Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed by CD4+ T cells and tempers their homeostatic expansion. Because CD4+ T cell proliferation is tightly coupled to ...bioenergetics, we investigate the role of LAG-3 in modulating naive CD4+ T cell metabolism. LAG-3 deficiency enhances the metabolic profile of naive CD4+ T cells by elevating levels of mitochondrial biogenesis. In vivo, LAG-3 blockade partially restores expansion and the metabolic phenotype of wild-type CD4+ T cells to levels of Lag3−/− CD4+ T cells, solidifying that LAG-3 controls these processes. Lag3−/− CD4+ T cells also demonstrate greater signal transducer and activator of transcription 5 (STAT5) activation, enabling resistance to interleukin-7 (IL-7) deprivation. These results implicate this pathway as a target of LAG-3-mediated inhibition. Additionally, enhancement of STAT5 activation, as a result of LAG-3 deficiency, contributes to greater activation potential in these cells. These results identify an additional mode of regulation elicited by LAG-3 in controlling CD4+ T cell responses.
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•LAG-3 limits CD4+ T cell oxygen consumption and spare respiratory capacity (SRC)•Naive CD4+ T cells utilize their SRC to support spontaneous proliferation•LAG-3 regulates STAT5 and Akt activation•Lag3−/− CD4+ T cells are less dependent upon IL-7 for survival and metabolism
Previte et al. show that LAG-3 expression regulates the metabolic profile of naive CD4+ T cells during homeostatic expansion. They observed that Lag3-deficient CD4+ T cells are resistant to Interleukin-7 deprivation due to enhanced STAT5 activation. Increased STAT5 signaling also mediated greater activation potential in these T cells following stimulation.
In spite of tolerance mechanisms, some individuals develop T-cell-mediated autoimmunity. Posttranslational modifications that increase the affinity of epitope presentation and/or recognition ...represent one means through which self-tolerance mechanisms can be circumvented. We investigated T-cell recognition of peptides that correspond to modified β-cell antigens in subjects with type 1 diabetes. Modified peptides elicited enhanced proliferation by autoreactive T-cell clones. Endoplasmic reticulum (ER) stress in insulinoma cells increased cytosolic calcium and the activity of tissue transglutaminase 2 (tTG2). Furthermore, stressed human islets and insulinomas elicited effector responses from T cells specific for modified peptides, suggesting that ER stress-derived tTG2 activity generated deamidated neoepitopes that autoreactive T cells recognized. Patients with type 1 diabetes had large numbers of T cells specific for these epitopes in their peripheral blood. T cells with these specificities were also isolated from the pancreatic draining lymph nodes of cadaveric donors with established diabetes. Together, these results suggest that self-antigens are enzymatically modified in β-cells during ER stress, giving rise to modified epitopes that could serve to initiate autoimmunity or to further broaden the antigenic repertoire, activating potentially pathogenic CD4
T cells that may not be effectively eliminated by negative selection.
For decades, Moore's Law has delivered the ability to integrate an exponentially increasing number of devices in the same silicon area at a roughly constant cost. This has enabled tremendous levels ...of integration, where the capabilities of computer systems that previously occupied entire rooms can now fit on a single integrated circuit.In recent times, the steady drum beat of Moore's Law has started to slow down. Whereas device density historically doubled every 18-24 months, the rate of recent silicon process advancements has declined. While improvements in device scaling continue, albeit at a reduced pace, the industry is simultaneously observing increases in manufacturing costs.In response, the industry is now seeing a trend toward reversing direction on the traditional march toward more integration. Instead, multiple industry and academic groups are advocating that systems on chips (SoCs) be "disintegrated" into multiple smaller "chiplets." This paper details the technology challenges that motivated AMD to use chiplets, the technical solutions we developed for our products, and how we expanded the use of chiplets from individual processors to multiple product families.
For decades, Moore's Law has delivered the ability to integrate an exponentially increasing number of devices in the same silicon area at a roughly constant cost. This has enabled tremendous levels ...of integration, where the capabilities of computer systems that previously occupied entire rooms can now fit on a single integrated circuit.
In recent times, the steady drum beat of Moore's Law has started to slow down. Whereas device density historically doubled every 18--24 months, the rate of recent silicon process advancements has declined. While improvements in device scaling continue, albeit at a reduced pace, the industry is simultaneously observing increases in manufacturing costs.
In response, the industry is now seeing a trend toward reversing direction on the traditional march toward more integration. Instead, multiple industry and academic groups are advocating that systems on chips (SoCs) be "disintegrated" into multiple smaller "chiplets." This paper details the technology challenges that motivated AMD to use chiplets, the technical solutions we developed for our products, and how we expanded the use of chiplets from individual processors to multiple product families.
'Zeppelin': An SoC for multichip architectures Beck, Noah; White, Sean; Paraschou, Milam ...
2018 IEEE International Solid - State Circuits Conference - (ISSCC),
2018-Feb.
Conference Proceeding
Codenamed "Zeppelin", AMD's next-generation System-on-a-Chip (SoC) was designed for use in multiple products and packages in multiple markets, including server, mainstream PC desktop, and high-end ...desktop. Utilizing GLOBALFOUNDRIES' 14nm LPP FinFET process technology, the "Zeppelin" SoC has over 4.8B transistors. It contains high-performance AMD x86 cores codenamed "Zen" 12, caches, memory controllers, PCIe®, SATA, and other IO controllers, and integrated x86 southbridge chipset capabilities. All these functions are connected on the SoC and between multichip packages and multi-socket systems by AMD Infinity Fabric.
