good power-performance. A vanilla on-chip network would send multiple unicast packets for each broadcast packet, resulting in latency, throughput and power overheads. Recent research in on-chip multicast support has proposed forking of broadcast/multicast packets within the network at the router buffers, but these techniques are far from ideal, since they increase buffer occupancy which lowers throughput, and packets incur delay and power penalties at each router. In this work, we analyze an ideal broadcast mesh; show the substantial gaps between state-of-the-art multicast NoCs and the ideal; then propose BOOM, which comprises a WHIRL routing protocol that ideally load balances broadcast traffic, a mXbar multicast crossbar circuit that enables multicast traversal at similar energy-delay as unicasts, and speculative bypassing of buffering for multicast flits. Together, they enable broadcast packets to approach the delay, energy, and throughput of the ideal fabric. Our simulations show BOOM realizing an average network latency that is 5% off ideal, attaining 96% of ideal throughput, with energy consumption that is 9% above ideal. Evaluations using synthetic traffic show BOOM achieving a latency reduction of 61%, throughput improvement of 63%, and buffer power reduction of 80% as compared to a baseline broadcast. Simulations with PARSEC benchmarks show BOOM reducing average request and network latency by 40% and 15% respectively
Kernel support for the Wisconsin Wind Tunnel
This paper describes a kernel interface that provides an untrusted user-level process (an executive) with protected access to memory management functions, including the ability to create, manipulate, and execute within subservient contexts (address spaces). Page motion callbacks not only give the executive limited control over physical memory management, but also shift certain responsibilities out of the kernel, greatly reducing kernel state and complexity. The executive interface was motivated by the requirements of the Wisconsin Wind Tunnel (WWT), a system for evaluating cache-coherent shared-memory parallel architectures. WWT uses the executive interface to implement a fine-grain user-level extension of Li's shared virtual memory on a Thinking Machines CM-5, a message-passing multicomputer. However, the interface is sufficiently general that an executive could act as a multiprogrammed operating system, exporting an alternative interface to the threads running in its subservient contexts. The executive interface is currently implemented as an extension to CMOST, the standard operating system for the CM-
Mechanisms for cooperative shared memory
This paper explores the complexity of implementing directory protocols by examining their mechanisms - primitive operations on directories, caches, and network interfaces. We compare the following protocols: Dir1B, Dir4B, Dir4NB, DirnNB, Dir1SW and an improved version of Dir1SW (Dir1SW+). The comparison shows that the mechanisms and mechanism sequencing of Dir1SW and Dir1SW+ are simpler than those for other protocols. We also compare protocol performance by running eight benchmarks on 32 processor systems. Simulations show that Dir1SW+'s performance is comparable to more complex directory protocols. The significant disparity in hardware complexity and the small difference in performance argue that Dir1SW+ may be a more effective use of resources. The small performance difference is attributable to two factors: the low degree of sharing in the benchmarks and Check-In/Check-Out (CICO) directives
Host Differences in Influenza-Specific CD4 T Cell and B Cell Responses Are Modulated by Viral Strain and Route of Immunization
The antibody response to influenza infection is largely dependent on CD4 T cell help for B cells. Cognate signals and secreted factors provided by CD4 T cells drive B cell activation and regulate antibody isotype switching for optimal antiviral activity. Recently, we analyzed HLA-DR1 transgenic (DR1) mice and C57BL/10 (B10) mice after infection with influenza virus A/New Caledonia/20/99 (NC) and defined epitopes recognized by virus-specific CD4 T cells. Using this information in the current study, we demonstrate that the pattern of secretion of IL-2, IFN-γ, and IL-4 by CD4 T cells activated by NC infection is largely independent of epitope specificity and the magnitude of the epitope-specific response. Interestingly, however, the characteristics of the virus-specific CD4 T cell and the B cell response to NC infection differed in DR1 and B10 mice. The response in B10 mice featured predominantly IFN-γ-secreting CD4 T cells and strong IgG2b/IgG2c production. In contrast, in DR1 mice most CD4 T cells secreted IL-2 and IgG production was IgG1-biased. Infection of DR1 mice with influenza PR8 generated a response that was comparable to that in B10 mice, with predominantly IFN-γ-secreting CD4 T cells and greater numbers of IgG2c than IgG1 antibody-secreting cells. The response to intramuscular vaccination with inactivated NC was similar in DR1 and B10 mice; the majority of CD4 T cells secreted IL-2 and most IgG antibody-secreting cells produced IgG2b or IgG2c. Our findings identify inherent host influences on characteristics of the virus-specific CD4 T cell and B cell responses that are restricted to the lung environment. Furthermore, we show that these host influences are substantially modulated by the type of infecting virus via the early induction of innate factors. Our findings emphasize the importance of immunization strategy for demonstrating inherent host differences in CD4 T cell and B cell responses
JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies
BACKGROUND. Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment
European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD.
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. METHODS: The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. RESULTS: Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? CONCLUSIONS: ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
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