bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulse pileup statistics for energy discriminating photon counting x‐ray detectors
Authors: Wang Adam S. , Harrison Daniel , Lobastov Vladimir , Tkaczyk J. Eric
Published: June 2011

Purpose:

Energy discriminating photon counting x‐ray detectors can be subject to a wide range of flux rates if applied in clinical settings. Even when the incident rate is a small fraction of the detector's maximum periodic rateN0, pulse pileup leads to count rate losses and spectral distortion. Although the deterministic effects can be corrected, the detrimental effect of pileup on image noise is not well understood and may limit the performance of photon counting systems. Therefore, the authors devise a method to determine the detector count statistics and imaging performance.

Methods:

The detector count statistics are derived analytically for an idealized pileup model with delta pulses of a nonparalyzable detector. These statistics are then used to compute the performance (e.g., contrast‐to‐noise ratio) for both single material and material decomposition contrast detection tasks via the Cramér‐Rao lower bound (CRLB) as a function of the detector input count rate. With more realistic unipolar and bipolar pulse pileup models of a nonparalyzable detector, the imaging task performance is determined by Monte Carlo simulations and also approximated by a multinomial method based solely on the mean detected output spectrum. Photon counting performance at different count rates is compared with ideal energy integration, which is unaffected by count rate.

Results:

The authors found that an ideal photon counting detector with perfect energy resolution outperforms energy integration for our contrast detection tasks, but when the input count rate exceeds 20%N0, many of these benefits disappear. The benefit with iodine contrast falls rapidly with increased count rate while water contrast is not as sensitive to count rates. The performance with a delta pulse model is overoptimistic when compared to the more realistic bipolar pulse model. The multinomial approximation predicts imaging performance very close to the prediction from Monte Carlo simulations. The monoenergetic image with maximum contrast‐to‐noise ratio from dual energy imaging with ideal photon counting is only slightly better than with dual kVp energy integration, and with a bipolar pulse model, energy integration outperforms photon counting for this particular metric because of the count rate losses. However, the material resolving capability of photon counting can be superior to energy integration with dual kVp even in the presence of pileup because of the energy information available to photon counting.

Conclusions:

A computationally efficient multinomial approximation of the count statistics that is based on the mean output spectrum can accurately predict imaging performance. This enables photon counting system designers to directly relate the effect of pileup to its impact on imaging statistics and how to best take advantage of the benefits of energy discriminating photon counting detectors, such as material separation with spectral imaging.
A general framework and review of scatter correction methods in x‐ray cone‐beam computerized tomography. Part 1: Scatter compensation approaches
Authors: Rührnschopf Ernst‐Peter , Klingenbeck Klaus
Published: June 2011

Since scattered radiation in cone‐beam volume CT implies severe degradation of CT images by quantification errors, artifacts, and noise increase, scatter suppression is one of the main issues related to image quality in CBCT imaging. The aim of this review is to structurize the variety of scatter suppression methods, to analyze the common structure, and to develop a general framework for scatter correction procedures. In general, scatter suppression combines hardware techniques of scatter rejection and software methods of scatter correction. The authors emphasize that scatter correction procedures consist of the main components scatter estimation (by measurement or mathematical modeling) and scatter compensation (deterministic or statistical methods). The framework comprises most scatter correction approaches and its validity also goes beyond transmission CT. Before the advent of cone‐beam CT, a lot of papers on scatter correction approaches in x‐ray radiography, mammography, emission tomography, and in Megavolt CT had been published. The opportunity to avail from research in those other fields of medical imaging has not yet been sufficiently exploited. Therefore additional references are included when ever it seems pertinent. Scatter estimation and scatter compensation are typically intertwined in iterative procedures. It makes sense to recognize iterative approaches in the light of the concept of self‐consistency. The importance of incorporating scatter compensation approaches into a statistical framework for noise minimization has to be underscored. Signal and noise propagation analysis is presented. A main result is the preservation of differential‐signal‐to‐noise‐ratio (dSNR) in CT projection data by ideal scatter correction. The objective of scatter compensation methods is the restoration of quantitative accuracy and a balance between low‐contrast restoration and noise reduction. In a synopsis section, the different deterministic and statistical methods are discussed with respect to their properties and applications. The current paper is focused on scatter compensation algorithms. The multitude of scatter estimation models will be dealt with in a separate paper.
Characteristics of an OSLD in the diagnostic energy range
Authors: Al‐Senan Rani M. , Hatab Mustapha R.
Published: June 2011

Purpose:

Optically stimulated luminescence (OSL) dosimetry has been recently introduced in radiation therapy as a potential alternative to the thermoluminescent dosimeter (TLD) system. The aim of this study was to investigate the feasibility of using OSL point dosimeters in the energy range used in diagnostic imaging.

Methods:

NanoDot OSL dosimeters (OSLDs) were used in this study, which started with testing the homogeneity of a new packet of nanoDots. Reproducibility and the effect of optical treatment (bleaching) were then examined, followed by an investigation of the effect of accumulated dose on the OSLD indicated doses. OSLD linearity, angular dependence, and energy dependence were also studied. Furthermore, comparison with LiF:Mg,Ti TLD chips using standard CT dose phantoms at 80 and 120 kVp settings was performed.

