bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single‐scan rest/stress imaging 18F‐labeled flow tracers
Authors: Alpert Nathaniel , Dean Fang Yu‐Hua , Fakhri Georges El 
Published: October 2012

Purpose:The authors report a novel measurement strategy to obtain both rest and stress blood flow during a single, relatively short, scan session.Methods:Measurement of rest‐stress myocardial blood flow with long‐lived tracers usually requires separate scan sessions to remove the confounding effects of residual radioactivity concentration in the blood and tissue. The innovation of this method is to treat the rest‐stress scan as a single entity in which the flow parameters change due to pharmacological challenge. With this approach the fate of a tracer molecule is naturally accounted for, no matter if it was introduced during the rest or stress phase of the study. Two new dual‐injection kinetic models are considered that represent the response to pharmacological stress as a transitional or transient increase of myocardial blood flow. The authors present the theory of the method followed by the specific application of the theory to18F‐Flurpiridaz, a new myocardial flow‐imaging agent.Results:Myocardial blood flow was accurately and precisely estimated from a single‐scan rest/stress study for the long half‐lived tracer18F‐Flurpiridaz. By accounting for the time‐dependence of the kinetic parameters, the proposed models achieved good accuracy and precision (5%) under different vasodilators and different ischemic states.Conclusions:Detailed simulations predict that accurate and precise rest‐stress blood flow measurements can be obtained in 20–30 min.
Advanced Yellow Fever Virus Genome Detection in Point-of-Care Facilities and Reference Laboratories
Authors: Domingo Cristina , Patel Pranav , Yillah Jasmin , Weidmann Manfred , Méndez Jairo A. , Nakouné Emmanuel Rivalyn , Niedrig Matthias 
Published: October 2012

ABSTRACT
Reported methods for the detection of the yellow fever viral genome are beset by limitations in sensitivity, specificity, strain detection spectra, and suitability to laboratories with simple infrastructure in areas of endemicity. We describe the development of two different approaches affording sensitive and specific detection of the yellow fever genome: a real-time reverse transcription-quantitative PCR (RT-qPCR) and an isothermal protocol employing the same primer-probe set but based on helicase-dependent amplification technology (RT-tHDA). Both assays were evaluated using yellow fever cell culture supernatants as well as spiked and clinical samples. We demonstrate reliable detection by both assays of different strains of yellow fever virus with improved sensitivity and specificity. The RT-qPCR assay is a powerful tool for reference or diagnostic laboratories with real-time PCR capability, while the isothermal RT-tHDA assay represents a useful alternative to earlier amplification techniques for the molecular diagnosis of yellow fever by field or point-of-care laboratories.
Is Streptococcus pyogenes Resistant or Susceptible to Trimethoprim-Sulfamethoxazole?
Authors: Bowen Asha C. , Lilliebridge Rachael A. , Tong Steven Y. C. , Baird Robert W. , Ward Peter , McDonald Malcolm I. , Currie Bart J. , Carapetis Jonathan R. 
Published: October 2012

ABSTRACT

Streptococcus pyogenes
is commonly believed to be resistant to trimethoprim-sulfamethoxazole (SXT), resulting in reservations about using SXT for skin and soft tissue infections (SSTI) where
S. pyogenes
is involved.
S. pyogenes
'
in vitro
susceptibility to SXT depends on the medium's thymidine content. Thymidine allows
S. pyogenes
to bypass the sulfur-mediated inhibition of folate metabolism and, historically, has resulted in apparently reduced susceptibility of
S. pyogenes
to sulfur antibacterials. The low thymidine concentration in Mueller-Hinton agar (MHA) is now regulated. We explored
S. pyogenes
susceptibility to SXT on various media. Using two sets of 100 clinical
S. pyogenes
isolates, we tested for susceptibility using SXT Etests on MHA containing defibrinated horse blood and 20 mg/liter β-NAD (MHF), MHA with sheep blood (MHS), MHA alone, MHA with horse blood (MHBA), and MHA with lysed horse blood (MHLHBA). European Committee on Antibacterial Susceptibility Testing (EUCAST) breakpoints defined susceptibility (MIC, ≤1 mg/liter) and resistance (MIC, >2 mg/liter). In study 1, 99% of
S. pyogenes
isolates were susceptible to SXT on MHA, MHBA, and MHLHBA, with geometric mean MICs of 0.04, 0.04, and 0.05 mg/liter, respectively. In study 2, all 100
S. pyogenes
isolates were susceptible to SXT on MHF, MHS, MHA, and MHLHBA with geometric mean MICs of 0.07, 0.16, 0.07, and 0.09 mg/liter, respectively. This study confirms the
in vitro
susceptibility of
S. pyogenes
to SXT, providing support for the use of SXT for SSTIs. A clinical trial using SXT for impetigo is ongoing.
Laser Cutting Eliminates Nucleic Acid Cross-Contamination in Dried-Blood-Spot Processing
Authors: Murphy Sean C. , Daza Glenda , Chang Ming , Coombs Robert 
Published: October 2012