"Zeppelin": An SoC for Multichip Architectures Burd, Thomas; Beck, Noah; White, Sean ...
IEEE journal of solid-state circuits,
2019-Jan., 2019-1-00, 20190101, Letnik:
54, Številka:
1
Journal Article
Recenzirano
AMD's "Zeppelin" system-on-a-chip (SoC) combines eight high-performance "Zen" cores with a shared 16-MB L3 Cache, along with six high-speed I/O links and two DDR4 channels, using the infinity fabric ...(IF) to provide a high speed, low latency, and power-efficient connectivity solution. This solution allows the same SoC silicon die to be designed into three separate packages and provides highly competitive solutions in three different market segments. IF is critical to this high-leverage design re-use, utilizing a coherent, scalable data fabric (SDF) for on-die communication, as well as inter-die links, extending up to eight dies across two packages. To support this scalability, an energy efficient, custom physical-layer link was designed for in-package, high-speed communication between the dies. Using an additional scalable control fabric (SCF), a hierarchical power and system management unit (SMU) was used to monitor and manage a distributed set of dies to ensure the products stay within infrastructure limits. It was essential that the floor plan of the SoC was co-designed with the package substrate. The SoC used a 14-nm FinFET process technology and contains 4.8B transistors on a 213 mm 2 die.
The multifactor investing framework has become very popular in the indexing community. Both academic and practitioner researchers have documented hundreds of equity factors. But which of these ...factors are likely to profit investors once implemented? We find that many of the documented factors lack robustness. Size and quality, two of the more prominent factors, show weak robustness, whereas value, momentum, illiquidity, and low beta are more robust. Further examining implementation characteristics, we find that liquidity-demanding factors, such as illiquidity and momentum, are associated with significantly higher trading costs than are other factors. Investors may be better off accessing these factors through active management rather than indexation.
A simulated portfolio deliberately based on stale price data--a Rip Van Winkle index fund--has both substantially higher performance and lower volatility than a portfolio that uses up-to-date cap ...weights. This holds true over the past 67 years in the United States and over shorter timespans in the world's developed and emerging economies. An examination of the term structure of the stale price anomaly demonstrates that, beyond one year (when short-term momentum prevails), the older the data, the better the performance. In addition, a portfolio based on 20-year-old stale prices adds fully one-third as much risk-adjusted alpha as a hypothetical portfolio based on 20 years of look-ahead clairvoyance. Stale cap weighting is not a sensible strategy, but it sheds more light on the rather stark inadequacies of weighting a portfolio in proportion to a firm's current price or market capitalization.
In spite of tolerance mechanisms, some individuals develop T-cell–mediated autoimmunity. Posttranslational modifications that increase the affinity of epitope presentation and/or recognition ...represent one means through which self-tolerance mechanisms can be circumvented. We investigated T-cell recognition of peptides that correspond to modified β-cell antigens in subjects with type 1 diabetes. Modified peptides elicited enhanced proliferation by autoreactive T-cell clones. Endoplasmic reticulum (ER) stress in insulinoma cells increased cytosolic calcium and the activity of tissue transglutaminase 2 (tTG2). Furthermore, stressed human islets and insulinomas elicited effector responses from T cells specific for modified peptides, suggesting that ER stress–derived tTG2 activity generated deamidated neoepitopes that autoreactive T cells recognized. Patients with type 1 diabetes had large numbers of T cells specific for these epitopes in their peripheral blood. T cells with these specificities were also isolated from the pancreatic draining lymph nodes of cadaveric donors with established diabetes. Together, these results suggest that self-antigens are enzymatically modified in β-cells during ER stress, giving rise to modified epitopes that could serve to initiate autoimmunity or to further broaden the antigenic repertoire, activating potentially pathogenic CD4+ T cells that may not be effectively eliminated by negative selection.
Providing up-to-date input to users' applications is an important data management problem for a distributed computing environment, where each data storage location and intermediate node may have ...specific data available, storage limitations, and communication links available. Sites in the network request data items and each request has an associated deadline and priority. In a military situation, the data staging problem involves positioning data for facilitating a faster access time when it is needed by programs that will aid in decision making. This work concentrates on solving a basic version of the data staging problem in which all parameter values for the communication system and the data request information represent the best known information collected so far and stay fixed throughout the scheduling process. The network is assumed to be oversubscribed and not all requests for data items can be satisfied. A mathematical model for the basic data staging problem is introduced. Then, three multiple-source shortest-path algorithm-based heuristics for finding a near-optimal schedule of the communication steps for staging the data are presented. Each heuristic can be used with each of four cost criteria developed. Thus, 12 implementations are examined. In addition, two different weightings for the relative importance of different priority levels are considered. The performance of the proposed heuristics are evaluated and compared by simulations. The proposed heuristics are shown to perform well with respect to upper and lower bounds. Furthermore, the heuristics and a complex cost criterion allow more highest priority messages to be received than a simple-cost-based heuristic that schedules all highest priority messages first.
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