bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversible Inhibition of Murine Cytomegalovirus Replication by Gamma Interferon (IFN-γ) in Primary Macrophages Involves a Primed Type I IFN-Signaling Subnetwork for Full Establishment of an Immediate-Early Antiviral State
Authors: Kropp Kai A. , Robertson Kevin A. , Sing Garwin , Rodriguez-Martin Sara , Blanc Mathieu , Lacaze Paul , Hassim Muhamad F. B. Noor , Khondoker Mizanur R. , Busche Andreas , Dickinson Paul , Forster Thorsten , Strobl Birgit , Mueller Mathias , Jonjic Stipan , Angulo Ana , Ghazal Peter 
Published: July 2011

ABSTRACTActivated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. Type I interferon (alpha/beta interferon [IFN-α/β]) and type II interferon (IFN-γ) play a crucial role in activating macrophages and subsequently restricting viral infections. Both types of IFNs signal through related but distinct signaling pathways, inducing a vast number of interferon-stimulated genes that are overlapping but distinguishable. The exact mechanism by which IFNs, particularly IFN-γ, inhibit DNA viruses such as cytomegalovirus (CMV) is still not fully understood. Here, we investigate the antiviral state developed in macrophages upon reversible inhibition of murine CMV by IFN-γ. On the basis of molecular profiling of the reversible inhibition, we identify a significant contribution of a restricted type I IFN subnetwork linked with IFN-γ activation. Genetic knockout of the type I-signaling pathway, in the context of IFN-γ stimulation, revealed an essential requirement for a primed type I-signaling process in developing a full refractory state in macrophages. A minimal transient induction of IFN-β upon macrophage activation with IFN-γ is also detectable. In dose and kinetic viral replication inhibition experiments with IFN-γ, the establishment of an antiviral effect is demonstrated to occur within the first hours of infection. We show that the inhibitory mechanisms at these very early times involve a blockade of the viral major immediate-early promoter activity. Altogether our results show that a primed type I IFN subnetwork contributes to an immediate-early antiviral state induced by type II IFN activation of macrophages, with a potential further amplification loop contributed by transient induction of IFN-β.
Pathogenic Old World Hantaviruses Infect Renal Glomerular and Tubular Cells and Induce Disassembling of Cell-to-Cell Contacts
Authors: Krautkrämer Ellen , Grouls Stephan , Stein Nadine , Reiser Jochen , Zeier Martin 
Published: July 2011

ABSTRACT

Viral hemorrhagic fevers are characterized by enhanced permeability. One of the most affected target organs of hantavirus-induced hemorrhagic fever with renal syndrome is the kidney, and an infection often results in acute renal failure. To study the underlying cellular effects leading to kidney dysfunction, we infected human renal cell types
in vitro
that are critical for the barrier functions of the kidney, and we examined kidney biopsy specimens obtained from hantavirus-infected patients. We analyzed the infection and pathogenic effects in tubular epithelial and glomerular endothelial renal cells and in podocytes. Both epithelial and endothelial cells and podocytes were susceptible to hantavirus infection
in vitro
. The infection disturbed the structure and integrity of cell-to-cell contacts, as demonstrated by redistribution and reduction of the tight junction protein ZO-1 and the decrease in the transepithelial resistance in infected epithelial monolayers. An analysis of renal biopsy specimens from hantavirus-infected patients revealed that the expression and the localization of the tight junction protein ZO-1 were altered compared to renal biopsy specimens from noninfected individuals. Both tubular and glomerular cells were affected by the infection. Furthermore, the decrease in glomerular ZO-1 correlates with disease severity induced by glomerular dysfunction. The finding that different renal cell types are susceptible to hantaviral infection and the fact that infection results in the breakdown of cell-to-cell contacts provide useful insights in hantaviral pathogenesis.
Anti-Severe Acute Respiratory Syndrome Coronavirus Spike Antibodies Trigger Infection of Human Immune Cells via a pH- and Cysteine Protease-Independent FcγR Pathway
Authors: Jaume Martial , Yip Ming S. , Cheung Chung Y. , Leung Hiu L. , Li Ping H. , Kien Francois , Dutry Isabelle , Callendret Benoît , Escriou Nicolas , Altmeyer Ralf , Nal Beatrice , Daëron Marc , Bruzzone Roberto , Peiris J. S. Malik 
Published: July 2011

