bluuebunny/crossref_metadata_2025 huggingface dataset:
End‐to‐end test of spatial accuracy in Gamma Knife treatments for trigeminal neuralgia a)
Authors: Brezovich Ivan A. , Wu Xingen , Duan Jun , Popple Richard A. , Shen Sui , Benhabib Sidi , Huang Mi , Christian Dobelbower M. , Fisher Winfield S.
Published: October 2014

Purpose:

Spatial accuracy is most crucial when small targets like the trigeminal nerve are treated. Although current quality assurance procedures typically verify that individual apparatus, like the MRI scanner, CT scanner, Gamma Knife, etc., are meeting specifications, the cumulative error of all equipment and procedures combined may exceed safe margins. This study uses an end‐to‐end approach to assess the overall targeting errors that may have occurred in individual patients previously treated for trigeminal neuralgia.

Methods:

The trigeminal nerve is simulated by a 3 mm long, 3.175 mm (1/8 in.) diameter MRI‐contrast filled cavity embedded within a PMMA plastic capsule. The capsule is positioned within the head frame such that the location of the cavity matches the Gamma Knife coordinates of an arbitrarily chosen, previously treated patient. Gafchromic EBT2 film is placed at the center of the cavity in coronal and sagittal orientations. The films are marked with a pinprick to identify the cavity center. Treatments are planned for radiation delivery with 4 mm collimators according to MRI and CT scans using the clinical localizer boxes and acquisition protocols. Shots are planned so that the 50% isodose surface encompasses the cavity. Following irradiation, the films are scanned and analyzed. Targeting errors are defined as the distance between the pinprick, which represents the intended target, and the centroid of the 50% isodose line, which is the center of the radiation field that was actually delivered.

Results:

Averaged over ten patient simulations, targeting errors along the x, y, and z coordinates (patient's left‐to‐right, posterior‐to‐anterior, and head‐to‐foot) were, respectively, −0.060 ± 0.363, −0.350 ± 0.253, and 0.348 ± 0.204 mm when MRI was used for treatment planning. Planning according to CT exhibited generally smaller errors, namely, 0.109 ± 0.167, −0.191 ± 0.144, and 0.211 ± 0.094 mm. The largest errors along individual axes in MRI‐ and CT‐planned treatments were, respectively, −0.761 mm in the y‐direction and 0.428 mm in the x‐direction, well within safe limits.

Conclusions:

The highly accurate dose delivery was possible because the Gamma Knife, MRI scanner, and other equipment performed within tight limits and scans were acquired using the thinnest slices and smallest pixel sizes available. Had the individual devices performed only near the limits of their specifications, the cumulative error could have left parts of the trigeminal nerve undertreated. The presented end‐to‐end test gives assurance that patients had received the expected high quality treatment. End‐to‐end tests should become part of clinical practice.
The effect of amorphous selenium detector thickness on dual‐energy digital breast imaging
Authors: Hu Yue‐Houng , Zhao Wei
Published: October 2014

Purpose:

Contrast enhanced (CE) imaging techniques for both planar digital mammography (DM) and three‐dimensional (3D) digital breast tomosynthesis (DBT) applications requires x‐ray photon energies higher than the k‐edge of iodine (33.2 keV). As a result, x‐ray tube potentials much higher (>40 kVp) than those typical for screening mammography must be utilized. Amorphous selenium (a‐Se) based direct conversion flat‐panel imagers (FPI) have been widely used in DM and DBT imaging systems. The a‐Se layer is typically 200 μm thick with quantum detective efficiency (QDE) >87% for x‐ray energies below 26 keV. However, QDE decreases substantially above this energy. To improve the object detectability of either CE‐DM or CE‐DBT, it may be advantageous to increase the thickness (dSe) of the a‐Se layer. Increasing the dSe will improve the detective quantum efficiency (DQE) at the higher energies used in CE imaging. However, because most DBT systems are designed with partially isocentric geometries, where the gantry moves about a stationary detector, the oblique entry of x‐rays will introduce additional blur to the system. The present investigation quantifies the effect of a‐Se thickness on imaging performance for both CE‐DM and CE‐DBT, discussing the effects of improving photon absorption and blurring from oblique entry of x‐rays.