Results:

Batch homogeneity showed a coefficient of variation of <5%. Single‐irradiation measurements with bleaching after each OSL readout was found to be associated with a 3.3% reproducibility (one standard deviation measured with a 8 mGy test dose), and no systematic change in OSLDs sensitivity could be noted from measurement to measurement. In contrast, the multiple‐irradiation readout without bleaching in between measurements was found to be associated with an uncertainty (using a 6 mGy test dose) that systematically increased with accumulated dose, reaching 42% at 82 mGy. Good linearity was shown by nanoDots under general x‐ray, CT, and mammography units with anR2 > 0.99. The angular dependence test showed a drop of approximately 70% in the OSLD response at 90° in mammography (25 kVp). With the general radiography unit, the maximum drop was 40% at 80 kVp and 20% at 120 kVp, and it was only 10% with CT at both 80 and 120 kVp. The energy dependence study showed a range of ion chamber‐to‐OSLDs ratios between 0.81 and 1.56, at the energies investigated (29–62 keV). A paired t‐test for comparing the OSLDs and TLDs showed no significant variation (p > 0.1).

Conclusions:

OSLDs exhibited good batch homogeneity (<5%) and reproducibility (3.3%), as well as a linear response. In addition, they showed no statistically significant difference with TLDs in CT measurements (p > 0.1). However, high uncertainty (42%) in the dose estimate was found as a result of relatively high accumulated dose. Furthermore, nanoDots showed high angular dependence (up to 70%) in low kVp techniques. Energy dependence of about 60% was found, and correction factors were suggested for the range of energies investigated. Therefore, if angular and energy dependences are taken into consideration and the uncertainty associated with accumulated dose is avoided, OSLDs (nanoDots) can be suitable for use as point dosimeters in diagnostic settings.
Pulmonary nodule registration: Rigid or nonrigid?
Authors: Gu Suicheng , Wilson David , Tan Jun , Pu Jiantao
Published: June 2011

Purpose:

The primary aim of this study is to investigate the performance difference of rigid and nonrigid registration schemes in matching corresponding pulmonary nodules depicted on sequential chest computed tomography (CT) examinations.

Methods:

A gradient descent based rigid registration algorithm with scaling was developed and it handled the involved geometric transformations (i.e., translation, rescaling, shearing, and rotation) separately instead of optimizing them in a single pass. Given two lung CT examinations, the scaling and translation parameters were simply estimated from the lung volume dimensions (e.g., size and mass center), while the rotation parameters were optimized progressively using gradient descent. To investigate the performance difference of rigid and nonrigid schemes in pulmonary nodule registration, the well‐known nonrigid Demons algorithm was implemented and tested along with the developed schemes against 60 diverse low‐dose clinical lung CT examinations with average 2‐yr follow‐up scans. A verified cancer and its correspondence in the follow‐up scan as well as their spatial locations (mass center) were identified in each examination. In addition to the computational efficiency, the accuracy of these registration procedures was assessed by computing the Euclidean distances between the corresponding nodules after the registration. To demonstrate the advantage of the developed algorithm, the authors also implemented a fast iterative closest point (ICP) based rigid algorithm and compared their performance.

Results:

Our experiments on the collected chest CT examinations showed that the nodule registration errors in 3D Euclidean distance for the developed rigid affine approach, the traditional ICP algorithm, and the refining nonrigid Demons algorithm were 9.6, 9.8, and 10.0 mm, respectively, and the corresponding computational costs in time were 5, 300, and 55 s, respectively.

Conclusions:

A rigid solution may be preferred in practice for the pulmonary nodule registration in longitudinal studies because of its relatively high efficiency and sufficient accuracy for the clinical need.
Reference‐free ground truth metric for metal artifact evaluation in CT images
Authors: Kratz Bärbel , Ens Svitlana , Müller Jan , Buzug Thorsten M.
Published: June 2011

Purpose:

In computed tomography (CT), metal objects in the region of interest introduce data inconsistencies during acquisition. Reconstructing these data results in an image with star shaped artifacts induced by the metal inconsistencies. To enhance image quality, the influence of the metal objects can be reduced by different metal artifact reduction (MAR) strategies. For an adequate evaluation of new MAR approaches a ground truth reference data set is needed. In technical evaluations, where phantoms can be measured with and without metal inserts, ground truth data can easily be obtained by a second reference data acquisition. Obviously, this is not possible for clinical data. Here, an alternative evaluation method is presented without the need of an additionally acquired reference data set.

Methods:

The proposed metric is based on an inherent ground truth for metal artifacts as well as MAR methods comparison, where no reference information in terms of a second acquisition is needed. The method is based on the forward projection of a reconstructed image, which is compared to the actually measured projection data.

Results:

The new evaluation technique is performed on phantom and on clinical CT data with and without MAR. The metric results are then compared with methods using a reference data set as well as an expert‐based classification. It is shown that the new approach is an adequate quantification technique for artifact strength in reconstructed metal or MAR CT images.

Conclusions:

The presented method works solely on the original projection data itself, which yields some advantages compared to distance measures in image domain using two data sets. Beside this, no parameters have to be manually chosen. The new metric is a useful evaluation alternative when no reference data are available.
Probing Individual Environmental Bacteria for Viruses by Using Microfluidic Digital PCR
Authors: Tadmor Arbel D. , Ottesen Elizabeth A. , Leadbetter Jared R. , Phillips Rob
Published: June 2011

Matching environmental phage with single, uncultured bacterial host cells reveals remarkable species specificity.
A Biological Screw in a Beetle’s Leg
Authors: van de Kamp Thomas , Vagovič Patrik , Baumbach Tilo , Riedel Alexander
Published: June 2011

Joints on the legs of weevils form a functional screw-and-nut system.
Mechanism of RAD51-Dependent DNA Interstrand Cross-Link Repair
Authors: Long David T. , Räschle Markus , Joukov Vladimir , Walter Johannes C.
Published: June 2011