ABSTRACTPublic health measures successfully contained outbreaks of the severe acute respiratory syndrome coronavirus (SARS-CoV) infection. However, the precursor of the SARS-CoV remains in its natural bat reservoir, and reemergence of a human-adapted SARS-like coronavirus remains a plausible public health concern. Vaccination is a major strategy for containing resurgence of SARS in humans, and a number of vaccine candidates have been tested in experimental animal models. We previously reported that antibody elicited by a SARS-CoV vaccine candidate based on recombinant full-length Spike-protein trimers potentiated infection of human B cell lines despite elicitingin vivoa neutralizing and protective immune response in rodents. These observations prompted us to investigate the mechanisms underlying antibody-dependent enhancement (ADE) of SARS-CoV infectionin vitro. We demonstrate here that anti-Spike immune serum, while inhibiting viral entry in a permissive cell line, potentiated infection of immune cells by SARS-CoV Spike-pseudotyped lentiviral particles, as well as replication-competent SARS coronavirus. Antibody-mediated infection was dependent on Fcγ receptor II but did not use the endosomal/lysosomal pathway utilized by angiotensin I converting enzyme 2 (ACE2), the accepted receptor for SARS-CoV. This suggests that ADE of SARS-CoV utilizes a novel cell entry mechanism into immune cells. Different SARS vaccine candidates elicit sera that differ in their capacity to induce ADE in immune cells despite their comparable potency to neutralize infection in ACE2-bearing cells. Our results suggest a novel mechanism by which SARS-CoV can enter target cells and illustrate the potential pitfalls associated with immunization against it. These findings should prompt further investigations into SARS pathogenesis.
Gamma Interferon Controls Mouse Polyomavirus InfectionIn Vivo
Authors: Wilson Jarad J. , Lin Eugene , Pack Christopher D. , Frost Elizabeth L. , Hadley Annette , Swimm Alyson I. , Wang Jun , Dong Ying , Breeden Cynthia P. , Kalman Daniel , Newell Kenneth A. , Lukacher Aron E. 
Published: July 2011

ABSTRACTHuman polyomaviruses are associated with substantial morbidity in immunocompromised patients, including those with HIV/AIDS, recipients of bone marrow and kidney transplants, and individuals receiving immunomodulatory agents for autoimmune and inflammatory diseases. No effective antipolyomavirus agents are currently available, and no host determinants have been identified to predict susceptibility to polyomavirus-associated diseases. Using the mouse polyomavirus (MPyV) infection model, we recently demonstrated that perforin-granzyme exocytosis, tumor necrosis factor alpha (TNF-α), and Fas did not contribute to control of infection or virus-induced tumors. Gamma interferon (IFN-γ) was recently shown to inhibit replication by human BK polyomavirus in primary cultures of renal tubular epithelial cells. In this study, we provide evidence that IFN-γ is an important component of the host defense against MPyV infection and tumorigenesis. In immortalized and primary cells, IFN-γ reduces expression of MPyV proteins and impairs viral replication. Mice deficient for the IFN-γ receptor (IFN-γR−/−) maintain higher viral loads during MPyV infection and are susceptible to MPyV-induced tumors; this increased viral load is not associated with a defective MPyV-specific CD8+T cell response. Using an acute MPyV infection kidney transplant model, we further show that IFN-γR−/−donor kidneys harbor higher MPyV levels than donor kidneys from wild-type mice. Finally, administration of IFN-γ to persistently infected mice significantly reduces MPyV levels in multiple organs, including the kidney, a major reservoir for persistent mouse and human polyomavirus infections. These findings demonstrate that IFN-γ is an antiviral effector molecule for MPyV infection.
Hepatitis B Virus Genotype C Isolates with Wild-Type Core Promoter Sequence Replicate Less Efficiently than Genotype B Isolates but Possess Higher Virion Secretion Capacity
Authors: Qin Yanli , Tang Xiaoli , Garcia Tamako , Hussain Munira , Zhang Jiming , Lok Anna , Wands Jack , Li Jisu , Tong Shuping 
Published: July 2011

