47 research outputs found
Flat Cellular (UMTS) Networks
Traditionally, cellular systems have been built in a hierarchical manner: many specialized cellular access network elements that collectively form a hierarchical cellular system. When 2G and later 3G systems were designed there was a good reason to make system hierarchical: from a cost-perspective it was better to concentrate traffic and to share the cost of processing equipment over a large set of users while keeping the base stations relatively cheap. However, we believe the economic reasons for designing cellular systems in a hierarchical manner have disappeared: in fact, hierarchical architectures hinder future efficient deployments. In this paper, we argue for completely flat cellular wireless systems, which need just one type of specialized network element to provide radio access network (RAN) functionality, supplemented by standard IP-based network elements to form a cellular network. While the reason for building a cellular system in a hierarchical fashion has disappeared, there are other good reasons to make the system architecture flat: (1) as wireless transmission techniques evolve into hybrid ARQ systems, there is less need for a hierarchical cellular system to support spatial diversity; (2) we foresee that future cellular networks are part of the Internet, while hierarchical systems typically use interfaces between network elements that are specific to cellular standards or proprietary. At best such systems use IP as a transport medium, not as a core component; (3) a flat cellular system can be self scaling while a hierarchical system has inherent scaling issues; (4) moving all access technologies to the edge of the network enables ease of converging access technologies into a common packet core; and (5) using an IP common core makes the cellular network part of the Internet
All-photonic multiplexed quantum repeaters based on concatenated bosonic and discrete-variable quantum codes
Long distance quantum communication will require the use of quantum repeaters
to overcome the exponential attenuation of signal with distance. One class of
such repeaters utilizes quantum error correction to overcome losses in the
communication channel. Here we propose a novel strategy of using the bosonic
Gottesman-Kitaev-Preskill (GKP) code in a two-way repeater architecture with
multiplexing. The crucial feature of the GKP code that we make use of is the
fact that GKP qubits easily admit deterministic two-qubit gates, hence allowing
for multiplexing without the need for generating large cluster states as
required in previous all-photonic architectures based on discrete-variable
codes. Moreover, alleviating the need for such clique-clusters entails that we
are no longer limited to extraction of at most one end-to-end entangled pair
from a single protocol run. In fact, thanks to the availability of the analog
information generated during the measurements of the GKP qubits, we can design
better entanglement swapping procedures in which we connect links based on
their estimated quality. This enables us to use all the multiplexed links so
that large number of links from a single protocol run can contribute to the
generation of the end-to-end entanglement. We find that our architecture allows
for high-rate end-to-end entanglement generation and is resilient to
imperfections arising from finite squeezing in the GKP state preparation and
homodyne detection inefficiency. In particular we show that long-distance
quantum communication over more than 1000 km is possible even with less than 13
dB of GKP squeezing. We also quantify the number of GKP qubits needed for the
implementation of our scheme and find that for good hardware parameters our
scheme requires around GKP qubits per repeater per protocol run.Comment: 31 + 25 pages, 40 figure
Rasgrp1 mutation increases naΓ―ve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies
Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1Anaef is mostly normal in vivo, although CD44 is overexpressed on naΓ―ve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1Anaef naΓ―ve CD4+ T cells. CD44 expression, CD4+ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1AnaefMtorchino double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1Anaef T cell dysregulation
Rasgrp1 mutation increases naΓ―ve T-cell CD44 expression and drives mTOR-dependent accumulation of HeliosβΊ T cells and autoantibodies
Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1ᴬβΏα΅α΅αΆ , with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1ᴬβΏα΅α΅αΆ mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi HeliosβΊ PD-1βΊ CD4βΊ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1ᴬβΏα΅α΅αΆ is mostly normal in vivo, although CD44 is overexpressed on naΓ―ve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1ᴬβΏα΅α΅αΆ naΓ―ve CD4βΊ T cells. CD44 expression, CD4βΊ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1ᴬβΏα΅α΅αΆ MtorαΆΚ°β±βΏα΅ double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1ᴬβΏα΅α΅αΆ T cell dysregulation
Liver Is Able to Activate NaΓ―ve CD8+ T Cells with Dysfunctional Anti-Viral Activity in the Murine System
The liver possesses distinct tolerogenic properties because of continuous exposure to bacterial constituents and nonpathogenic food antigen. The central immune mediators required for the generation of effective immune responses in the liver environment have not been fully elucidated. In this report, we demonstrate that the liver can indeed support effector CD8+ T cells during adenovirus infection when the T cells are primed in secondary lymphoid tissues. In contrast, when viral antigen is delivered predominantly to the liver via intravenous (IV) adenovirus infection, intrahepatic CD8+ T cells are significantly impaired in their ability to produce inflammatory cytokines and lyse target cells. Additionally, intrahepatic CD8+ T cells generated during IV adenovirus infection express elevated levels of PD-1. Notably, lower doses of adenovirus infection do not rescue the impaired effector function of intrahepatic CD8+ T cell responses. Instead, intrahepatic antigen recognition limits the generation of potent anti-viral responses at both priming and effector stages of the CD8+ T cell response and accounts for the dysfunctional CD8+ T cell response observed during IV adenovirus infection. These results also implicate that manipulation of antigen delivery will facilitate the design of improved vaccination strategies to persistent viral infection
Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease
During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted
Systemic IL-12 Administration Alters Hepatic Dendritic Cell Stimulation Capabilities
The liver is an immunologically unique organ containing tolerogenic dendritic cells (DC) that maintain an immunosuppressive microenvironment. Although systemic IL-12 administration can improve responses to tumors, the effects of IL-12-based treatments on DC, in particular hepatic DC, remain incompletely understood. In this study, we demonstrate systemic IL-12 administration induces a 2β3 fold increase in conventional, but not plasmacytoid, DC subsets in the liver. Following IL-12 administration, hepatic DC became more phenotypically and functionally mature, resembling the function of splenic DC, but differed as compared to their splenic counterparts in the production of IL-12 following co-stimulation with toll-like receptor (TLR) agonists. Hepatic DCs from IL-12 treated mice acquired enhanced T cell proliferative capabilities similar to levels observed using splenic DCs. Furthermore, IL-12 administration preferentially increased hepatic T cell activation and IFNΞ³ expression in the RENCA mouse model of renal cell carcinoma. Collectively, the data shows systemic IL-12 administration enables hepatic DCs to overcome at least some aspects of the inherently suppressive milieu of the hepatic environment that could have important implications for the design of IL-12-based immunotherapeutic strategies targeting hepatic malignancies and infections
Kupffer Cells Hasten Resolution of Liver Immunopathology in Mouse Models of Viral Hepatitis
Kupffer cells (KCs) are widely considered important contributors to liver injury during viral hepatitis due to their pro-inflammatory activity. Herein we utilized hepatitis B virus (HBV)-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus-specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1) protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology
Rasgrp1 mutation increases naΓ―ve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies
Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1(Anaef), with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1(Anaef) mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44(hi) Helios(+) PD-1(+) CD4(+) T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1(Anaef) is mostly normal in vivo, although CD44 is overexpressed on naΓ―ve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1(Anaef) naΓ―ve CD4(+) T cells. CD44 expression, CD4(+) T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1(Anaef)Mtor(chino) double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1(Anaef) T cell dysregulation. DOI: http://dx.doi.org/10.7554/eLife.01020.00