ABSTRACT
Dried blood spots (DBS) are useful for molecular assays but are prone to false positives from cross-contamination. In our malaria DBS assay, cross-contamination was encountered despite cleaning techniques suitable for HIV-1. We therefore developed a contact-free laser cutting system that effectively eliminated cross-contamination during DBS processing.
Bovine Ephemeral Fever Virus Uses a Clathrin-Mediated and Dynamin 2-Dependent Endocytosis Pathway That Requires Rab5 and Rab7 as Well as Microtubules
Authors: Cheng Ching Y. , Shih Wing L. , Huang Wei R. , Chi Pei I. , Wu Ming H. , Liu Hung J. 
Published: October 2012

ABSTRACT
The specific cell pathways involved in bovine ephemeral fever virus (BEFV) cell entry have not been determined. In this work, colocalization of the M protein of BEFV with clathrin or dynamin 2 was observed under a fluorescence microscope. To better understand BEFV entry, we carried out internalization studies with a fluorescently labeled BEFV by using a lipophilic dye, 3,30-dilinoleyloxacarbocyanine perchlorate (DiO), further suggesting that BEFV uses a clathrin-mediated endocytosis pathway. Our results suggest that clathrin-mediated and dynamin 2-dependent endocytosis is an important avenue of BEFV entry. Suppression of Rab5 or Rab7a through the use of a Rab5 dominant negative mutant and Rab7a short hairpin RNA (shRNA) demonstrated that BEFV requires both early and late endosomes for endocytosis and subsequent infection in MDBK and Vero cells. Treatment of BEFV-infected cells with nocodazole significantly decreased the M protein synthesis and viral yield, indicating that microtubules play an important role in BEFV productive infection, likely by mediating trafficking of BEFV-containing endosomes. Furthermore, BEFV infection was strongly blocked by different inhibitors of endosomal acidification, suggesting that virus enters host cells by clathrin-mediated and dynamin 2-dependent endocytosis in a pH-dependent manner.
Differential Pathological and Immune Responses in Newly Weaned Ferrets Are Associated with a Mild Clinical Outcome of Pandemic 2009 H1N1 Infection
Authors: Huang Stephen S. H. , Banner David , Degousee Norbert , Leon Alberto J. , Xu Louling , Paquette Stephane G. , Kanagasabai Thirumagal , Fang Yuan , Rubino Salvatore , Rubin Barry , Kelvin David J. , Kelvin Alyson A. 
Published: October 2012

ABSTRACT
Young children are typically considered a high-risk group for disease associated with influenza virus infection. Interestingly, recent clinical reports suggested that young children were the smallest group of cases with severe pandemic 2009 H1N1 (H1N1pdm) influenza virus infection. Here we established a newly weaned ferret model for the investigation of H1N1pdm infection in young age groups compared to adults. We found that young ferrets had a significantly milder fever and less weight loss than adult ferrets, which paralleled the mild clinical symptoms in the younger humans. Although there was no significant difference in viral clearance, disease severity was associated with pulmonary pathology, where newly weaned ferrets had an earlier pathology improvement. We examined the immune responses associated with protection of the young age group during H1N1pdm infection. We found that interferon and regulatory interleukin-10 responses were more robust in the lungs of young ferrets. In contrast, myeloperoxidase and major histocompatibility complex responses were persistently higher in the adult lungs; as well, the numbers of inflammation-prone granulocytes were highly elevated in the adult peripheral blood. Importantly, we observed that H1N1pdm infection triggered formation of lung structures that resembled inducible bronchus-associated lymphoid tissues (iBALTs) in young ferrets which were associated with high levels of homeostatic chemokines CCL19 and CXCL13, but these were not seen in the adult ferrets with severe disease. These results may be extrapolated to a model of the mild disease seen in human children. Furthermore, these mechanistic analyses provide significant new insight into the developing immune system and effective strategies for intervention and vaccination against respiratory viruses.
Human Cytomegalovirus Infection of M1 and M2 Macrophages Triggers Inflammation and Autologous T-Cell Proliferation
Authors: Bayer Carina , Varani Stefania , Wang Li , Walther Paul , Zhou Shaoxia , Straschewski Sarah , Bachem Max , Söderberg-Naucler Cecilia , Mertens Thomas , Frascaroli Giada 
Published: October 2012