ABSTRACTInfection by hepatitis B virus (HBV) genotype C is associated with a prolonged viremic phase, delayed hepatitis B e antigen (HBeAg) seroconversion, and an increased incidence of liver cirrhosis and hepatocellular carcinoma compared with genotype B infection. Genotype C is also associated with the more frequent emergence of core promoter mutations, which increase genome replication and are independently associated with poor clinical outcomes. We amplified full-length HBV genomes from serum samples from Chinese and U. S. patients with chronic HBV infection and transfected circularized genome pools or dimeric constructs of individual clones into Huh7 cells. The two genotypes could be differentiated by Western blot analysis due to the reactivities of M and L proteins toward a monoclonal pre-S2 antibody and slightly different S-protein mobilities. Great variability in replication capacity was observed for both genotypes. The A1762T/G1764A core promoter mutations were prevalent in genotype C isolates and correlated with increased replication capacity, while the A1752G/T mutation frequently found in genotype B isolates correlated with a low replication capacity. Importantly, most genotype C isolates with wild-type core promoter sequence replicated less efficiently than the corresponding genotype B isolates due to less efficient transcription of the 3.5-kb RNA. However, genotype C isolates often displayed more efficient virion secretion. We propose that the low intracellular levels of viral DNA and core protein of wild-type genotype C delay immune clearance and trigger the subsequent emergence of A1762T/G1764A core promoter mutations to upregulate replication; efficient virion secretion compensates for the low replication capacity to ensure the establishment of persistent infection by genotype C.
Immediate-Early Protein ME53 Forms Foci and Colocalizes with GP64 and the Major Capsid Protein VP39 at the Cell Membranes of Autographa californica Multiple Nucleopolyhedrovirus-Infected Cells
Authors: de Jong Jondavid , Theilmann David A. , Arif Basil M. , Krell Peter J. 
Published: July 2011

ABSTRACT

me53
is an immediate-early/late gene found in all lepidopteran baculoviruses sequenced to date. Deletion of
me53
results in a greater-than-1,000-fold reduction in budded-virus production in tissue culture (J. de Jong, B. M. Arif, D. A. Theilmann, and P. J. Krell, J. Virol. 83:7440-7448, 2009). We investigated the localization of ME53 using an ME53 construct fused to green fluorescent protein (GFP). ME53:GFP adopted a primarily cytoplasmic distribution at early times postinfection and a primarily nuclear distribution at late times postinfection. Additionally, at late times ME53:GFP formed distinct foci at the cell periphery. These foci colocalized with the major envelope fusion protein GP64 and frequently with VP39 capsid protein, suggesting that these cell membrane regions may represent viral budding sites. Deletion of
vp39
did not influence the distribution of ME53:GFP; however, deletion of
gp64
abolished ME53:GFP foci at the cell periphery, implying an association between ME53 and GP64. Despite the association of ME53 and GP64, ME53 fractionated with the nucleocapsid only after budded-virus fractionation. Together these findings suggest that ME53 may be providing a scaffold that bridges the viral envelope and nucleocapsid.
Emerging Theme: Cellular PDZ Proteins as Common Targets of Pathogenic Viruses
Authors: Javier Ronald T. , Rice Andrew P. 
Published: July 2011