An in vitro system reveals the steps involved in repairing covalent links between DNA strands of the double helix.
Solvated Electrons in High-Temperature Melts and Glasses of the Room-Temperature Stable Electride [Ca
24
Al
28
O
64
]
4+
⋅4e
−
Authors: Kim Sung Wng , Shimoyama Terumasa , Hosono Hideo
Published: June 2011

Solvated electrons persist in high-temperature melts and quenched melts of a calcium aluminum oxide.
Pattern in Escalations in Insurgent and Terrorist Activity
Authors: Johnson Neil , Carran Spencer , Botner Joel , Fontaine Kyle , Laxague Nathan , Nuetzel Philip , Turnley Jessica , Tivnan Brian
Published: June 2011

The escalation of fatal attacks by insurgent groups follows a common pattern.
Protease Sets Site-1 on Lysosomes
Authors: Ye Jin
Published: June 2011

Transport of enzymes to lysosomes requires the action of an enzyme known to process various transcription factors.
Some Summer Suggestions
Authors: Suter Sherman J.
Published: June 2011

Our reviewers sample a variety of stops that would reward science-minded travelers.
AIDS: Let Science Inform Policy
Authors: Fauci Anthony S.
Published: June 2011

Thirty years have passed since the first cases of acquired immune deficiency syndrome (AIDS) were reported by the U.S. Centers for Disease Control and Prevention. How does this anniversary compare to the 20th or the 10th? The differences are considerable, because we now have an unprecedented opportunity, based on solid scientific data, to control and ultimately end the AIDS pandemic.
Suit Seeks Redress for a Start-Up Package Gone Sour
Authors: Mervis Jeffrey
Published: June 2011

An electrophysiologist at the University of Texas at San Antonio has filed suit against the university for failing to honor its commitment to support her research in a timely fashion.
The Highs and Lows of Shuttle Science
Authors: Charles Dan
Published: June 2011

The contributions of the shuttle to science have come in many flavors and at an irregular pace.
Science
has created a timeline of shuttle science missions.
Immunogenicity of Inactivated Polio Vaccine with Concurrent Antiviral V-073 Administration in Mice
Authors: Kouiavskaia Diana , Collett Marc S. , Dragunsky Eugenia M. , Sarafanov Andrey , Chumakov Konstantin M.
Published: June 2011

Immunization of mice with inactivated polio vaccine (IPV) with concurrent dosing of poliovirus antiviral V-073 showed no detrimental impact on the elicitation of serum-neutralizing antibodies. A strategy involving coadministration of antiviral V-073 and IPV can be considered for the management of poliovirus incidents.
Diagnostic Issues, Clinical Characteristics, and Outcomes for Patients with Fungemia
Authors: Arendrup Maiken Cavling , Sulim Sofia , Holm Anette , Nielsen Lene , Nielsen Susanne Dam , Knudsen Jenny Dahl , Drenck Niels Erik , Christensen Jens Jørgen , Johansen Helle Krogh
Published: June 2011

This study investigated microbiological, clinical, and management issues and outcomes for Danish fungemia patients. Isolates and clinical information were collected at six centers. A total of 334 isolates, 316 episodes, and 305 patients were included, corresponding to 2/3 of the national episodes. Blood culture positivity varied by system, species, and procedure. Thus, cases with concomitant bacteremia were reported less commonly by BacT/Alert than by the Bactec system (9% [11/124 cases] versus 28% [53/192 cases];
P
< 0.0001), and cultures with
Candida glabrata
or those drawn via arterial lines needed longer incubation. Species distribution varied by age, prior antifungal treatment (57% occurrence of
C. glabrata
,
Saccharomyces cerevisiae
, or
C. krusei
in patients with prior antifungal treatment versus 28% occurrence in those without it;
P
= 0.007), and clinical specialty (61% occurrence of
C. glabrata
or
C. krusei
in hematology wards versus 27% occurrence in other wards;
P
= 0.002). Colonization samples were not predictive for the invasive species in 11/100 cases. Fifty-six percent of the patients had undergone surgery, 51% were intensive care unit (ICU) patients, and 33% had malignant disease. Mortality increased by age (
P
= 0.009) and varied by species (36% for
C. krusei
, 25% for
C. parapsilosis
, and 14% for other
Candida
species), severity of underlying disease (47% for ICU patients versus 24% for others;
P
= 0.0001), and choice but not timing of initial therapy (12% versus 48% for patients with
C. glabrata
infection receiving caspofungin versus fluconazole;
P
= 0.023). The initial antifungal agent was deemed suboptimal upon species identification in 15% of the cases, which would have been 6.5% if current guidelines had been followed. A large proportion of Danish fungemia patients were severely ill and received suboptimal initial antifungal treatment. Optimization of diagnosis and therapy is possible.
Mycobacterium haemophilum and Histoplasma capsulatum Coinfection in a Renal Transplant Patient
Authors: Clement Cecilia G. , Loeffelholz Michael J. , Eltorky Mahmoud A. , Tang Yi-Wei , Williams-Bouyer Natalie
Published: June 2011

We report the case of a 22-year-old man who presented with a
Mycobacterium haemophilum
and
Histoplasma capsulatum
coinfection occurring 21 years after a living-donor-related renal transplant.
Evaluation of Commercial Universal rRNA Gene PCR plus Sequencing Tests for Identification of Bacteria and Fungi Associated with Infectious Endocarditis
Authors: Kühn Christian , Disqué Claudia , Mühl Helge , Orszag Peter , Stiesch Meike , Haverich Axel
Published: June 2011

