bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient‐specific dose estimation for pediatric chest CT
Authors: Li Xiang , Samei Ehsan , Segars W. Paul , Sturgeon Gregory M. , Colsher James G. , Frush Donald P.
Published: December 2008

Current methods for organ and effective dose estimations in pediatric CT are largely patient generic. Physical phantoms and computer models have only been developed for standard/limited patient sizes at discrete ages (e.g., 0, 1, 5, 10, old) and do not reflect the variability of patient anatomy and body habitus within the same size/age group. In this investigation, full‐body computer models of seven pediatric patients in the same size/protocol group (weight: ) were created based on the patients’ actual multi‐detector array CT (MDCT) data. Organs and structures in the scan coverage were individually segmented. Other organs and structures were created by morphing existing adult models (developed from visible human data) to match the framework defined by the segmented organs, referencing the organ volume and anthropometry data in ICRP Publication 89. Organ and effective dose of these patients from a chest MDCT scan protocol (64 slice LightSpeed VCT scanner, , 70 or , gantry rotation period, pitch of 1.375, beam collimation, and small body scan field‐of‐view) was calculated using a Monte Carlo program previously developed and validated to simulate radiation transport in the same CT system. The seven patients had normalized effective dose of (coefficient of variation: 10.8%). Normalized lung dose and heart dose were and , respectively. Organ dose variations across the patients were generally small for large organs in the scan coverage , but large for small organs in the scan coverage (9%–18%) and for partially or indirectly exposed organs (11%–77%). Normalized effective dose correlated weakly with body weight (correlation coefficient: ). Normalized lung dose and heart dose correlated strongly with mid‐chest equivalent diameter (lung: , heart: ); these strong correlation relationships can be used to estimate patient‐specific organ dose for any other patient in the same size/protocol group who undergoes the chest scan. In summary, this work reported the first assessment of dose variations across pediatric CT patients in the same size/protocol group due to the variability of patient anatomy and body habitus and provided a previously unavailable method for patient‐specific organ dose estimation, which will help in assessing patient risk and optimizing dose reduction strategies, including the development of scan protocols.
Centromere-Associated Female Meiotic Drive Entails Male Fitness Costs in Monkeyflowers
Authors: Fishman Lila , Saunders Arpiar
Published: December 2008

Female meiotic drive, in which paired chromosomes compete for access to the egg, is a potentially powerful but rarely documented evolutionary force. In interspecific monkeyflower (
Mimulus
) hybrids, a driving
M. guttatus
allele (
D
) exhibits a 98:2 transmission advantage via female meiosis. We show that extreme interspecific drive is most likely caused by divergence in centromere-associated repeat domains and document cytogenetic and functional polymorphism for drive within a population of
M. guttatus.
In conspecific crosses,
D
had a 58:42 transmission advantage over nondriving alternative alleles. However, individuals homozygous for the driving allele suffered reduced pollen viability. These fitness effects and molecular population genetic data suggest that balancing selection prevents the fixation or loss of
D
and that selfish chromosomal transmission may affect both individual fitness and population genetic load.
Generation and Regeneration of Cells of the Liver and Pancreas
Authors: Zaret Kenneth S. , Grompe Markus
Published: December 2008

Liver and pancreas progenitors develop from endoderm cells in the embryonic foregut. Shortly after their specification, liver and pancreas progenitors rapidly acquire markedly different cellular functions and regenerative capacities. These changes are elicited by inductive signals and genetic regulatory factors that are highly conserved among vertebrates. Interest in the development and regeneration of the organs has been fueled by the intense need for hepatocytes and pancreatic β cells in the therapeutic treatment of liver failure and type I diabetes. Studies in diverse model organisms have revealed evolutionarily conserved inductive signals and transcription factor networks that elicit the differentiation of liver and pancreatic cells and provide guidance for how to promote hepatocyte and β cell differentiation from diverse stem and progenitor cell types.
Response to Comment on "Phytoplankton Calcification in a High-CO
2
World"
Authors: Iglesias-Rodriguez M. Debora , Buitenhuis Erik T. , Raven John A. , Schofield Oscar , Poulton Alex J. , Gibbs Samantha , Halloran Paul R. , de Baar Hein J. W.
Published: December 2008

Recently reported increasing calcification rates and primary productivity in the coccolithophore
Emiliania huxleyi
were obtained by equilibrating seawater with mixtures of carbon dioxide in air. The noted discrepancy with previously reported decreasing calcification is likely due to the previously less realistic simulation of bicarbonate due to addition of acid or base to obtain simulated future CO
2
partial pressure conditions.
Quasi-Periodic Bedding in the Sedimentary Rock Record of Mars
Authors: Lewis Kevin W. , Aharonson Oded , Grotzinger John P. , Kirk Randolph L. , McEwen Alfred S. , Suer Terry-Ann
Published: December 2008

Widespread sedimentary rocks on Mars preserve evidence of surface conditions different from the modern cold and dry environment, although it is unknown how long conditions favorable to deposition persisted. We used 1-meter stereo topographic maps to demonstrate the presence of rhythmic bedding at several outcrops in the Arabia Terra region. Repeating beds are ∼10 meters thick, and one site contains hundreds of meters of strata bundled into larger units at a ∼10:1 thickness ratio. This repetition likely points to cyclicity in environmental conditions, possibly as a result of astronomical forcing. If deposition were forced by orbital variation, the rocks may have been deposited over tens of millions of years.
Patterning Mechanisms of Branched Organs
Authors: Lu Pengfei , Werb Zena
Published: December 2008

