bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peroxiredoxin II Regulates Effector and Secondary Memory CD8+T Cell Responses
Authors: Michalek Ryan D. , Crump Katie E. , Weant Ashley E. , Hiltbold Elizabeth M. , Juneau Daniel G. , Moon Eun-Yi , Yu Dae-Yeul , Poole Leslie B. , Grayson Jason M. 
Published: October 2012

ABSTRACTReactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in cellular responses. However, the effect of increased H2O2on an antigen-specific CD8+T cell response was unknown. Following T cell receptor (TCR) stimulation, the expression and oxidation of peroxiredoxin II (PrdxII), a critical antioxidant enzyme, increased in CD8+T cells. Deletion of PrdxII increased ROI, S phase entry, division, and death duringin vitrodivision. During primary acute viral and bacterial infection, the number of effector CD8+T cells in PrdxII-deficient mice was increased, while the number of memory cells were similar to those of the wild-type cells. Adoptive transfer of P14 TCR transgenic cells demonstrated that the increased expansion of effector cells was T cell autonomous. After rechallenge, effector CD8+T cells in mutant animals were more skewed to memory phenotype than cells from wild-type mice, resulting in a larger secondary memory CD8+T cell pool. During chronic viral infection, increased antigen-specific CD8+T cells accumulated in the spleens of PrdxII mutant mice, causing mortality. These results demonstrate that PrdxII controls effector CD8+T cell expansion, secondary memory generation, and immunopathology.
Efficiency of Bridging-Sheet Recruitment Explains HIV-1 R5 Envelope Glycoprotein Sensitivity to Soluble CD4 and Macrophage Tropism
Authors: O'Connell Olivia , Repik Alexander , Reeves Jacqueline D. , Gonzalez-Perez Maria Paz , Quitadamo Briana , Anton Elizabeth D. , Duenas-Decamp Maria , Peters Paul , Lin Rongheng , Zolla-Pazner Susan , Corti Davide , Wallace Aaron , Wang Shixia , Kong Xiang-Peng , Lu Shan , Clapham Paul R. 
Published: October 2012

ABSTRACTHIV-1 R5 viruses vary extensively in their capacity to infect macrophages. R5 viruses that confer efficient infection of macrophages are able to exploit low levels of CD4 for infection and predominate in brain tissue, where macrophages are a major target for infection. HIV-1 R5 founder viruses that are transmitted were reported to be non-macrophage-tropic. Here, we investigated the sensitivities of macrophage-tropic and non-macrophage-tropic R5 envelopes to neutralizing antibodies. We observed striking differences in the sensitivities of Env+pseudovirions to soluble CD4 (sCD4) and to neutralizing monoclonal antibodies (MAbs) that target the CD4 binding site. Macrophage-tropic R5 Envs were sensitive to sCD4, while non-macrophage-tropic Envs were significantly more resistant. In contrast, all Envs were sensitive to VRC01 regardless of tropism, while MAb b12 conferred an intermediate neutralization pattern where all the macrophage-tropic and about half of the non-macrophage-tropic Envs were sensitive. CD4, b12, and VRC01 share binding specificities on the outer domain of gp120. However, these antibodies differ in their ability to induce conformational changes on the trimeric envelope and in specificity for residues on the V1V2 loop stem and β20-21 junction that are targets for CD4 in recruiting the bridging sheet. These distinct specificities of CD4, b12, and VRC01 likely explain the observed differences in Env sensitivity to inhibition by these reagents and provide an insight into the envelope mechanisms that control macrophage tropism. We present a model where the efficiency of bridging-sheet recruitment by CD4 is a major determinant of HIV-1 R5 envelope sensitivity to soluble CD4 and macrophage tropism.
Inhibitory Potential of Subpopulations of CD8+T Cells in HIV-1-Infected Elite Suppressors
Authors: Buckheit Robert W. , Salgado Maria , Silciano Robert F. , Blankson Joel N. 
Published: October 2012