Two new commercially available universal rRNA gene PCR plus sequencing tests, SepsiTest and universal microbe detection (UMD; Molzym, Bremen, Germany), were evaluated using blood specimens and heart valves from 30 patients with suspected infectious endocarditis (IE). The sensitivity of PCR (85%) was nearly twice as high as that of culture (45%), which in 10/20 IE cases presumably stayed negative as a consequence of growth inhibition of the pathogens by antibiotics. Further, PCR provided the basis for reclassification of 5/10 non-IE cases into IE cases. Culture-negative infections were identified by PCR, including single infections due to streptococci and Gram-negative bacteria (
Escherichia coli
,
Haemophilus parainfluenzae
) and mixed infections involving two Gram-positive bacteria or
Candida
spp. with Gram-positive bacteria. The new commercial tests proved to be of value for the rapid diagnosis of IE, particularly in cases of culture-negative infections. Issues regarding the feasibility of these tests for routine use are discussed.
Evaluation of High-Throughput Sequencing for Identifying Known and Unknown Viruses in Biological Samples
Authors: Cheval Justine , Sauvage Virginie , Frangeul Lionel , Dacheux Laurent , Guigon Ghislaine , Dumey Nicolas , Pariente Kevin , Rousseaux Claudine , Dorange Fabien , Berthet Nicolas , Brisse Sylvain , Moszer Ivan , Bourhy Hervé , Manuguerra Claude Jean , Lecuit Marc , Burguiere Ana , Caro Valérie , Eloit Marc
Published: June 2011

High-throughput sequencing furnishes a large number of short sequence reads from uncloned DNA and has rapidly become a major tool for identifying viruses in biological samples, and in particular when the target sequence is undefined. In this study, we assessed the analytical sensitivity of a pipeline for detection of viruses in biological samples based on either the Roche-454 genome sequencer or Illumina genome analyzer platforms. We sequenced biological samples artificially spiked with a wide range of viruses with genomes composed of single or double-stranded DNA or RNA, including linear or circular single-stranded DNA. Viruses were added at a very low concentration most often corresponding to 3 or 0.8 times the validated level of detection of quantitative reverse transcriptase PCRs (RT-PCRs). For the viruses represented, or resembling those represented, in public nucleotide sequence databases, we show that the higher output of Illumina is associated with a much greater sensitivity, approaching that of optimized quantitative (RT-)PCRs. In this blind study, identification of viruses was achieved without incorrect identification. Nevertheless, at these low concentrations, the number of reads generated by the Illumina platform was too small to facilitate assembly of contigs without the use of a reference sequence, thus precluding detection of unknown viruses. When the virus load was sufficiently high,
de novo
assembly permitted the generation of long contigs corresponding to nearly full-length genomes and thus should facilitate the identification of novel viruses.
NF-κB Protects Human Papillomavirus Type 38 E6/E7-Immortalized Human Keratinocytes against Tumor Necrosis Factor Alpha and UV-Mediated Apoptosis
Authors: Hussain Ishraq , Fathallah Ikbal , Accardi Rosita , Yue Jiping , Saidj Djamel , Shukla Ruchi , Hasan Uzma , Gheit Tarik , Niu Yamei , Tommasino Massimo , Sylla Bakary S.
Published: June 2011

Constitutive activation of NF-κB signaling is a key event in virus- and non-virus-induced carcinogenesis. We have previously reported that cutaneous human papillomavirus type 38 (HPV38) displays transforming properties in
in vitro
and
in vivo
experimental models. However, the involvement of NF-κB signaling in HPV38-induced cell growth transformation remains to be determined. In this study, we showed that HPV38 E6 and E7 activate NF-κB and that inhibition of the pathway with the IκBα superrepressor sensitizes HPV38E6E7-immortalized human keratinocytes to tumor necrosis factor alpha (TNF-α)- and UVB radiation-mediated apoptosis. Accordingly, inhibition of NF-κB signaling resulted in the downregulation of NF-κB-regulated antiapoptotic genes, including cIAP1, cIAP2, and xIAP genes. These findings demonstrate a critical role of NF-κB activity in the survival of HPV38E6E7-immortalized human keratinocytes exposed to cytokine or UV radiation. Our data provide additional evidence for cooperation between beta HPV infection and UV irradiation in skin carcinogenesis.
Passive Immunotherapies Protect WRvFire and IHD-J-Luc Vaccinia Virus-Infected Mice from Lethality by Reducing Viral Loads in the Upper Respiratory Tract and Internal Organs
Authors: Zaitseva Marina , Kapnick Senta M. , Meseda Clement A. , Shotwell Elisabeth , King Lisa R. , Manischewitz Jody , Scott John , Kodihalli Shantha , Merchlinsky Michael , Nielsen Henriette , Lantto Johan , Weir Jerry P. , Golding Hana
Published: June 2011

Whole-body bioimaging was employed to study the effects of passive immunotherapies on lethality and viral dissemination in BALB/c mice challenged with recombinant vaccinia viruses expressing luciferase. WRvFire and IHD-J-Luc vaccinia viruses induced lethality with similar times to death following intranasal infection, but WRvFire replicated at higher levels than IHD-J-Luc in the upper and lower respiratory tracts. Three types of therapies were tested: licensed human anti-vaccinia virus immunoglobulin intravenous (VIGIV); recombinant anti-vaccinia virus immunoglobulin (rVIG; Symphogen, Denmark), an investigational product containing a mixture of 26 human monoclonal antibodies (HuMAbs) against mature virion (MV) and enveloped virion (EV); and HuMAb compositions targeting subsets of MV or EV proteins. Bioluminescence recorded daily showed that pretreatment with VIGIV (30 mg) or with rVIG (100 μg) on day −2 protected mice from death but did not prevent viral replication at the site of inoculation and dissemination to internal organs. Compositions containing HuMAbs against MV or EV proteins were protective in both infection models at 100 μg per animal, but at 30 μg, only anti-EV antibodies conferred protection. Importantly, the
t
statistic of the mean total fluxes revealed that viral loads in surviving mice were significantly reduced in at least 3 sites for 3 consecutive days (days 3 to 5) postchallenge, while significant reduction for 1 or 2 days in any individual site did not confer protection. Our data suggest that reduction of viral replication at multiple sites, including respiratory tract, spleen, and liver, as monitored by whole-body bioluminescence can be used to predict the effectiveness of passive immunotherapies in mouse models.
Gouléako Virus Isolated from West African Mosquitoes Constitutes a Proposed Novel Genus in the Family Bunyaviridae
Authors: Marklewitz M. , Handrick S. , Grasse W. , Kurth A. , Lukashev A. , Drosten C. , Ellerbrok H. , Leendertz F. H. , Pauli G. , Junglen S.
Published: June 2011