Branching morphogenesis is one of the earliest events essential for the success of metazoans. By branching out and forming cellular or tissue extensions, cells can maximize their surface area and overcome space constraints posed by organ size. Over the past decade, tremendous progress has been made toward understanding the branching mechanisms of various invertebrate and vertebrate organ systems. Despite their distinct origins, morphologies and functions, different cell and tissue types use a remarkably conserved set of tools to undergo branching morphogenesis. Recent studies have shed important light on the basis of molecular conservation in the formation of branched structures in diverse organs.
Cardiogenesis and the Complex Biology of Regenerative Cardiovascular Medicine
Authors: Chien Kenneth R. , Domian Ibrahim J. , Parker Kevin Kit
Published: December 2008

The heart is a complex organ system composed of a highly diverse set of muscle and nonmuscle cells. Understanding the pathways that drive the formation, migration, and assembly of these cells into the heart muscle tissue, the pacemaker and conduction system, and the coronary vasculature is a central problem in developmental biology. Efforts to unravel the biological complexity of in vivo cardiogenesis have identified a family of closely related multipotent cardiac progenitor cells. These progenitors must respond to non–cell-autonomous signaling cues to expand, differentiate, and ultimately integrate into the three-dimensional heart structures. Coupling tissue-engineering technologies with patient-specific cardiac progenitor biology holds great promise for the development of human cell models of human disease and may lay the foundation for novel approaches in regenerative cardiovascular medicine.
Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission
Authors: Rouach Nathalie , Koulakoff Annette , Abudara Veronica , Willecke Klaus , Giaume Christian
Published: December 2008

Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.
Morphogenetic Cell Movements: Diversity from Modular Mechanical Properties
Authors: Montell Denise J.
Published: December 2008

Animal tissue and organ development requires the orchestration of cell movements, including those of interconnected cell groups, termed collective cell movements. Such movements are incredibly diverse. Recent work suggests that two core cellular properties, cell-cell adhesion and contractility, can largely determine geometry, packing, sorting, and rearrangement of epithelial cell layers. Two additional force-generating properties, the ability to generate cell protrusions and cell adhesion to the extracellular matrix, contribute to active motility. These mechanical properties can be regulated independently in cells, suggesting that they can be employed in a combinatorial manner. A small number of properties used in combination could, in principle, generate a diverse array of cell shapes and arrangements and thus orchestrate the varied morphogenetic events observed during metazoan organ development.
Maternal Alloantigens Promote the Development of Tolerogenic Fetal Regulatory T Cells in Utero
Authors: Mold Jeff E. , Michaëlsson Jakob , Burt Trevor D. , Muench Marcus O. , Beckerman Karen P. , Busch Michael P. , Lee Tzong-Hae , Nixon Douglas F. , McCune Joseph M.
Published: December 2008

As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (T
regs
) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25
high
FoxP3+ T
regs
that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth.
Revaccination with Marek's Disease Vaccines Induces Productive Infection and Superior Immunity
Authors: Wu Changxin , Gan Junji , Jin Qiao , Chen Chuangfu , Liang Ping , Wu Yantao , Liu Xuefen , Ma Li , Davison Fred
Published: December 2008

The most common lymphoproliferative disease in chickens is Marek's disease (MD), which is caused by the oncogenic herpesvirus Marek's disease virus (MDV). The emergence of hypervirulent pathotypes of MDV has led to vaccine failures, which have become common and which have resulted in serious economic losses in some countries, and a revaccination strategy has been introduced in practice. The mechanism by which revaccination invokes superior immunity against MD is unknown. After field trials which showed that revaccination provided protection superior to that provided by a single vaccination were performed, experiments were conducted to explore the interaction between revaccinated chickens and MDV. The results showed that the chickens in the revaccination groups experienced two consecutive productive infections but that the chickens in the single-vaccination groups experienced one productive infection, demonstrating that revaccination of viruses caused the chickens to have productive and then latent infections. Revaccination of the virus induced in the chickens a higher and a longer temporary expansion of the CD8
+
, CD4
+
, and CD3
+
T-lymphocyte subpopulations, stronger peripheral blood lymphocyte proliferative activity; and higher levels of neutralizing antibody than single vaccination. These findings disagree with the postulate that MDV antigens persist, stimulate the immune system, and maintain a high level immunity after vaccination. The suppression of productive infection by maternal antibodies in chickens receiving the primary vaccination and a lower level of productive infection in the revaccination groups challenged with MDV were observed. The information obtained in this study suggests that the productive infection with revaccinated MDV in chickens plays a crucial role in the induction of superior immunity. This finding may be exploited for the development of a novel MD vaccine that results in the persistence of the antigen supply and that maintains a high level of immunity and may also have implications for other viral oncogenic diseases in humans and animals.
Normal Ranges of Streptococcal Antibody Titers Are Similar Whether Streptococci Are Endemic to the Setting or Not
Authors: Steer Andrew C. , Vidmar Suzanna , Ritika Roselyn , Kado Joseph , Batzloff Michael , Jenney Adam W. J. , Carlin John B. , Carapetis Jonathan R.
Published: December 2008