ABSTRACT
Macrophages (Mϕ) are first targets during human cytomegalovirus (HCMV) infection and are thought to be crucial for viral persistence and dissemination. However, since Mϕ are also a first line of defense and key modulators of the immune response, these cells are at the crossroad between protection and viral pathogenesis. To date, the Mϕ-specific contribution to the immune response against HCMV is still poorly understood. In view of the opposite roles of M1 and M2 Mϕ during initiation and resolution of the immune response, we characterized the effects of HCMV infection on classically activated M1 Mϕ and alternatively activated M2 Mϕ. Although HCMV susceptibility was higher in M2 Mϕ, HCMV established a productive and persistent infection in both types of Mϕ. Upon HCMV encounter, both types of Mϕ acquired similar features of classical activation and secreted high levels of proinflammatory cytokines and chemokines. As a functional consequence, conditioned media obtained from HCMV-infected M1 and M2 Mϕ potently activated freshly isolated monocytes. Finally, compared to HCMV-infected monocyte-derived dendritic cells, infected M1 and M2 Mϕ were more efficient in stimulating proliferation of autologous T cells from HCMV-seropositive donors at early times (24 h) postinfection, while the Mϕ immunostimulatory properties were reduced, but not abrogated, at later times (72 h postinfection). In summary, our findings indicate that Mϕ preserve proper antigen presentation capacity upon HCMV infection while enhancing inflammation, thus suggesting that Mϕ play a role in the maintenance of the large HCMV-specific T-cell repertoire in seropositive individuals.
Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1
Authors: Carlson Jonathan M. , Brumme Chanson J. , Martin Eric , Listgarten Jennifer , Brockman Mark A. , Le Anh Q. , Chui Celia K. S. , Cotton Laura A. , Knapp David J. H. F. , Riddler Sharon A. , Haubrich Richard , Nelson George , Pfeifer Nico , DeZiel Charles E. , Heckerman David , Apps Richard , Carrington Mary , Mallal Simon , Harrigan P. Richard , John Mina , Brumme Zabrina L. ,   the International HIV Adaptation Collaborative
Published: October 2012

ABSTRACTHLA class I-associated polymorphisms identified at the population level mark viral sites under immune pressure by individual HLA alleles. As such, analysis of their distribution, frequency, location, statistical strength, sequence conservation, and other properties offers a unique perspective from which to identify correlates of protective cellular immunity. We analyzed HLA-associated HIV-1 subtype B polymorphisms in 1,888 treatment-naïve, chronically infected individuals using phylogenetically informed methods and identified characteristics of HLA-associated immune pressures that differentiate protective and nonprotective alleles. Over 2,100 HLA-associated HIV-1 polymorphisms were identified, approximately one-third of which occurred inside or within 3 residues of an optimally defined cytotoxic T-lymphocyte (CTL) epitope. Differential CTL escape patterns between closely related HLA alleles were common and increased with greater evolutionary distance between allele group members. Among 9-mer epitopes, mutations at HLA-specific anchor residues represented the most frequently detected escape type: these occurred nearly 2-fold more frequently than expected by chance and were computationally predicted to reduce peptide-HLA binding nearly 10-fold on average. Characteristics associated with protective HLA alleles (defined using hazard ratios for progression to AIDS from natural history cohorts) included the potential to mount broad immune selection pressures across all HIV-1 proteins except Nef, the tendency to drive multisite and/or anchor residue escape mutations within known CTL epitopes, and the ability to strongly select mutations in conserved regions within HIV's structural and functional proteins. Thus, the factors defining protective cellular immune responses may be more complex than simply targeting conserved viral regions. The results provide new information to guide vaccine design and immunogenicity studies.
Infection of Vascular Endothelial Cells with Human Cytomegalovirus under Fluid Shear Stress Reveals Preferential Entry and Spread of Virus in Flow Conditions Simulating Atheroprone Regions of the Artery
Authors: DuRose Jenny B. , Li Julie , Chien Shu , Spector Deborah H. 
Published: October 2012