The family
Bunyaviridae
is the most diversified family of RNA viruses. We describe a novel prototypic bunyavirus, tentatively named Gouléako virus, isolated from various mosquito species trapped in Côte d'Ivoire. The S segment comprised 1,087 nucleotides (nt), the M segment 3,188 nt, and the L segment 6,358 nt, constituting the shortest bunyavirus genome known so far. The virus had shorter genome termini than phleboviruses and showed no evidence of encoded NSs and NSm proteins. An uncharacterized 105-amino-acid (aa) putative open reading frame (ORF) was detected in the S segment. Genetic equidistance to other bunyaviruses (74 to 88% aa identity) and absence of serological cross-reactivity with phleboviruses suggested a proposed novel
Bunyaviridae
genus.
Replication-Competent Simian Immunodeficiency Virus (SIV) Gag Escape Mutations Archived in Latent Reservoirs during Antiretroviral Treatment of SIV-Infected Macaques
Authors: Queen Suzanne E. , Mears Brian M. , Kelly Kathleen M. , Dorsey Jamie L. , Liao Zhaohao , Dinoso Jason B. , Gama Lucio , Adams Robert J. , Zink M. Christine , Clements Janice E. , Kent Stephen J. , Mankowski Joseph L.
Published: June 2011

In response to pressure exerted by major histocompatibility complex (MHC) class I-mediated CD8
+
T cell control, human immunodeficiency virus (HIV) escape mutations often arise in immunodominant epitopes recognized by MHC class I alleles. While the current standard of care for HIV-infected patients is treatment with highly active antiretroviral therapy (HAART), suppression of viral replication in these patients is not absolute and latently infected cells persist as lifelong reservoirs. To determine whether HIV escape from MHC class I-restricted CD8
+
T cell control develops during HAART treatment and then enters latent reservoirs in the periphery and central nervous system (CNS), with the potential to emerge as replication-competent virus, we tracked the longitudinal development of the simian immunodeficiency virus (SIV) Gag escape mutation K165R in HAART-treated SIV-infected pigtailed macaques. Key findings of these studies included: (i) SIV Gag K165R escape mutations emerged in both plasma and cerebrospinal fluid (CSF) during the decaying phase of viremia after HAART initiation before suppression of viral replication, (ii) SIV K165R Gag escape mutations were archived in latent proviral DNA reservoirs, including the brain in animals receiving HAART that suppressed viral replication, and (iii) replication-competent SIV Gag K165R escape mutations were present in the resting CD4
+
T cell reservoir in HAART-treated SIV-infected macaques. Despite early administration of aggressive antiretroviral treatment, HIV immune escape from CD8
+
T cell control can still develop during the decaying phases of viremia and then persist in latent reservoirs, including the brain, with the potential to emerge if HAART therapy is interrupted.
Human Leukocyte Antigen Variants B*44 and B*57 Are Consistently Favorable during Two Distinct Phases of Primary HIV-1 Infection in Sub-Saharan Africans with Several Viral Subtypes
Authors: Tang Jianming , Cormier Emmanuel , Gilmour Jill , Price Matthew A. , Prentice Heather A. , Song Wei , Kamali Anatoli , Karita Etienne , Lakhi Shabir , Sanders Eduard J. , Anzala Omu , Amornkul Pauli N. , Allen Susan , Hunter Eric , Kaslow Richard A. ,   for the IAVI African HIV Research Network
Published: June 2011

As part of an ongoing study of early human immunodeficiency virus type 1 (HIV-1) infection in sub-Saharan African countries, we have identified 134 seroconverters (SCs) with distinct acute-phase (peak) and early chronic-phase (set-point) viremias. SCs with class I human leukocyte antigen (HLA) variants B*44 and B*57 had much lower peak viral loads (VLs) than SCs without these variants (adjusted linear regression beta values of −1.08 ± 0.26 log
10
[mean ± standard error] and −0.83 ± 0.27 log
10
, respectively;
P
< 0.005 for both), after accounting for several nongenetic factors, including gender, age at estimated date of infection, duration of infection, and country of origin. These findings were confirmed by alternative models in which major viral subtypes (A1, C, and others) in the same SCs replaced country of origin as a covariate (
P
≤ 0.03). Both B*44 and B*57 were also highly favorable (
P
≤ 0.03) in analyses of set-point VLs. Moreover, B*44 was associated with relatively high CD4
+
T-cell counts during early chronic infection (
P
= 0.02). Thus, at least two common
HLA-B
variants showed strong influences on acute-phase as well as early chronic-phase VL, regardless of the infecting viral subtype. If confirmed, the identification of B*44 as another favorable marker in primary HIV-1 infection should help dissect mechanisms of early immune protection against HIV-1 infection.
Potent and Broad Anti-HIV-1 Activity Exhibited by a Glycosyl-Phosphatidylinositol-Anchored Peptide Derived from the CDR H3 of Broadly Neutralizing Antibody PG16
Authors: Liu Lihong , Wen Michael , Wang Weiming , Wang Shumei , Yang Lifei , Liu Yong , Qian Mengran , Zhang Linqi , Shao Yiming , Kimata Jason T. , Zhou Paul
Published: June 2011