Group A streptococcal (GAS) serology is used for the diagnosis of post-streptococcal diseases, such as acute rheumatic fever, and occasionally for the diagnosis of streptococcal pharyngitis. Experts recommend that the upper limits of normal for streptococcal serology be determined for individual populations because of differences in the epidemiology of GAS between populations. Therefore, we performed a study to determine the values of the upper limit of normal for anti-streptolysin O (ASO) and anti-DNase B (ADB) titers in Fiji. Participants with a history of GAS disease, including pharyngitis or impetigo, were excluded. A total of 424 serum samples from people of all ages (with a sample enriched for school-aged children) were tested for their ASO and ADB titers. Reference values, including titers that were 80% of the upper limit of normal, were obtained by regression analysis by use of a curve-fitting method instead of the traditional nonparametric approach. Normal values for both the ASO titer and the ADB titer rose sharply during early childhood and then declined gradually with age. The estimated titers that were 80% of the upper limit or normal at age 10 years were 276 IU/ml for ASO and 499 IU/ml for ADB. Data from our study are similar to those found in countries with temperate climates, suggesting that a uniform upper limit of normal for streptococcal serology may be able to be applied globally.
Case of Indolent Endocarditis Due to
Pseudomonas stutzeri
with Genetic Evidence of Relapse after 4 Years
Authors: Grimaldi David , Podglajen Isabelle , Aubert Agnès , Buu-Hoï Annie , Diebold Benoit , Mainardi Jean-Luc
Published: December 2008

Pseudomonas stutzeri
, a gram-negative bacterium, is a common inhabitant of soil and water. We report an unusual case of a relapse of infective endocarditis due to
P. stutzeri
4 years after the initial episode. The identity of the strains was proven by genomic analysis.
Evaluation of an Immunochromatographic Assay Kit for Rapid Identification of
Mycobacterium tuberculosis
Complex in Clinical Isolates
Authors: Park Mi Young , Kim Young Jin , Hwang Sang Hyun , Kim Hyoung Hoi , Lee Eun Yup , Jeong Seok Hoon , Chang Chulhun L.
Published: December 2008

We evaluated a new immunochromatographic assay (ICA) using mouse monoclonal anti-MPT64 antibody for rapid discrimination between
Mycobacterium tuberculosis
and nontuberculous mycobacteria in clinical isolates. A study with mycobacteria and other organisms showed excellent sensitivity (≅99%) and specificity (100%) and an appropriate detection limit (10
5
CFU/ml) when tested with
M. tuberculosis
H37Rv. This ICA can simplify the identification of
M. tuberculosis
in clinical laboratories.
Phylogeny and Identification of
Pantoea
Species and Typing of
Pantoea agglomerans
Strains by Multilocus Gene Sequencing
Authors: Delétoile Alexis , Decré Dominique , Courant Stéphanie , Passet Virginie , Audo Jennifer , Grimont Patrick , Arlet Guillaume , Brisse Sylvain
Published: December 2008

Pantoea agglomerans
and other
Pantoea
species cause infections in humans and are also pathogenic to plants, but the diversity of
Pantoea
strains and their possible association with hosts and disease remain poorly known, and identification of
Pantoea
species is difficult. We characterized 36
Pantoea
strains, including 28 strains of diverse origins initially identified as
P. agglomerans
, by multilocus gene sequencing based on six protein-coding genes, by biochemical tests, and by antimicrobial susceptibility testing. Phylogenetic analysis and comparison with other species of
Enterobacteriaceae
revealed that the genus
Pantoea
is highly diverse. Most strains initially identified as
P. agglomerans
by use of API 20E strips belonged to a compact sequence cluster together with the type strain, but other strains belonged to diverse phylogenetic branches corresponding to other species of
Pantoea
or
Enterobacteriaceae
and to probable novel species. Biochemical characteristics such as fosfomycin resistance and utilization of
d
-tartrate could differentiate
P. agglomerans
from other
Pantoea
species. All 20 strains of
P. agglomerans
could be distinguished by multilocus sequence typing, revealing the very high discrimination power of this method for strain typing and population structure in this species, which is subdivided into two phylogenetic groups. PCR detection of the
repA
gene, associated with pathogenicity in plants, was positive in all clinical strains of
P. agglomerans
, suggesting that clinical and plant-associated strains do not form distinct populations. We provide a multilocus gene sequencing method that is a powerful tool for
Pantoea
species delineation and identification and for strain tracking.
Epstein-Barr Virus BGLF4 Kinase Suppresses the Interferon Regulatory Factor 3 Signaling Pathway
Authors: Wang Jiin-Tarng , Doong Shin-Lian , Teng Shu-Chun , Lee Chung-Pei , Tsai Ching-Hwa , Chen Mei-Ru
Published: December 2008