ABSTRACTElite controllers or suppressors (ES) are HIV-1-infected individuals who suppress viral replication to clinically undetectable levels without antiretroviral therapy. Understanding the mechanisms by which ES control viral replication may prove informative for the design of a therapeutic vaccine. Qualitative differences in the CD8+T cell response have been implicated in control. Therefore, we isolated CD8+T cells from ES and characterized the ability of sorted memory and activation subpopulations to control viral replication at various effector-to-target cell ratios using a novel modification of a CD8+T cell suppression assay. The effector memory and terminal effector subpopulations of memory CD8+T cells had the highest inhibitory potential over the course of a 3-dayin vitroinfection. Interestingly, after 5 days of infection, central memory CD8+T cells were also very effective at suppressing viral replication. No significant correlation between the suppression of viral replication and the number of HIV-1-specific CD8+T cells was observed. HLA-DR−CD38+CD8+T cells possessed the lowest inhibitory potential of the activation subpopulations. Taken together, our data suggest that there are key differences in the magnitude and kinetics of the suppression of HIV-1 replication by different CD8+T cell subsets. These data should guide the development of an effective, cellular therapeutic vaccine that has the potential to elicit similar CD8+T cell responses.
Aérgia
Authors: Das Reetuparna , Mutlu Onur , Moscibroda Thomas , Das Chita R. 
Published: October 2012

Traditional Network-on-Chips (NoCs) employ simple arbitration strategies, such as round-robin or oldest-first, to decide which packets should be prioritized in the network. This is counter-intuitive since different packets can have very different effects on system performance due to, e.g., different level of memory-level parallelism (MLP) of applications. Certain packets may be performance-critical because they cause the processor to stall, whereas others may be delayed for a number of cycles with no effect on application-level performance as their latencies are hidden by other outstanding packets'latencies. In this paper, we define slack as a key measure that characterizes the relative importance of a packet. Specifically, the slack of a packet is the number of cycles the packet can be delayed in the network with no effect on execution time. This paper proposes new router prioritization policies that exploit the available slack of interfering packets in order to accelerate performance-critical packets and thus improve overall system performance. When two packets interfere with each other in a router, the packet with the lower slack value is prioritized. We describe mechanisms to estimate slack, prevent starvation, and combine slack-based prioritization with other recently proposed application-aware prioritization mechanisms.
We evaluate slack-based prioritization policies on a 64-core CMP with an 8x8 mesh NoC using a suite of 35 diverse applications. For a representative set of case studies, our proposed policy increases average system throughput by 21.0% over the commonlyused round-robin policy. Averaged over 56 randomly-generated multiprogrammed workload mixes, the proposed policy improves system throughput by 10.3%, while also reducing application-level unfairness by 30.8%.
Silicon-photonic network architectures for scalable, power-efficient multi-chip systems
Authors: Koka Pranay , McCracken Michael O. , Schwetman Herb , Zheng Xuezhe , Ho Ron , Krishnamoorthy Ashok V. 
Published: October 2012

Scaling trends of logic, memories, and interconnect networks lead towards dense many-core chips. Unfortunately, process yields and reticle sizes limit the scalability of large single-chip systems. Multi-chip systems break free of these areal limits, but in turn require enormous chip-to-chip bandwidth. The "macrochip" concept presented here integrates multiple many-core processor chips in a single package with silicon-photonic interconnects. This design enables a multi-chip system to approach the performance of a single large die.
In this paper we propose three silicon-photonic network designs that provide low-power, high-bandwidth inter-die communication: a static wavelength-routed point-to-point network, a "two-phase" arbitrated network, and a limited-connectivity point-to-point network. We also adapt two existing intra-chip silicon-photonic interconnects: a token-ring-based crossbar and a circuit-switched torus.
We simulate a 64-die, 512-core cache-coherent macrochip using all of the above networks with synthetic kernels, and kernels from Splash-2 and PARSEC. We evaluate the networks on performance, optical power and complexity. Despite a narrow data-path width compared to the token-ring or torus, the point-to-point performs 3.3x and 3.9x better respectively. We show that the point-to-point is over 10x more power-efficient than the other networks. We also show that, contrary to electronic network designs, a point-to-point network has the lowest design complexity for an inter-chip silicon-photonic network.
Resistive computation
Authors: Guo Xiaochen , Ipek Engin , Soyata Tolga 
Published: October 2012