ABSTRACT
More than a decade ago, three viral oncoproteins, adenovirus type 9 E4-ORF1, human T-lymphotropic virus type 1 Tax, and high-risk human papillomavirus E6, were found to encode a related carboxyl-terminal PDZ domain-binding motif (PBM) that mediates interactions with a select group of cellular PDZ proteins. Recent studies have shown that many other viruses also encode PBM-containing proteins that bind to cellular PDZ proteins. Interestingly, these recently recognized viruses include not only some with oncogenic potential (hepatitis B virus, rhesus papillomavirus, cottontail rabbit papillomavirus) but also many without this potential (influenza virus, Dengue virus, tick-borne encephalitis virus, rabies virus, severe acute respiratory syndrome coronavirus, human immunodeficiency virus). Examination of the cellular PDZ proteins that are targets of viral PBMs reveals that the viral proteins often interact with the same or similar types of PDZ proteins, most notably Dlg1 and other members of the membrane-associated guanylate kinase protein family, as well as Scribble. In addition, cellular PDZ protein targets of viral PBMs commonly control tight junction formation, cell polarity establishment, and apoptosis. These findings reveal a new theme in virology wherein many different virus families encode proteins that bind and perturb the function of cellular PDZ proteins. The inhibition or perturbation of the function of cellular PDZ proteins appears to be a widely used strategy for viruses to enhance their replication, disseminate in the host, and transmit to new hosts.
Should privacy impact assessments be mandatory?
Authors: Wright David 
Published: July 2011

Privacy impact assessments should be integrated into the overall approach to risk management with other strategic planning instruments.
This article considers the issue of whether privacy impact assessments (PIAs) should be mandatory. I will examine the benefits and disadvantages of PIAs, the case for and against mandatory PIAs, and ultimately conclude they should be mandatory. Even if they are made mandatory, however, other factors, such as independent audits, must be taken into account to make them truly effective.
Cyberwarfare
Authors: Goel Sanjay 
Published: July 2011

Perpetrators and victims usually act as if it never happened, while the evidence is designed to erase itself.
Cyberwarfare is a potent weapon in political conflicts, espionage, and propaganda. Difficult to detect a priori, it is often recognized only after significant damage has been done. Gaining offensive capability on the cyber battlefield figures prominently in the national strategies of many countries and is explicitly stated in the doctrines of several, including China, Russia, and the U.S. It is generally understood they are laying the groundwork for potential cyber conflicts by hacking the networks of adversaries and allies alike.
Rate vs. buffer size--greedy information gathering on the line
Authors: Rosén Adi , Scalosub Gabriel 
Published: July 2011

We consider packet networks with limited buffer space at the nodes, and are interested in the question of maximizing the number of packets that arrive to destination rather than being dropped due to full buffers.
We initiate a more refined analysis of the throughput competitive ratio of admission and scheduling policies in the Competitive Network Throughput model [Aiello et al. 2005], taking into account not only the network size but also the buffer size and the injection rate of the traffic.
We specifically consider the problem of information gathering on the line, with limited buffer space, under adversarial traffic. We examine how the buffer size and the injection rate of the traffic affect the performance of the greedy protocol for this problem. We establish upper bounds on the competitive ratio of the greedy protocol in terms of the network size, the buffer size, and the adversary's rate, and present lower bounds which are tight up to constant factors. These results show, for example, that provisioning the network with sufficiently large buffers may substantially improve the performance of the greedy protocol in some cases, whereas for some high-rate adversaries, using larger buffers does not have any effect on the competitive ratio of the protocol.
JavaGI
Authors: Wehr Stefan , Thiemann Peter 
Published: July 2011

The language JavaGI extends Java 1.5 conservatively by a generalized interface mechanism. The generalization subsumes retroactive and type-conditional interface implementations, binary methods, symmetric multiple dispatch, interfaces over families of types, and static interface methods. These features make certain coding patterns redundant, increase the expressiveness of the type system, and permit solutions to extension and integration problems with components in binary form, for which previously several unrelated extensions had been suggested.
This article explains JavaGI and motivates its design. Moreover, it formalizes a core calculus for JavaGI and proves type soundness, decidability of typechecking, and determinacy of evaluation. The article also presents the implementation of a JavaGI compiler and an accompanying run-time system. The compiler, based on the Eclipse Compiler for Java, offers mostly modular static typechecking and fully modular code generation. It defers certain well-formedness checks until load time to increase flexibility and to enable full support for dynamic loading. Benchmarks show that the code generated by the compiler offers good performance. Several case studies demonstrate the practical utility of the language and its implementation.
Dynamic cache contention detection in multi-threaded applications
Authors: Zhao Qin , Koh David , Raza Syed , Bruening Derek , Wong Weng-Fai , Amarasinghe Saman 
Published: July 2011