ABSTRACT

Atherosclerosis is a major pathogenic factor in cardiovascular diseases, which are the leading cause of mortality in developed countries. While risk factors for atherosclerosis tend to be systemic, the distribution of atherosclerotic plaques within the vasculature is preferentially located at branch points and curves where blood flow is disturbed and shear stress is low. It is now widely accepted that hemodynamic factors can modulate endothelial gene expression and function and influence the pathophysiological changes associated with atherosclerosis. Human cytomegalovirus (HCMV), a ubiquitous pathogen, has long been proposed as a risk factor for atherosclerosis. To date, the role of HCMV in atherogenesis has been explored only in static conditions, and it is not known how HCMV infection is influenced by the physiological context of flow. In this study, we utilized a parallel-plate flow system to simulate the effects of shear stresses in different regions of the vasculature
in vitro
. We found that endothelial cells cultured under low shear stress, which simulates the flow condition of atheroprone regions
in vivo
, are more permissive to HCMV infection than cells experiencing high shear stress or static conditions. Cells exposed to low shear stress show increased entry of HCMV compared to cells exposed to high shear stress or static conditions. Viral structural gene expression, viral titers, and viral spread are also enhanced in endothelial cells exposed to low shear stress. These results suggest that hemodynamic factors modulate HCMV infection of endothelial cells, thus providing new insights into the induction/acceleration of atherosclerosis by HCMV.
WiDGET
Authors: Watanabe Yasuko , Davis John D. , Wood David A. 
Published: October 2012

The recent paradigm shift to multi-core systems results in high system throughput within a specified power budget. However, future systems still require good single thread performance--no longer the predominant design priority--to mitigate sequential bottlenecks and/or to guarantee service-level agreements. Unfortunately, near saturation in voltage scaling necessitates a long-term alternative to dynamic voltage and frequency scaling.
We propose an energy-proportional computing infrastructure, called WiDGET, that decouples thread context management from a sea of simple execution units (EUs). WiDGET's decoupled design provides flexibility to alter resource allocation for a particular power-performance target while turning off unallocated resources. In other words, WiDGET enables dynamic customization of different combinations of small and/or powerful cores on a single chip, consuming power in proportion to the delivered performance.

Over all SPEC CPU2006 benchmarks, WiDGET provides average per-thread performance that is 26% better than a Xeon-like processor while using 8% less power. WiDGET can also scale down to a level comparable to an Atom-like processor, turning off resources to reduce average power by 58%. WiDGET achieves high power efficiency (BIPS
3
/W), exceeding Xeon-like and Atom-like processors by up to 2x and 21x, respectively.
Forwardflow
Authors: Gibson Dan , Wood David A. 
Published: October 2012

Chip Multiprocessors (CMPs) are now commodity hardware, but commoditization of parallel software remains elusive. In the near term, the current trend of increased core-per-socket count will continue, despite a lack of parallel software to exercise the hardware. Future CMPs must deliver thread-level parallelism when software provides threads to run, but must also continue to deliver performance gains for single threads by exploiting instruction-level parallelism and memory-level parallelism. However, power limitations will prevent conventional cores from exploiting both simultaneously.
This work presents the Forwardflow Architecture, which can scale its execution logic up to run single threads, or down to run multiple threads in a CMP. Forwardflow dynamically builds an explicit internal dataflow representation from a conventional instruction set architecture, using forward dependence pointers to guide instruction wakeup, selection, and issue. Forwardflow's backend is organized into discrete units that can be individually (de-)activated, allowing each core's performance to be scaled by system software at the architectural level.
On single threads, Forwardflow core scaling yields a mean runtime reduction of 21% for a 37% increase in power consumption. For multithreaded workloads, a Forwardflow-based CMP allows system software to select the performance point that best matches available power.
The impact of management operations on the virtualized datacenter
Authors: Soundararajan Vijayaraghavan , Anderson Jennifer M. 
Published: October 2012