As CMOS scales beyond the 45nm technology node, leakage concerns are starting to limit microprocessor performance growth. To keep dynamic power constant across process generations, traditional MOSFET scaling theory prescribes reducing supply and threshold voltages in proportion to device dimensions, a practice that induces an exponential increase in subthreshold leakage. As a result, leakage power has become comparable to dynamic power in current-generation processes, and will soon exceed it in magnitude if voltages are scaled down any further. Beyond this inflection point, multicore processors will not be able to afford keeping more than a small fraction of all cores active at any given moment. Multicore scaling will soon hit a power wall.
This paper presents resistive computation, a new technique that aims at avoiding the power wall by migrating most of the functionality of a modern microprocessor from CMOS to spin-torque transfer magnetoresistive RAM (STT-MRAM)---a CMOS-compatible, leakage-resistant, non-volatile resistive memory technology. By implementing much of the on-chip storage and combinational logic using leakage-resistant, scalable RAM blocks and lookup tables, and by carefully re-architecting the pipeline, an STT-MRAM based implementation of an eight-core Sun Niagara-like CMT processor reduces chip-wide power dissipation by 1.7× and leakage power by 2.1× at the 32nm technology node, while maintaining 93% of the system throughput of a CMOS-based design.
Cohesion
Authors: Kelm John H. , Johnson Daniel R. , Tuohy William , Lumetta Steven S. , Patel Sanjay J. 
Published: October 2012

Two broad classes of memory models are available today: models with hardware cache coherence, used in conventional chip multiprocessors, and models that rely upon software to manage coherence, found in compute accelerators. In some systems, both types of models are supported using disjoint address spaces and/or physical memories. In this paper we present Cohesion, a hybrid memory model that enables fine-grained temporal reassignment of data between hardware-managed and software-managed coherence domains, allowing a system to support both. Cohesion can be used to dynamically adapt to the sharing needs of both applications and runtimes. Cohesion requires neither copy operations nor multiple address spaces.
Cohesion offers the benefits of reduced message traffic and on-die directory overhead when software-managed coherence can be used and the advantages of hardware coherence for cases in which software-managed coherence is impractical. We demonstrate our protocol using a hierarchical, cached 1024-core processor with a single address space that supports both software-enforced coherence and a directory-based hardware coherence protocol. Relative to an optimistic, hardware-coherent baseline, a realizable Cohesion design achieves competitive performance with a 2× reduction in message traffic, 2.1× reduction in directory utilization, and greater robustness to on-die directory capacity.
Inhibiting Interactions of Lysine Demethylase LSD1 with Snail/Slug Blocks Cancer Cell Invasion
Authors: Ferrari-Amorotti Giovanna , Fragliasso Valentina , Esteki Roza , Prudente Zelia , Soliera Angela Rachele , Cattelani Sara , Manzotti Gloria , Grisendi Giulia , Dominici Massimo , Pieraccioli Marco , Raschellà Giuseppe , Chiodoni Claudia , Colombo Mario Paolo , Calabretta Bruno 
Published: October 2012

Abstract
The process of epithelial–mesenchymal transition (EMT) which is required for cancer cell invasion is regulated by a family of E-box–binding transcription repressors, which include Snail (SNAIL1) and Slug (SNAI2). Snail appears to repress the expression of the EMT marker E-cadherin by epigenetic mechanisms dependent on the interaction of its N-terminal SNAG domain with chromatin-modifying proteins including lysine-specific demethylase 1 (LSD1/KDM1A). We assessed whether blocking Snail/Slug-LSD1 interaction by treatment with Parnate, an enzymatic inhibitor of LSD1, or TAT-SNAG, a cell-permeable peptide corresponding to the SNAG domain of Slug, suppresses the motility and invasiveness of cancer cells of different origin and genetic background. We show here that either treatment blocked Slug-dependent repression of the E-cadherin promoter and inhibited the motility and invasion of tumor cell lines without any effect on their proliferation. These effects correlated with induction of epithelial and repression of mesenchymal markers and were phenocopied by LSD1 or Slug downregulation. Parnate treatment also inhibited bone marrow homing/engraftment of Slug-expressing K562 cells. Together, these studies support the concept that targeting Snail/Slug-dependent transcription repression complexes may lead to the development of novel drugs selectively inhibiting the invasive potential of cancer cells. Cancer Res; 73(1); 235–45. ©2012 AACR.
Impact of Tumor Progression on Cancer Incidence Curves
Authors: Luebeck E. Georg , Curtius Kit , Jeon Jihyoun , Hazelton William D. 
Published: October 2012