In today's multi-core systems, cache contention due to true and false sharing can cause unexpected and significant performance degradation. A detailed understanding of a given multi-threaded application's behavior is required to precisely identify such performance bottlenecks. Traditionally, however, such diagnostic information can only be obtained after lengthy simulation of the memory hierarchy.
In this paper, we present a novel approach that efficiently analyzes interactions between threads to determine thread correlation and detect true and false sharing. It is based on the following key insight: although the slowdown caused by cache contention depends on factors including the thread-to-core binding and parameters of the memory hierarchy, the amount of data sharing is primarily a function of the cache line size and application behavior. Using memory shadowing and dynamic instrumentation, we implemented a tool that obtains detailed sharing information between threads without simulating the full complexity of the memory hierarchy. The runtime overhead of our approach --- a 5x slowdown on average relative to native execution --- is significantly less than that of detailed cache simulation. The information collected allows programmers to identify the degree of cache contention in an application, the correlation among its threads, and the sources of significant false sharing. Using our approach, we were able to improve the performance of some applications up to a factor of 12x. For other contention-intensive applications, we were able to shed light on the obstacles that prevent their performance from scaling to many cores.
Fast and space-efficient virtual machine checkpointing
Authors: Park Eunbyung , Egger Bernhard , Lee Jaejin 
Published: July 2011

Checkpointing, i.e., recording the volatile state of a virtual machine (VM) running as a guest in a virtual machine monitor (VMM) for later restoration, includes storing the memory available to the VM. Typically, a full image of the VM's memory along with processor and device states are recorded. With guest memory sizes of up to several gigabytes, the size of the checkpoint images becomes more and more of a concern.
In this work we present a technique for fast and space-efficient checkpointing of virtual machines. In contrast to existing methods, our technique eliminates redundant data and stores only a subset of the VM's memory pages. Our technique transparently tracks I/O operations of the guest to external storage and maintains a list of memory pages whose contents are duplicated on non-volatile storage. At a checkpoint, these pages are excluded from the checkpoint image.
We have implemented the proposed technique for paravirtualized as well as fully-virtualized guests in the Xen VMM. Our experiments with a paravirtualized guest (Linux) and two fullyvirtualized guests (Linux, Windows) show a significant reduction in the size of the checkpoint image as well as the time required to complete the checkpoint. Compared to the current Xen implementation, we achieve, on average, an 81% reduction in the stored data and a 74% reduction in the time required to take a checkpoint for the paravirtualized Linux guest. In a fully-virtualized environment runningWindows and Linux guests, we achieve a 64% reduction of the image size along with a 62% reduction in checkpointing time.
Fast restore of checkpointed memory using working set estimation
Authors: Zhang Irene , Garthwaite Alex , Baskakov Yury , Barr Kenneth C. 
Published: July 2011

In order to make save and restore features practical, saved virtual machines (VMs) must be able to quickly restore to normal operation. Unfortunately, fetching a saved memory image from persistent storage can be slow, especially as VMs grow in memory size. One possible solution for reducing this time is to lazily restore memory after the VM starts. However, accesses to unrestored memory after the VM starts can degrade performance, sometimes rendering the VM unusable for even longer. Existing performance metrics do not account for performance degradation after the VM starts, making it difficult to compare lazily restoring memory against other approaches. In this paper, we propose both a better metric for evaluating the performance of different restore techniques and a better scheme for restoring saved VMs.
Existing performance metrics do not reflect what is really important to the user -- the time until the VM returns to normal operation. We introduce the time-to-responsiveness metric, which better characterizes user experience while restoring a saved VM by measuring the time until there is no longer a noticeable performance impact on the restoring VM. We propose a new lazy restore technique, called working set restore, that minimizes performance degradation after the VM starts by prefetching the working set. We also introduce a novel working set estimator based on memory tracing that we use to test working set restore, along with an estimator that uses access-bit scanning. We show that working set restore can improve the performance of restoring a saved VM by more than 89% for some workloads.