The BGLF4 protein kinase of Epstein-Barr virus (EBV) is a member of the conserved family of herpesvirus protein kinases which, to some extent, have a function similar to that of the cellular cyclin-dependent kinase in regulating multiple cellular and viral substrates. In a yeast two-hybrid screening assay, a splicing variant of interferon (IFN) regulatory factor 3 (IRF3) was found to interact with the BGLF4 protein. This interaction was defined further by coimmunoprecipitation in transfected cells and glutathioneS-transferase (GST) pull-down in vitro. Using reporter assays, we show that BGLF4 effectively suppresses the activities of the poly(I:C)-stimulated IFN-β promoter and IRF3-responsive element. Moreover, BGLF4 represses the poly(I:C)-stimulated expression of endogenous IFN-β mRNA and the phosphorylation of STAT1 at Tyr701. In searching for a possible mechanism, BGLF4 was shown not to affect the dimerization, nuclear translocation, or CBP recruitment of IRF3 upon poly(I:C) treatment. Notably, BGLF4 reduces the amount of active IRF3 recruited to the IRF3-responsive element containing the IFN-β promoter region in a chromatin immunoprecipitation assay. BGLF4 phosphorylates GST-IRF3 in vitro, but Ser339-Pro340 phosphorylation-dependent, Pin1-mediated downregulation is not responsible for the repression. Most importantly, we found that three proline-dependent phosphorylation sites at Ser123, Ser173, and Thr180, which cluster in a region between the DNA binding and IRF association domains of IRF3, contribute additively to the BGLF4-mediated repression of IRF3(5D) transactivation activity. IRF3 signaling is activated in reactivated EBV-positive NA cells, and the knockdown of BGLF4 further stimulates IRF3-responsive reporter activity. The data presented here thus suggest a novel mechanism by which herpesviral protein kinases suppress host innate immune responses and facilitate virus replication.
Differential Sensitivity of Differentiated Epithelial Cells to Respiratory Viruses Reveals Different Viral Strategies of Host Infection
Authors: Goris Katherina , Uhlenbruck Sabine , Schwegmann-Wessels Christel , Köhl Wiebke , Niedorf Frank , Stern Michael , Hewicker-Trautwein Marion , Bals Robert , Taylor Geraldine , Braun Armin , Bicker Gerd , Kietzmann Manfred , Herrler Georg
Published: December 2008

To address the initiation of virus infection in the respiratory tract, we established two culture systems for differentiated bovine airway epithelial cells (BAEC). Filter-grown BAEC differentiated under air-liquid interface (ALI) conditions to generate a pseudo-stratified mucociliary epithelium. Alternatively, precision-cut lung slices (PCLS) from the bovine airways were generated that retained the original composition and distribution of differentiated epithelial cells. With both systems, epithelial cells were readily infected by bovine parainfluenza virus 3 (BPIV3). Ciliated cells were the most prominent cell type affected by BPIV3. Surprisingly, differentiated BAEC were resistant to infection by bovine respiratory syncytial virus (BRSV), when the virus was applied at the same multiplicity of infection that was sufficient for infection by BPIV3. In the case of PCLS, infection by BRSV was observed in cells located in lower cell layers but not in epithelial cells facing the lumen of the airways. The identity of the infected cells could not be determined because of a lack of specific antibodies. Increasing the virus titer 30-fold resulted in infection of the ALI cultures of BAEC, whereas in PCLS the ciliated epithelium was still refractory to infection by BRSV. These results indicate that differentiated BAEC are readily infected by BPIV3 but rather resistant to infection by BRSV. Disease caused by BRSV may require that calves encounter environmental stimuli that render BAEC susceptible to infection.
The C Proteins of Human Parainfluenza Virus Type 1 (HPIV1) Control the Transcription of a Broad Array of Cellular Genes That Would Otherwise Respond to HPIV1 Infection
Authors: Boonyaratanakornkit Jim B. , Bartlett Emmalene J. , Amaro-Carambot Emerito , Collins Peter L. , Murphy Brian R. , Schmidt Alexander C.
Published: December 2008

Human parainfluenza virus type 1 (HPIV1) is an important respiratory pathogen in children and the most common cause of viral croup. We performed a microarray-based analysis of gene expression kinetics to examine how wild-type (wt) HPIV1 infection altered gene expression in human respiratory epithelial cells and what role beta interferon played in this response. We similarly evaluated HPIV1-P(C−), a highly attenuated and apoptosis-inducing virus that does not express any of the four C proteins, and HPIV1-C
F170S
, a less attenuated mutant that contains a single point mutation in C and, like wt HPIV1, does not efficiently induce apoptosis, to examine the role of the C proteins in controlling host gene expression. We also used these data to investigate whether the phenotypic differences between the two C mutants could be explained at the transcriptional level. Mutation or deletion of the C proteins of HPIV1 permitted the activation of over 2,000 cellular genes that otherwise would be repressed by HPIV1 infection. Thus, the C proteins profoundly suppress the response of human respiratory cells to HPIV1 infection. Cellular pathways targeted by the HPIV1 C proteins were identified and their transcriptional control was analyzed using bioinformatics. Transcription factor binding sites for IRF and NF-κB were overrepresented in some of the C protein-targeted pathways, but other pathways were dominated by less-known factors, such as forkhead transcription factor FOXD1. Surprisingly, the host responses to the P(C−) and C
F170S
mutants were very similar, and only subtle differences in the expression kinetics of caspase 3 and TRAIL receptor 2 were observed. Thus, changes in host cell transcription did not reflect the striking phenotypic differences observed between these two viruses.
Influenza A Virus Polymerase Is an Integral Component of the CPSF30-NS1A Protein Complex in Infected Cells
Authors: Kuo Rei-Lin , Krug Robert M.
Published: December 2008