Virtualization has the potential to dramatically reduce the total cost of ownership of datacenters and increase the flexibility of deployments for general-purpose workloads. If present trends continue, the datacenter of the future will be largely virtualized. The base platform in such a datacenter will consist of physical hosts that run hypervisors, and workloads will run within virtual machines on these platforms. From a system management perspective, the virtualized environment enables a number of new workflows in the datacenter. These workflows involve operations on the physical hosts themselves, such as upgrading the hypervisor, as well as operations on the virtual machines, such as reconfiguration or reverting from snapshots. While traditional datacenter design has focused on the cost vs. capability tradeoffs for the end-user applications running in the datacenter, we argue that the management workload from these workflows must be factored into the design of the virtualized datacenter.
In this paper, we examine data from real-world virtualized deployments to characterize common management workflows and assess their impact on resource usage in the datacenter. We show that while many end-user applications are fairly light on I/O requirements, the management workload has considerable network and disk I/O requirements. We show that the management workload scales with the increasing compute power in the datacenter. Finally, we discuss the implications of this management workload for the datacenter.
The rebirth of neural networks
Authors: Temam Olivier 
Published: October 2012

After the hype of the 1990s, where companies like Intel or Philips built commercial hardware systems based on neural networks, the approach quickly lost ground for multiple reasons: hardware neural networks were no match for software neural networks run on rapidly progressing general-purpose processors, their application scope was considered too limited, and even progress in machine-learning theory overshadowed neural networks.
However, in the past few years, a remarkable convergence of trends and innovations is casting a new light on neural networks and could make them valuable components of future computing systems. Trends in technology call for architectures which can sustain a large number of defects, something neural networks are intrinsically capable of. Tends in applications, summarized in the recent RMS categorization, highlight a number of key algorithms which are eligible to neural networks implementations. At the same time, innovations in technology, such as the recent realization of a memristor, are creating the conditions for the efficient hardware implementation of neural networks. Innovations in machine learning, with the recent advent of Deep Networks, have revived interest in neural networks. Finally, recent findings in neurobiology carry even greater prospects, where detailed explanations of how complex functions, such as vision, can be implemented further open up the defect-tolerance and application potential of neural network architectures.
Sensitization of TRAIL-Induced Cell Death by 20(S)-Ginsenoside Rg3 via CHOP-Mediated DR5 Upregulation in Human Hepatocellular Carcinoma Cells
Authors: Lee Ju-Yeon , Jung Kyung Hee , Morgan Michael J. , Kang Yi-Rae , Lee Hee-Seung , Koo Gi-Bang , Hong Soon-Sun , Kwon Sung Won , Kim You-Sun 
Published: October 2012

AbstractThe TRAIL pathway is a potential therapeutic target for anticancer drugs due to selective cytotoxicity in cancer cells. Despite considerable promise, TRAIL or TRAIL receptor agonists have been used thus far with limited success in multiple clinical trials, in part due to acquired TRAIL resistance during chemotherapeutic treatment. Hepatocellular carcinoma (HCC) is a common solid tumor and the third leading cause of cancer-related death worldwide. Classical chemotherapy is not effective for HCC treatment and targeted therapy is limited to sorafenib. Isolated from Panax ginseng CA Meyer, 20(S)-ginsenoside Rg3 is a steroidal saponin with high pharmacologic activity that has been shown to sensitize cells to some chemotherapeutic agents. We investigated the sensitizing effect of Rg3 on TRAIL-induced cell death in HCC cells. We show Rg3 is capable of promoting TRAIL-induced apoptosis in a number of HCC cell lines, including HepG2, SK-Hep1, Huh-7, and Hep3B, but not in normal HL-7702 hepatocytes, indicating that Rg3 sensitization to TRAIL may be specific to cancer cells. Mechanistically, we found that Rg3 upregulates DR5 expression at the transcriptional level. DR5 upregulation in this case is mediated by C/EBP homology protein (CHOP), an important endoplasmic reticulum stress responsive protein. Furthermore, Rg3 is well tolerated and enhances the therapeutic efficacy of TRAIL in mouse xenograft models, suggesting that chemosensitization also occurs in vivo. Taken together, our study identifies Rg3 as a novel anticancer therapeutic agent and supports the further development of Rg3 as a chemosensitizer in combined therapy with TRAIL. Mol Cancer Ther; 12(3); 274–85. ©2012 AACR.