PG9 and PG16 are two recently isolated quaternary-specific human monoclonal antibodies that neutralize 70 to 80% of circulating HIV-1 isolates. The crystal structure of PG16 shows that it contains an exceptionally long CDR H3 that forms a unique stable subdomain that towers above the antibody surface to confer fine specificity. To determine whether this unique architecture of CDR H3 itself is sufficient for epitope recognition and neutralization, we cloned CDR H3 subdomains derived from human monoclonal antibodies PG16, PG9, b12, E51, and AVF and genetically linked them to a glycosyl-phosphatidylinositol (GPI) attachment signal. Each fusion gene construct is expressed and targeted to lipid rafts of plasma membranes through a GPI anchor. Moreover, GPI-CDR H3(PG16, PG9, and E51), but not GPI-CDR H3(b12 and AVF), specifically neutralized multiple clades of HIV-1 isolates with a great degree of potency when expressed on the surface of transduced TZM-bl cells. Furthermore, GPI-anchored CDR H3(PG16), but not GPI-anchored CDR H3(AVF), specifically confers resistance to HIV-1 infection when expressed on the surface of transduced human CD4
+
T cells. Finally, the CDR H3 mutations (Y100HF, D100IA, and G7) that were previously shown to compromise the neutralization activity of antibody PG16 also abolished the neutralization activity of GPI-CDR H3(PG16). Thus, we conclude that the CDR H3 subdomain of PG16 neutralizes HIV-1 when targeted to the lipid raft of the plasma membrane of HIV-1-susceptible cells and that GPI-CDR H3 can be an alternative approach for determining whether the CDR H3 of certain antibodies alone can exert epitope recognition and neutralization.
Glyceraldehyde 3-Phosphate Dehydrogenase Negatively Regulates the Replication of Bamboo Mosaic Virus and Its Associated Satellite RNA
Authors: Prasanth K. Reddisiva , Huang Ying-Wen , Liou Ming-Ru , Wang Robert Yung-Liang , Hu Chung-Chi , Tsai Ching-Hsiu , Meng Menghsiao , Lin Na-Sheng , Hsu Yau-Heiu
Published: June 2011

The identification of cellular proteins associated with virus replicase complexes is crucial to our understanding of virus-host interactions, influencing the host range, replication, and virulence of viruses. A previous
in vitro
study has demonstrated that partially purified
Bamboo mosaic virus
(BaMV) replicase complexes can be employed for the replication of both BaMV genomic and satellite BaMV (satBaMV) RNAs. In this study, we investigated the BaMV and satBaMV 3′ untranslated region (UTR) binding proteins associated with these replicase complexes. Two cellular proteins with molecular masses of ∼35 and ∼55 kDa were specifically cross-linked with RNA elements, whereupon the ∼35-kDa protein was identified as the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Gel mobility shift assays confirmed the direct interaction of GAPDH with the 3′ UTR sequences, and competition gel shift analysis revealed that GAPDH binds preferentially to the positive-strand BaMV and satBaMV RNAs over the negative-strand RNAs. It was observed that the GAPDH protein binds to the pseudoknot poly(A) tail of BaMV and stem-loop-C poly(A) tail of satBaMV 3′ UTR RNAs. It is important to note that knockdown of GAPDH in
Nicotiana benthamiana
enhances the accumulation of BaMV and satBaMV RNA; conversely, transient overexpression of GAPDH reduces the accumulation of BaMV and satBaMV RNA. The recombinant GAPDH principally inhibits the synthesis of negative-strand RNA in exogenous RdRp assays. These observations support the contention that cytosolic GAPDH participates in the negative regulation of BaMV and satBaMV RNA replication.
The Herpes Simplex Virus 1 Latency-Associated Transcript Promotes Functional Exhaustion of Virus-Specific CD8
+
T Cells in Latently Infected Trigeminal Ganglia: a Novel Immune Evasion Mechanism
Authors: Chentoufi Aziz A. , Kritzer Elizabeth , Tran Michael V. , Dasgupta Gargi , Lim Chang Hyun , Yu David C. , Afifi Rasha E. , Jiang Xianzhi , Carpenter Dale , Osorio Nelson , Hsiang Chinhui , Nesburn Anthony B. , Wechsler Steven L. , BenMohamed Lbachir
Published: June 2011