The NS1A protein of influenza A virus binds the cellular CPSF30 protein, thereby inhibiting the 3′-end processing of all cellular pre-mRNAs, including beta interferon pre-mRNA. X-ray crystallography identified the CPSF30-binding pocket on the influenza virus A/Udorn/72 (Ud) NS1A protein and the critical role of two hydrophobic NS1A amino acids outside the pocket, F103 and M106, in stabilizing the CPSF30-NS1A complex. Although the NS1A protein of the 1997 H5N1 influenza A/Hong Kong/483/97 (HK97) virus contains L (not F) at position 103 and I (not M) at position 106, it binds CPSF30 in vivo to a significant extent because cognate (HK97) internal proteins stabilize the CPSF30-NS1A complex in infected cells. Here we show that the cognate HK97 polymerase complex, containing the viral polymerase proteins (PB1, PB2, and PA) and the nucleocapsid protein (NP), is responsible for this stabilization. The noncognate Ud polymerase complex cannot carry out this stabilization, but it can stabilize CPSF30 binding to a mutated (F103L M106I) cognate Ud NS1A protein. These results suggested that the viral polymerase complex is an integral component of the CPSF30-NS1A protein complex in infected cells even when the cognate NS1A protein contains F103 and M106, and we show that this is indeed the case. Finally, we show that cognate PA protein and NP, but not cognate PB1 and PB2 proteins, are required for stabilizing the CPSF30-NS1A complex, indicating that the NS1A protein interacts primarily with its cognate PA protein and NP in a complex that includes the cellular CPSF30 protein.
Tight Junction Proteins Claudin-1 and Occludin Control Hepatitis C Virus Entry and Are Downregulated during Infection To Prevent Superinfection
Authors: Liu Shufeng , Yang Wei , Shen Le , Turner Jerrold R. , Coyne Carolyn B. , Wang Tianyi
Published: December 2008

A tight junction (TJ) protein, claudin-1 (CLDN1), was identified recently as a key factor for hepatitis C virus (HCV) entry. Here, we show that another TJ protein, occludin, is also required for HCV entry. Mutational study of CLDN1 revealed that its tight junctional distribution plays an important role in mediating viral entry. Together, these data support the model in which HCV enters liver cells from the TJ. Interestingly, HCV infection of Huh-7 hepatoma cells downregulated the expression of CLDN1 and occludin, preventing superinfection. The altered TJ protein expression may contribute to the morphological and functional changes observed in HCV-infected hepatocytes.
Multiple Nucleic Acid Binding Sites and Intrinsic Disorder of Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Protein: Implications for Ribonucleocapsid Protein Packaging
Authors: Chang Chung-Ke , Hsu Yen-Lan , Chang Yuan-Hsiang , Chao Fa-An , Wu Ming-Chya , Huang Yu-Shan , Hu Chin-Kun , Huang Tai-Huang
Published: December 2008

The nucleocapsid protein (N) of the severe acute respiratory syndrome coronavirus (SARS-CoV) packages the viral genomic RNA and is crucial for viability. However, the RNA-binding mechanism is poorly understood. We have shown previously that the N protein contains two structural domains—the N-terminal domain (NTD; residues 45 to 181) and the C-terminal dimerization domain (CTD; residues 248 to 365)—flanked by long stretches of disordered regions accounting for almost half of the entire sequence. Small-angle X-ray scattering data show that the protein is in an extended conformation and that the two structural domains of the SARS-CoV N protein are far apart. Both the NTD and the CTD have been shown to bind RNA. Here we show that all disordered regions are also capable of binding to RNA. Constructs containing multiple RNA-binding regions showed Hill coefficients greater than 1, suggesting that the N protein binds to RNA cooperatively. The effect can be explained by the “coupled-allostery” model, devised to explain the allosteric effect in a multidomain regulatory system. Although the N proteins of different coronaviruses share very low sequence homology, the physicochemical features described above may be conserved across different groups of
Coronaviridae
. The current results underscore the important roles of multisite nucleic acid binding and intrinsic disorder in N protein function and RNP packaging.
A Conserved Domain in the Leader Proteinase of Foot-and-Mouth Disease Virus Is Required for Proper Subcellular Localization and Function
Authors: de los Santos Teresa , Diaz-San Segundo Fayna , Zhu James , Koster Marla , Dias Camila C. A. , Grubman Marvin J.
Published: December 2008