Abstract
Cancer arises through a multistage process, but it is not fully clear how this process influences the age-specific incidence curve. Studies of colorectal and pancreatic cancer using the multistage clonal expansion (MSCE) model have identified two phases of the incidence curves. One phase is linear, beginning about age of 60 years, suggesting that at least two rare rate-limiting mutations occur before clonal expansion of premalignant cells. A second phase is exponential, seen in early-onset cancers occurring before the age of 60 years that are associated with premalignant clonal expansion. Here, we extend the MSCE model to include clonal expansion of malignant cells, an advance that permits study of the effects of tumor growth and extinction on the incidence of colorectal, gastric, pancreatic, and esophageal adenocarcinomas in the digestive tract. After adjusting the age-specific incidence for birth-cohort and calendar-year trends, we found that initiating mutations and premalignant cell kinetics can explain the primary features of the incidence curve. However, we also found that the incidence data of these cancers harbored information on the kinetics of malignant clonal expansion before clinical detection, including tumor growth rates and extinction probabilities on three characteristic time scales for tumor progression. In addition, the data harbored information on the mean sojourn times for premalignant clones until occurrence of either the first malignant cell or the first persistent (surviving) malignant clone. Finally, the data also harbored information on the mean sojourn time of persistent malignant clones to the time of diagnosis. In conclusion, cancer incidence curves can harbor significant information about hidden processes of tumor initiation, premalignant clonal expansion, and malignant transformation, and even some limited information on tumor growth before clinical detection. Cancer Res; 73(3); 1086–96. ©2012 AACR.
Epithelial-to-Mesenchymal Transition Induced by TGF-β1 Is Mediated by Blimp-1–Dependent Repression of BMP-5
Authors: Romagnoli Mathilde , Belguise Karine , Yu Ziyang , Wang Xiaobo , Landesman-Bollag Esther , Seldin David C. , Chalbos Dany , Barillé-Nion Sophie , Jézéquel Pascal , Seldin Margaret L. , Sonenshein Gail E. 
Published: October 2012

Abstract
Induction of epithelial-to-mesenchymal transition (EMT) by TGF-β1 requires Ras signaling. We recently identified the transcriptional repressor Blimp-1 (PRDM1) as a downstream effector of the NF-κB, RelB/Bcl-2/Ras-driven pathway that promotes breast cancer cell migration. As the RelB/Blimp-1 pathway similarly required Ras signaling activation, we tested whether Blimp-1 plays a role in TGF-β1–mediated EMT. Here, TGF-β1 treatment of untransformed NMuMG mammary epithelial and MDA-MB-231 breast cancer cells was shown to induce Blimp-1 expression, which promoted an EMT signature and cell migration. TGFB1 and BLIMP1 RNA levels were correlated in patient breast tumors. BLIMP1 gene transcription was activated by TGF-β1 via a c-Raf (RAF1) to AP-1 pathway. Blimp-1 induced expression of the EMT master regulator Snail (SNAI1) via repressing BMP-5, which inhibited Snail expression upon TGF-β1 treatment. Interestingly, a similar cascade was observed during postnatal mouse mammary gland development. RelB expression was detected early in pregnancy followed progressively by Blimp-1 and then Snail; whereas, BMP-5 levels were high in nulliparous and regressing glands. Finally, lower BMP5 RNA levels were detected in patient breast tumors versus normal tissues, and correlated with cancer recurrence. Thus, the Ras effector Blimp-1 plays an essential role in TGF-β1–induced EMT via repression of BMP-5 in breast cancer. Cancer Res; 72(23); 6268–78. ©2012 AACR.
Plasma factor Xa inhibition can predict antithrombotic effects of oral direct factor Xa inhibitors in rabbit atherothrombosis models
Authors: Yamashita Atsushi , Kaku Seiji , Iwatsuki Yoshiyuki , Asada Yujiro , Funatsu Toshiyuki 
Published: October 2012

SummaryWe evaluated the relationship between antithrombotic effects and pharmacodynamic (PD) marker changes produced by the novel factor (F)Xa inhibitors darexaban (YM150) and rivaroxaban in a rabbit model of plaque disruption-induced arterial thrombosis. Animals were subjected to catheter-induced endothelial denudation via the femoral artery followed by a two-week high-cholesterol diet. Plaque disruption was induced by balloon angioplasty, and then stasis was achieved by ligation at the distal side of the injured segment. Darexaban and rivaroxaban were administered orally 1 hour (h) before and 9 h after plaque disruption, and their antithrombotic effects were evaluated 24 h after the initiation of ligation. Prothrombin time (PT), activated partial thromboplastin time (APTT), and plasma FXa activity were measured using blood samples collected before and 1 h after administration. Darexaban and rivaroxaban significantly reduced thrombus formation. The thrombus weight obtained in the 30 mg/kg darexaban group was comparable to that in the 1 mg/kg rivaroxaban group (2.17 ± 0.63 and 3.23 ± 1.64 mg, respectively, vs. 8.01 ± 1.08 mg in the control group). Plasma FXa activity correlated with the antithrombotic effects of darexaban and rivaroxaban, while PT only correlated with those of darexaban. Our findings suggest that the degree of plasma FXa inhibition may be useful for predicting antithrombotic effects of darexaban and rivaroxaban in arterial thrombosis. PT may also be useful in evaluating antithrombotic effects of darexaban in particular.
The Retrieval of Profiles of Particulate Extinction from Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) Data: Uncertainty and Error Sensitivity Analyses
Authors: Young Stuart A. , Vaughan Mark A. , Kuehn Ralph E. , Winker David M. 
Published: October 2012

