IMP: Indirect Memory Prefetcher

Machine learning, graph analytics and sparse linear algebra-based applications are dominated by irregular memory accesses resulting from following edges in a graph or non-zero elements in a sparse matrix. These accesses have little temporal or spatial locality, and thus incur long memory stalls and large bandwidth requirements. A traditional streaming or striding prefetcher cannot capture these irregular access patterns. A majority of these irregular accesses come from indirect patterns of the form A[B[i]]. We propose an efficient hardware indirect memory prefetcher (IMP) to capture this access pattern and hide latency. We also propose a partial cacheline accessing mechanism for these prefetches to reduce the network and DRAM bandwidth pressure from the lack of spatial locality. Evaluated on 7 applications, IMP shows 56% speedup on average (up to 2.3×) compared to a baseline 64 core system with streaming prefetchers. This is within 23% of an idealized system. With partial cacheline accessing, we see another 9.4% speedup on average (up to 46.6%).Intel Science and Technology Center for Big Dat

Discrete Generation of Superoxide and Hydrogen Peroxide by T Cell Receptor Stimulation: Selective Regulation of Mitogen-Activated Protein Kinase Activation and Fas Ligand Expression

Receptor-stimulated generation of reactive oxygen species (ROS) has been shown to regulate signal transduction, and previous studies have suggested that T cell receptor (TCR) signals may involve or be sensitive to ROS. In this study, we have shown for the first time that TCR cross-linking induced rapid (within 15 min) generation of both hydrogen peroxide and superoxide anion, as defined with oxidation-sensitive dyes, selective pharmacologic antioxidants, and overexpression of specific antioxidant enzymes. Furthermore, the data suggest the novel observation that superoxide anion and hydrogen peroxide are produced separately by distinct TCR-stimulated pathways. Unexpectedly, TCR-stimulated activation of the Fas ligand (FasL) promoter and subsequent cell death was dependent upon superoxide anion, but independent of hydrogen peroxide, while nuclear factor of activated T cells (NFAT) activation or interleukin 2 transcription was independent of all ROS. Anti-CD3 induced phosphorylation of extracellular signal–regulated kinase (ERK)1/2 required hydrogen peroxide generation but was unaffected by superoxide anion. Thus, antigen receptor signaling induces generation of discrete species of oxidants that selectively regulate two distinct redox sensitive pathways, a proapoptotic (FasL) and a proliferative pathway (ERK)

Regulators of Tfh cell differentiation

The follicular helper T (Tfh) cells help is critical for activation of B cells, antibody class switching and germinal center formation. The Tfh cells are characterized by the expression of CXCR5, ICOS, PD-1, Bcl-6, and IL-21. They are involved in clearing infections and are adversely linked with autoimmune diseases and also have a role in viral replication as well as clearance. Tfh cells are generated from naïve CD4 T cells with sequential steps involving cytokine signaling (IL-21, IL-6, IL-12, activin A), migration and positioning in the germinal center by CXCR5, surface receptors (ICOS/ICOSL, SAP/SLAM) as well as transcription factor (Bcl-6, c-Maf, STAT3) signaling and repressor miR155. On the other hand Tfh generation is negatively regulated at specific steps of Tfh generation by specific cytokine (IL-2, IL-7), surface receptor (PD-1, CTLA-4), transcription factors Blimp-1, STAT5, T-bet, KLF-2 signaling and repressor miR 146a. Interestingly, miR 17-92 and FOXO1 acts as a positive as well as a negative regulator of Tfh differentiation depending on the time of expression and disease specificity. Tfh cells are also generated from the conversion of other effector T cells as exemplified by Th1 cells converting into Tfh during viral infection. The mechanistic details of effector T cells conversion into Tfh are yet to be clear. To manipulate Tfh cells for therapeutic implication and or for effective vaccination strategies, it is important to know positive and negative regulators of Tfh generation. Hence, in this review we have highlighted and interlinked molecular signaling from cytokines, surface receptors, transcription factors, ubiquitin Ligase and miRNA as positive and negative regulators for Tfh differentiation

Banshee: Bandwidth-Efficient DRAM Caching via Software/Hardware Cooperation

© 2017 Association for Computing Machinery. Placing the DRAM in the same package as a processor enables several times higher memory bandwidth than conventional offpackage DRAM. Yet, the latency of in-package DRAM is not appreciably lower than that of off-package DRAM. A promising use of in-package DRAM is as a large cache. Unfortunately, most previous DRAM cache designs optimize mainly for cache hit latency and do not consider bandwidth efficiency as a first-class design constraint. Hence, as we show in this paper, these designs are suboptimal for use with in-package DRAM. We propose a new DRAM cache design, Banshee, that optimizes for both in-package and off-package DRAM bandwidth efficiency without degrading access latency. Banshee is based on two key ideas. First, it eliminates the tag lookup overhead by tracking the contents of the DRAM cache using TLBs and page table entries, which is efficiently enabled by a new lightweight TLB coherence protocol we introduce. Second, it reduces unnecessary DRAM cache replacement traffic with a new bandwidth-aware frequency-based replacement policy. Our evaluations show that Banshee significantly improves performance (15% on average) and reduces DRAM traffic (35.8% on average) over the best-previous latency-optimized DRAM cache design

Inducible Costimulator Expressing T Cells Promote Parasitic Growth During Blood Stage Plasmodium berghei ANKA Infection

The lethality of blood stage Plasmodium berghei ANKA (PbA) infection is associated with the expression of T-bet and production of cytokine IFN-γ. Expression of inducible costimulator (ICOS) and its downstream signaling has been shown to play a critical role in the T-bet expression and IFN-γ production. Although earlier studies have examined the role of ICOS in the control of acute blood-stage infection of Plasmodium chabaudi chabaudi AS (a non-lethal model of malaria infection), its significance in the lethal blood-stage of PbA infection remains unclear. Thus, to address the seminal role of ICOS in lethal blood-stage of PbA infection, we treated PbA-infected mice with anti-ICOS antibody and observed that these mice survived longer than their infected counterparts with significantly lower parasitemia. Anti-ICOS treatment notably depleted ICOS expressing CD4+ and CD8+ T cells with a concurrent reduction in plasma IFN-γ, which strongly indicated that ICOS expressing T cells are major IFN-γ producers. Interestingly, we observed that while ICOS expressing CD4+ and CD8+ T cells produced IFN-γ, ICOS−CD8+ T cells were also found to be producers of IFN-γ. However, we report that ICOS+CD8+ T cells were higher producers of IFN-γ than ICOS−CD8+ T cells. Moreover, correlation of ICOS expression with IFN-γ production in ICOS+IFN-γ+ T cell population (CD4+ and CD8+ T cells) suggested that ICOS and IFN-γ could positively regulate each other. Further, master transcription factor T-bet importantly involved in regulating IFN-γ production was also found to be expressed by ICOS expressing CD4+ and CD8+ T cells during PbA infection. As noted above with IFN-γ and ICOS, a positive correlation of expression of ICOS with the transcription factor T-bet suggested that both of them could regulate each other. Taken together, our results depicted the importance of ICOS expressing CD4+ and CD8+ T cells in malaria parasite growth and lethality through IFN-γ production and T-bet expression