The leader proteinase (L
pro
) of foot-and-mouth disease virus (FMDV) is involved in antagonizing the innate immune response by blocking the expression of interferon (IFN) and by reducing the immediate-early induction of IFN-β mRNA and IFN-stimulated genes. In addition to its role in shutting off cap-dependent host mRNA translation, L
pro
is associated with the degradation of the p65/RelA subunit of nuclear factor κB (NF-κB). Bioinformatics analysis suggests that L
pro
contains a SAP (for SAF-A/B, Acinus, and PIAS) domain, a protein structure associated in some cases with the nuclear retention of molecules involved in transcriptional control. We have introduced a single or a double mutation in conserved amino acid residues contained within this domain of L
pro
. Although three stable mutant viruses were obtained, only the double mutant displayed an attenuated phenotype in cell culture. Indirect immunofluorescence analysis showed that L
pro
subcellular distribution is altered in cells infected with the double mutant virus. Interestingly, nuclear p65/RelA staining disappeared from wild-type (WT) FMDV-infected cells but not from double mutant virus-infected cells. Consistent with these results, NF-κB-dependent transcription was not inhibited in cells infected with double mutant virus in contrast to cells infected with WT virus. However, degradation of the translation initiation factor eIF-4G was very similar for both the WT and the double mutant viruses. Since L
pro
catalytic activity was demonstrated to be a requirement for p65/RelA degradation, our results indicate that mutation of the SAP domain reveals a novel separation-of-function activity for FMDV L
pro
.
Peripheral NKT Cells in Simian Immunodeficiency Virus-Infected Macaques
Authors: Fernandez Caroline S. , Chan Angela C. , Kyparissoudis Konstantinos , De Rose Robert , Godfrey Dale I. , Kent Stephen J.
Published: December 2008

NKT cells are a specialized population of T lymphocytes that have an increasingly recognized role in immunoregulation, including controlling the response to viral infections. The characteristics of NKT cells in the peripheral blood of macaques during simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency virus (HIV) (SHIV) infection were assessed. NKT cells comprised a mean of 0.19% of peripheral blood lymphocytes across the 64 uninfected macaques studied. Although the range in the percentages of NKT cells was large (0 to 2.2%), levels were stable over time within individual macaques without SIV/SHIV infection. The majority of NKT cells in macaques were CD4+(on average 67%) with smaller populations being CD8+(21%) and CD4/CD8 double positive (13%). A precipitous decline in CD4+NKT cells occurred in all six macaques infected with CXCR4-tropic SHIVmn229early after infection, with a concomitant rise in CD8+NKT cells in some animals. The depletion of CD4+NKT cells was tightly correlated with the depletion of total CD4+T cells. R5-tropic SIVmac251infection of macaques resulted in a slower and more variable decline in CD4+NKT cells, with animals that were able to control SIV virus levels maintaining higher levels of CD4+NKT cells. An inverse correlation between the depletion of total and CD4+NKT cells and SIV viral load during chronic infection was observed. Our results demonstrate the infection-driven depletion of peripheral CD4+NKT cells during both SHIV and SIV infection of macaques. Further studies of the implications of the loss of NKT cell subsets in the pathogenesis of HIV disease are needed.
COMPUTED TOMOGRAPHIC IMAGING SPECTROMETER (CTIS) AND A SNAPSHOT HYPERSPECTRAL IMAGER AND POLARIMETER
Authors: HARTKE JOHN , HAGAN NATHAN , KINDER BRIAN A. , DERENIAK EUSTACE L.
Published: December 2008

A Computed Tomographic Imagining Spectrometer (CTIS) is an imaging spectrometer system that acquires all the information required to reconstruct the data cube in a single integration time. This is compared to conventional systems such as whiskbroom systems, pushbroom systems, and filter wheel systems that requiring scanning in one or more coordinate direction.

CTIS systems have been designed and tested in several different singular spectral bands as well as a dual band system. In addition to hyperspectral imaging spectrometers, CTIS systems have been used as an imaging spectropolarimeter and as a ranging imaging spectrometer. An imaging spectropolarimeter not only reconstructs the spectral content at every point in the scene of interest, but also provides the Stokes parameters at every point. So instead of just one data cube, we get four data cubes, one for each element of the Stokes vector. The ranging CTIS incorporates a LADAR system with the CTIS to provide the range information to targets in scene as well as the reconstructed data cube.

The physical principles behind the CTIS system are presented as well as some of representative data from single band systems, the dual band proof of concept, the spectropolarimeter, and the ranging imaging spectrometer.
Benefits of Topology Aware Mapping for Mesh Interconnects
Authors: Bhatelé Abhinav , Kalé Laxmikant V.
Published: December 2008

The fastest supercomputers today such as Blue Gene/L, Blue Gene/P, Cray XT3 and XT4 are connected by a three-dimensional torus/mesh interconnect. Applications running on these machines can benefit from topology-awareness while mapping tasks to processors at runtime. By co-locating communicating tasks on nearby processors, the distance traveled by messages and hence the communication traffic can be minimized, thereby reducing communication latency and contention on the network. This paper describes preliminary work utilizing this technique and performance improvements resulting from it in the context of a n-dimensional k-point stencil program. It shows that even for simple benchmarks, topology-aware mapping can have a significant impact on performance. Automated topology-aware mapping by the runtime using similar ideas can relieve the application writer from this burden and result in better performance. Preliminary work towards achieving this for a molecular dynamics application, NAMD, is also presented. Results on up to 32,768 processors of IBM's Blue Gene/L, 4,096 processors of IBM's Blue Gene/P and 2,048 processors of Cray's XT3 support the ideas discussed in the paper.
Are disks the dominant contributor for storage failures?
Authors: Jiang Weihang , Hu Chongfeng , Zhou Yuanyuan , Kanevsky Arkady
Published: December 2008

Building reliable storage systems becomes increasingly challenging as the complexity of modern storage systems continues to grow. Understanding storage failure characteristics is crucially important for designing and building a reliable storage system. While several recent studies have been conducted on understanding storage failures, almost all of them focus on the failure characteristics of one component—disks—and do not study other storage component failures.