Following ocular herpes simplex virus 1 (HSV-1) infection of C57BL/6 mice, HSV-specific (HSV-gB
498–505
tetramer
+
) CD8
+
T cells are induced, selectively retained in latently infected trigeminal ganglia (TG), and appear to decrease HSV-1 reactivation. The HSV-1 latency-associated transcript (LAT) gene, the only viral gene that is abundantly transcribed during latency, increases reactivation. Previously we found that during latency with HSV-1 strain McKrae-derived viruses, more of the total TG resident CD8 T cells expressed markers of exhaustion with LAT
+
virus compared to LAT
−
virus. Here we extend these findings to HSV-1 strain 17syn+-derived LAT
+
and LAT
−
viruses and to a virus expressing just the first 20% of LAT. Thus, the previous findings were not an artifact of HSV-1 strain McKrae, and the LAT function involved mapped to the first 1.5 kb of LAT. Importantly, to our knowledge, we show here for the first time that during LAT
+
virus latency, most of the HSV-1-specific TG resident CD8 T cells were functionally exhausted, as judged by low cytotoxic function and decreased gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. This resulted in LAT
−
TG having more functional HSV-gB
498–505
tetramer
+
CD8
+
T cells compared to LAT
+
TG. In addition, LAT expression, in the absence of other HSV-1 gene products, appeared to be able to directly or indirectly upregulate both PD-L1 and major histocompatibility complex class I (MHC-I) on mouse neuroblastoma cells (Neuro2A). These findings may constitute a novel immune evasion mechanism whereby the HSV-1 LAT directly or indirectly promotes functional exhaustion (i.e., dysfunction) of HSV-specific CD8
+
T cells in latently infected TG, resulting in increased virus reactivation.
Phenotypic and Immunologic Comparison of Clade B Transmitted/Founder and Chronic HIV-1 Envelope Glycoproteins
Authors: Wilen Craig B. , Parrish Nicholas F. , Pfaff Jennifer M. , Decker Julie M. , Henning Elizabeth A. , Haim Hillel , Petersen Josiah E. , Wojcechowskyj Jason A. , Sodroski Joseph , Haynes Barton F. , Montefiori David C. , Tilton John C. , Shaw George M. , Hahn Beatrice H. , Doms Robert W.
Published: June 2011

Sexual transmission of human immunodeficiency virus type 1 (HIV-1) across mucosal barriers is responsible for the vast majority of new infections. This relatively inefficient process results in the transmission of a single transmitted/founder (T/F) virus, from a diverse viral swarm in the donor, in approximately 80% of cases. Here we compared the biological activities of 24 clade B T/F envelopes (Envs) with those from 17 chronic controls to determine whether the genetic bottleneck that occurs during transmission is linked to a particular Env phenotype. To maximize the likelihood of an intact mucosal barrier in the recipients and to enhance the sensitivity of detecting phenotypic differences, only T/F Envs from individuals infected with a single T/F variant were selected. Using pseudotyping to assess Env function in single-round infectivity assays, we compared coreceptor tropism, CCR5 utilization efficiencies, primary CD4
+
T cell subset tropism, dendritic cell
trans
-infections, fusion kinetics, and neutralization sensitivities. T/F and chronic Envs were phenotypically equivalent in most assays; however, T/F Envs were modestly more sensitive to CD4 binding site antibodies b12 and VRC01, as well as pooled human HIV Ig. This finding was independently validated with a panel of 14 additional chronic HIV-1 Env controls. Moreover, the enhanced neutralization sensitivity was associated with more efficient binding of b12 and VRC01 to T/F Env trimers. These data suggest that there are subtle but significant structural differences between T/F and chronic clade B Envs that may have implications for HIV-1 transmission and the design of effective vaccines.
Epigenetic Silencing of HIV-1 by the Histone H3 Lysine 27 Methyltransferase Enhancer of Zeste 2
Authors: Friedman Julia , Cho Won-Kyung , Chu Chung K. , Keedy Kara S. , Archin Nancie M. , Margolis David M. , Karn Jonathan
Published: June 2011

Latent HIV proviruses are silenced as the result of deacetylation and methylation of histones located at the viral long terminal repeat (LTR). Inhibition of histone deacetylases (HDACs) leads to the reemergence of HIV-1 from latency, but the contribution of histone lysine methyltransferases (HKMTs) to maintaining HIV latency remains uncertain. Chromatin immunoprecipitation experiments using latently infected Jurkat T-cell lines demonstrated that the HKMT enhancer of Zeste 2 (EZH2) was present at high levels at the LTR of silenced HIV proviruses and was rapidly displaced following proviral reactivation. Knockdown of EZH2, a key component of the Polycomb repressive complex 2 (PRC2) silencing machinery, and the enzyme which is required for trimethyl histone lysine 27 (H3K27me3) synthesis induced up to 40% of the latent HIV proviruses. In contrast, there was less than 5% induction of latent proviruses following knockdown of SUV39H1, which is required for H3K9me3 synthesis. Knockdown of EZH2 also sensitized latent proviruses to external stimuli, such as T-cell receptor stimulation, and slowed the reversion of reactivated proviruses to latency. Similarly, cell populations that responded poorly to external stimuli carried HIV proviruses that were enriched in H3K27me3 and relatively depleted in H3K9me3. Treating latently infected cells with the HKMT inhibitor 3-deazaneplanocin A, which targets EZH2, led to the reactivation of silenced proviruses, whereas chaetocin and BIX01294 showed only minimal reactivation activities. These findings suggest that PRC2-mediated silencing is an important feature of HIV latency and that inhibitors of histone methylation may play a useful role in induction strategies designed to eradicate latent HIV pools.
The Role of Amino-Terminal Sequences in Cellular Localization and Antiviral Activity of APOBEC3B
Authors: Pak Vladimir , Heidecker Gisela , Pathak Vinay K. , Derse David
Published: June 2011