Abstract
Profiles of atmospheric cloud and aerosol extinction coefficients are retrieved on a global scale from measurements made by the lidar on board the Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) mission since mid-June 2006. This paper presents an analysis of how the uncertainties in the inputs to the extinction retrieval algorithm propagate as the retrieval proceeds downward to lower levels of the atmosphere. The mathematical analyses, which are being used to calculate the uncertainties reported in the current (version 3) data release, are supported by figures illustrating the retrieval uncertainties in both simulated and actual data. Equations are also derived that describe the sensitivity of the extinction retrieval algorithm to errors in profile calibration and in the lidar ratios used in the retrievals. Biases that could potentially result from low signal-to-noise ratios in the data are also examined. Using simulated data, the propagation of bias errors resulting from errors in profile calibration and lidar ratios is illustrated.
Data Assimilation with Gaussian Mixture Models Using the Dynamically Orthogonal Field Equations. Part I: Theory and Scheme
Authors: Sondergaard Thomas , Lermusiaux Pierre F. J. 
Published: October 2012

AbstractThis work introduces and derives an efficient, data-driven assimilation scheme, focused on a time-dependent stochastic subspace that respects nonlinear dynamics and captures non-Gaussian statistics as it occurs. The motivation is to obtain a filter that is applicable to realistic geophysical applications, but that also rigorously utilizes the governing dynamical equations with information theory and learning theory for efficient Bayesian data assimilation. Building on the foundations of classical filters, the underlying theory and algorithmic implementation of the new filter are developed and derived. The stochastic Dynamically Orthogonal (DO) field equations and their adaptive stochastic subspace are employed to predict prior probabilities for the full dynamical state, effectively approximating the Fokker–Planck equation. At assimilation times, the DO realizations are fit to semiparametric Gaussian Mixture Models (GMMs) using the Expectation-Maximization algorithm and the Bayesian Information Criterion. Bayes’s law is then efficiently carried out analytically within the evolving stochastic subspace. The resulting GMM-DO filter is illustrated in a very simple example. Variations of the GMM-DO filter are also provided along with comparisons with related schemes.
Data Assimilation with Gaussian Mixture Models Using the Dynamically Orthogonal Field Equations. Part II: Applications
Authors: Sondergaard Thomas , Lermusiaux Pierre F. J. 
Published: October 2012

AbstractThe properties and capabilities of the Gaussian Mixture Model–Dynamically Orthogonal filter (GMM-DO) are assessed and exemplified by applications to two dynamical systems: 1) the double well diffusion and 2) sudden expansion flows; both of which admit far-from-Gaussian statistics. The former test case, or twin experiment, validates the use of the Expectation-Maximization (EM) algorithm and Bayesian Information Criterion with GMMs in a filtering context; the latter further exemplifies its ability to efficiently handle state vectors of nontrivial dimensionality and dynamics with jets and eddies. For each test case, qualitative and quantitative comparisons are made with contemporary filters. The sensitivity to input parameters is illustrated and discussed. Properties of the filter are examined and its estimates are described, including the equation-based and adaptive prediction of the probability densities; the evolution of the mean field, stochastic subspace modes, and stochastic coefficients; the fitting of GMMs; and the efficient and analytical Bayesian updates at assimilation times and the corresponding data impacts. The advantages of respecting nonlinear dynamics and preserving non-Gaussian statistics are brought to light. For realistic test cases admitting complex distributions and with sparse or noisy measurements, the GMM-DO filter is shown to fundamentally improve the filtering skill, outperforming simpler schemes invoking the Gaussian parametric distribution.