This article analyzes the failure characteristics of storage subsystems. More specifically, we analyzed the storage logs collected from about 39,000 storage systems commercially deployed at various customer sites. The dataset covers a period of 44 months and includes about 1,800,000 disks hosted in about 155,000 storage-shelf enclosures. Our study reveals many interesting findings, providing useful guidelines for designing reliable storage systems. Some of our major findings include: (1) In addition to disk failures that contribute to 20--55% of storage subsystem failures, other components such as physical interconnects and protocol stacks also account for a significant percentage of storage subsystem failures. (2) Each individual storage subsystem failure type, and storage subsystem failure as a whole, exhibits strong self-correlations. In addition, these failures exhibit “bursty” patterns. (3) Storage subsystems configured with redundant interconnects experience 30--40% lower failure rates than those with a single interconnect. (4) Spanning disks of a RAID group across multiple shelves provides a more resilient solution for storage subsystems than within a single shelf.
Write off-loading
Authors: Narayanan Dushyanth , Donnelly Austin , Rowstron Antony
Published: December 2008

In enterprise data centers power usage is a problem impacting server density and the total cost of ownership. Storage uses a significant fraction of the power budget and there are no widely deployed power-saving solutions for enterprise storage systems. The traditional view is that enterprise workloads make spinning disks down ineffective because idle periods are too short. We analyzed block-level traces from 36 volumes in an enterprise data center for one week and concluded that significant idle periods exist, and that they can be further increased by modifying the read/write patterns using
write off-loading
. Write off-loading allows write requests on spun-down disks to be temporarily redirected to persistent storage elsewhere in the data center.

The key challenge is doing this transparently and efficiently at the block level, without sacrificing consistency or failure resilience. We describe our write off-loading design and implementation that achieves these goals. We evaluate it by replaying portions of our traces on a rack-based testbed. Results show that just spinning disks down when idle saves 28--36% of energy, and write off-loading further increases the savings to 45--60%.
Angiotensin-(1–7) activates growth-stimulatory pathways in human mesangial cells
Authors: Zimpelmann Joseph , Burns Kevin D.
Published: December 2008

Angiotensin-(1–7) [Ang-(1–7)] is generated in part via ACE2-dependent degradation of angiotensin II (ANG II). In proximal tubular cells, Ang-(1–7) inhibits ANG II-stimulated phosphorylation of the mitogen-activated protein kinases (MAPKs) p38, extracellular signal-related kinase (ERK1/ERK2), and c-jun N-terminal kinase (JNK), suggesting that Ang-(1–7) protects against ANG II-mediated tubulointerstitial injury. We determined the effect of Ang-(1–7) on signaling and growth responses in cultured human mesangial cells. Ang-(1–7) increased phosphorylation of p38, ERK1/ERK2, and JNK MAPKs, which was blocked by the Ang-(1–7) antagonist A-779. Neither the AT1receptor antagonist losartan, nor the AT2antagonist PD123319 affected specific binding of [125I]Ang-(1–7) or Ang-(1–7)-stimulated p38 phosphorylation. Ang-(1–7) increased cell arachidonic acid release, an effect blocked by A-779. The p38 MAPK antagonist SB202190 completely prevented Ang-(1–7)-stimulated release of arachidonic acid, whereas inhibitors of ERK or JNK had no effect. Ang-(1–7) significantly enhanced DNA synthesis and increased production of transforming growth factor-β1 (TGF-β1), fibronectin, and collagen IV. Both A-779 and SB202190 blocked the Ang-(1–7)-stimulated increases in TGF-β1, fibronectin, and collagen IV. These data indicate that Ang-(1–7) activates MAPK phosphorylation via binding to a specific receptor in human mesangial cells. Stimulation of p38 MAPK phosphorylation by Ang-(1–7) leads to release of arachidonic acid and production of TGF-β1 and extracellular matrix proteins. We conclude that Ang-(1–7) exerts growth-stimulatory effects in human mesangial cells.
Why Sniff Fast? The Relationship Between Sniff Frequency, Odor Discrimination, and Receptor Neuron Activation in the Rat
Authors: Wesson Daniel W. , Verhagen Justus V. , Wachowiak Matt
Published: December 2008