Human APOBEC3B (A3B) has been described as a potent inhibitor of retroviral infection and retrotransposition. However, we found that the predominantly nuclear A3B only weakly restricted infection by HIV-1, HIV-1Δ
vif
, and human T-cell leukemia virus type 1 (HTLV-1), while significantly inhibiting LINE-1 retrotransposition. The chimeric construct A3G/B, in which the first 60 amino acids of A3B were replaced with those of A3G, restricted HIV-1, HIV-1Δ
vif
, and HTLV-1 infection, as well as LINE-1 retrotransposition. In contrast to the exclusively cytoplasmic A3G, which is inactive against LINE-1 retrotransposition, the A3G/B protein, while localized mainly to the cytoplasm, was also present in the nucleus. Further mutational analysis revealed that residues 18, 19, 22, and 24 in A3B were the major determinants for nuclear versus cytoplasmic localization and antiretroviral activity. HIV-1Δ
vif
packages A3G, A3B, and A3G/B into particles with close-to-equal efficiencies. Mutation E68Q or E255Q in the active centers of A3G/B resulted in loss of the inhibitory activity against HIV-1Δ
vif
, while not affecting activity against LINE-1 retrotransposition. The low inhibition of HIV-1Δ
vif
by A3B correlated with a low rate of G-to-A hypermutation. In contrast, viruses that had been exposed to A3G/B showed a high number of G-to-A transitions. The mutation pattern was similar to that previously reported for A3B, with a preference for the GA context. In summary, these observations suggest that changing 4 residues in the amino terminus of A3B not only retargets the protein from the nucleus to the cytoplasm but also enhances its ability to restrict HIV while retaining inhibition of retrotransposition.
Activation of the Retroviral Budding Factor ALIX
Authors: Zhai Qianting , Landesman Michael B. , Chung Hyo-Young , Dierkers Adam , Jeffries Cy M. , Trewhella Jill , Hill Christopher P. , Sundquist Wesley I.
Published: June 2011

The cellular ALIX protein functions within the ESCRT pathway to facilitate intralumenal endosomal vesicle formation, the abscission stage of cytokinesis, and enveloped virus budding. Here, we report that the C-terminal proline-rich region (PRR) of ALIX folds back against the upstream domains and auto-inhibits V domain binding to viral late domains. Mutations designed to destabilize the closed conformation of the V domain opened the V domain, increased ALIX membrane association, and enhanced virus budding. These observations support a model in which ALIX activation requires dissociation of the autoinhibitory PRR and opening of the V domain arms.
The Cytoplasmic Domain of Rhesus Cytomegalovirus Rh178 Interrupts Translation of Major Histocompatibility Class I Leader Peptide-Containing Proteins prior to Translocation
Authors: Richards Rebecca , Scholz Isabel , Powers Colin , Skach William R. , Früh Klaus
Published: June 2011

Cytomegalovirus (CMV) efficiently evades many host immune defenses and encodes a number of proteins that prevent antigen presentation by major histocompatibility complex class I (MHC-I) molecules in order to evade recognition and killing of infected cells by cytotoxic CD8
+
T cells. We recently showed that rhesus CMV-specific Rh178 intercepts MHC-I protein translation before interference of MHC-I maturation by homologues of the human CMV US6 family. Here, we demonstrate that Rh178 localizes to the membrane of the endoplasmic reticulum, displaying a short luminal and large cytosolic domain, and that the membrane-proximal cytosolic portion is essential for inhibition of MHC-I expression. We further observed that Rh178 does not require synthesis of full-length MHC-I heavy chains but is capable of inhibiting the translation of short, unstable amino-terminal fragments of MHC-I. Moreover, the transfer of amino-terminal fragments containing the MHC-I signal peptide renders recipient proteins susceptible to targeting by Rh178. The cytosolic orientation of Rh178 and its ability to target protein fragments carrying the MHC-I signal peptide are consistent with Rh178 intercepting partially translated MHC-I heavy chains after signal recognition particle-dependent transfer to the endoplasmic reticulum membrane. However, interference with MHC-I translation by Rh178 seems to occur prior to SEC61-dependent protein translocation, since inhibition of MHC-I translocation by eeyarestatin 1 resulted in a full-length degradation intermediate that can be stabilized by proteasome inhibitors. These data are consistent with Rh178 blocking protein translation of MHC-I heavy chains at a step prior to the start of translocation, thereby downregulating MHC-I at a very early stage of translation.
Effects of statin medication on mortality risk associated with type 2 diabetes in older persons: the population-based AGES-Reykjavik Study
Authors: Olafsdottir Elin , Aspelund Thor , Sigurdsson Gunnar , Thorsson Bolli , Eiriksdottir Gudny , Harris Tamara B , Launer Lenore J , Benediktsson Rafn , Gudnason Vilmundur
Published: June 2011

Objective

To examine if the beneficial effect of statin medication on mortality seen in randomised clinical trials of type 2 diabetes applies equally to observational studies in the general population of older people.

Design

A prospective, population-based cohort study.

Setting

Reykjavik, Iceland.

Participants

5152 men and women from the Age, Gene/Environment Susceptibility-Reykjavik Study, mean age 77 years, range of 66–96 years.

Main outcome measure

Cardiovascular and all-cause mortalities and the RR of dying according to statin use and history of coronary heart disease (CHD) in persons with type 2 diabetes and those without diabetes with a median follow-up time of 5.3 years, until end of 2009.

Results

The prevalence of type 2 diabetes was 12.4% of which 35% used statins. Statin use was associated with a 50% (95% CI 8% to 72%) lower cardiovascular mortality and 53% (29% to 68%) lower all-cause mortalities in persons with diabetes. For those without diabetes, statin use was associated with a 16% (−24% to 43%) lower cardiovascular and 30% (11% to 46%) lower all-cause mortalities. Persons with diabetes using statins had a comparable risk of cardiovascular and all-cause mortality to that of the general population without diabetes. The effect was independent of the level of glycaemic control.

Conclusion

This observational study lends important support to existing data from randomised clinical trials. These data suggest that in the general population of older people with diabetes, statin medication markedly reduces the excess cardiovascular and all-cause mortality risk, irrespective of the presence or absence of coronary heart disease or glucose-lowering medication.