Many mammals display brief bouts of high-frequency (4–10 Hz) sniffing when sampling odors. Given this, high-frequency sniffing is thought to play an important role in odor information processing. Here, we asked what role rapid sampling behavior plays in odor coding and odor discrimination by monitoring sniffing during performance of discrimination tasks under different paradigms and across different levels of difficulty and by imaging olfactory receptor neuron (ORN) input to the olfactory bulb (OB) during behavior. To eliminate confounds of locomotion and object approach, all experiments were performed in head-fixed rats. Rats showed individual differences in sniffing strategies that emerged during discrimination learning, with some rats showing brief bouts of rapid sniffing on odorant onset and others showing little or no change in sniff frequency. All rats performed with high accuracy, indicating that rapid sniffing is not necessary for odor discrimination. Sniffing strategies remained unchanged even when task difficulty was increased. In the imaging experiments, rapid sniff bouts did not alter the magnitude of odorant-evoked inputs compared with trials in which rapid sniffing was not expressed. Furthermore, rapid sniff bouts typically began before detectable activation of ORNs and ended immediately afterward. Thus rapid sniffing did not enable multiple samples of an odorant before decision-making. These results suggest that the major functional contribution of rapid sniffing to odor discrimination performance is to enable the animal to acquire the stimulus more quickly once it is available rather than to directly influence the low-level neural processes underlying odor perception.
Modeling and Formulation of a Novel Microoptoelectromechanical Gyroscope
Authors: Sun Bohua , Zhang Bo , Khan Mohamed Toriq
Published: December 2008

This paper proposed a novel design of microgyroscope based on MEMS structures and optic interferometric microdisplacement measurement technique. The gyroscope consists of microvibrator and interferometric readout. Using Coriolis force, the vibrator transfers the system rotation into a forced vibration; the induced vibration can be sensed by the interferometric microdisplacement measurement system. The optic measurement system has two mirrors which will reflect two rays into a detector. The comprehensive studies on the formulation and analysis of the proposed gyroscope have been undertaken; two key sensor equations have been derived in the first time in the world: (1) relation between rotation and phase shift of light Δφ = (4πl0/λ) + (8π/λ)(xmax Qy/ωy)Ω(t)sin (ωdt), (2) relation between rotation and interferometric intensity of light I(t) ≈ (8π/λ)(xmax Qy/ωy)Ω(t)sin (ωdt)sin (4πl0/λ). The comparison of the proposed gyroscope and well‐know Sagnac formulation has been investigated; it shown that the proposed model is much better than Sagnac ones. The new model has finally get rid of needing very long fiber in the case of Sagnac gyroscope. The innovative model gives a new hope to fabricate high accurate and cheaper gyroscope. To date, the proposed gyroscope is the most accurate gyroscope.
Ambient Pressure Synthesis of Nanostructured Tungsten Oxide Crystalline Films
Authors: Zhang H. X. , Yang B. Q. , Feng P. X.
Published: December 2008

We report the results of the ambient pressure synthesis of tungsten oxide nanowires and nanoparticles on AlN substrates using the hot filament CVD techniques. The morphologic surface, crystallographic structures, chemical compositions, and bond structures of the obtained samples have been investigated using scanning electron microscopy (SEM), X‐ray diffraction (XRD), energy dispersive X‐ray spectroscopy (EDX), and Raman scattering, respectively. Different morphologies were observed for different substrate temperatures, but otherwise identical growth conditions. The experimental measurements reveal the evolutions of the crystalline states and bond structures following the substrate temperatures. Besides, different substrate materials also affected the tungsten oxide nanostructures. Bundles of wire‐type tungsten oxide nanowires with a length of up to 5 mm were obtained on Al2O3 substrate. Furthermore, the sensitive properties of the super long nanowires to the gas and different temperature were investigated. The dependence of the sensitivity of tungsten oxide nanowires to the methane as a function of the time was obtained. The sensitive properties of the tungsten oxide nanowires have almost linear relationship with the temperature.
BAX and BAK proteins are required for cyclin-dependent kinase inhibitory drugs to cause apoptosis
Authors: Garrofé-Ochoa Xènia , Melero-Fernández de Mera Raquel M. , Fernández-Gómez Franciso J. , Ribas Judit , Jordán Joaquín , Boix Jacint
Published: December 2008

In previous reports, we have shown in SH-SY5 cells that olomoucine and roscovitine, two inhibitory drugs of cyclin-dependent kinases, caused apoptosis independent of the extrinsic pathway. In this experimental paradigm, apoptosis was refractory to the protective effects of either Bcl-2 or Bcl-XL overexpression. We are now reporting that the failure of Bcl-XL to prevent dell death was consistent with no effect on the kinetics of caspase activation and cytochrome c release. To further characterize this issue, we have discarded a direct effect of either olomoucine or roscovitine on mitochondrial permeability transition. Moreover, we have evidence that an intrinsic pathway took place in SH-SY5Y cells by showing the mitochondrial translocation of a GFP-Bax construct on transfection and treatment with cyclin-dependent kinase inhibitory drugs. Finally, we tested the effect of olomoucine and roscovitine on wild-type, bax−/−, bak−/−, and double bax−/−bak−/− mouse embryonic fibroblasts (MEF). In wild-type MEFs, both drugs induced cell death by apoptosis in a dose-dependent manner. In bax−/−, bak−/−, and, particularly, double bax−/−bak−/− MEFs, we observed the inhibition of apoptosis. In conclusion, olomoucine and roscovitine caused apoptosis through an intrinsic pathway, with Bax and Bak proteins being involved. [Mol Cancer Ther 2008;7(12):3800–6]