Methods:

In this paper, a cascaded linear system model (CLSM) was used to investigate the effect of dSe on the imaging performance (i.e., MTF, NPS, and DQE) of FPI in CE‐DM and CE‐DBT. The results from the model are used to calculate the ideal observer signal‐to‐noise ratio, d′, which is used as a figure‐of‐merit to determine the total effect of increasing dSe for CE‐DM and CE‐DBT.

Results:

The results of the CLSM show that increasing dSe causes a substantial increase in QDE at the high energies used in CE‐DM. However, at the oblique projection angles used in DBT, the increased length of penetration through a‐Se introduces additional image blur. The reduced MTF and DQE at high spatial frequencies lead to reduced two‐dimensional d′. These losses in projection image resolution may subsequently result in a decrease in the 3D d′, but the degree of which is largely dependent on the DBT reconstruction algorithm. For a filtered backprojection (FBP) algorithm with spectral apodization and slice‐thickness filters, which dominate the blur for reconstructed images at oblique angles, the effect of oblique entry of x‐rays on 3D d′ is minimal. Thus, increasing dSe results in an improvement in d′ for both CE‐DM and CE‐DBT with typical FBP reconstruction parameters.

Conclusions:

Increased dSe improves CE breast imaging performance by increasing QDE of detectors at higher energies, e.g., 49 kVp. Although there is additional blur in the oblique angled projections of a DBT scan, the overall 3D d′ for DBT is not degraded because the dominant source blur at these angles results from the reconstruction filters of the employed FBP algorithm.
A method to estimate the fractional fat volume within a ROI of a breast biopsy for WAXS applications: Animal tissue evaluation
Authors: Tang Robert Y. , McDonald Nancy , Laamanen Curtis , LeClair Robert J.
Published: October 2014

Purpose:

To develop a method to estimate the mean fractional volume of fat () within a region of interest (ROI) of a tissue sample for wide‐angle x‐ray scatter (WAXS) applications. A scatter signal from the ROI was obtained and use of in a WAXS fat subtraction model provided a way to estimate the differential linear scattering coefficient μs of the remaining fatless tissue.

Methods:

The efficacy of the method was tested using animal tissue from a local butcher shop. Formalin fixed samples, 5 mm in diameter 4 mm thick, were prepared. The two main tissue types were fat and meat (fibrous). Pure as well as composite samples consisting of a mixture of the two tissue types were analyzed. For the latter samples, νfat for the tissue columns of interest were extracted from corresponding pixels in CCD digital x‐ray images using a calibration curve. The means were then calculated for use in a WAXS fat subtraction model. For the WAXS measurements, the samples were interrogated with a 2.7 mm diameter 50 kV beam and the 6° scattered photons were detected with a CdTe detector subtending a solid angle of 7.75 × 10−5 sr. Using the scatter spectrum, an estimate of the incident spectrum, and a scatter model, μs was determined for the tissue in the ROI. For the composite samples, a WAXS fat subtraction model was used to estimate the μs of the fibrous tissue in the ROI. This signal was compared to μs of fibrous tissue obtained using a pure fibrous sample.

Results:

For chicken and beef composites, and 0.32 ± 0.05, respectively. The subtractions of these fat components from the WAXS composite signals provided estimates of μs for chicken and beef fibrous tissue. The differences between the estimates and μs of fibrous obtained with a pure sample were calculated as a function of the momentum transfer x. A t‐test showed that the mean of the differences did not vary from zero in a statistically significant way thereby validating the methods.

Conclusions:

The methodology to estimate in a ROI of a tissue sample via CCD x‐ray imaging was quantitatively accurate. The WAXS fat subtraction model allowed μs of fibrous tissue to be obtained from a ROI which had some fat. The fat estimation method coupled with the WAXS models can be used to compare μs coefficients of fibroglandular and cancerous breast tissue.
Shigella
Disables Defenses
Authors: Berndt Jason D.
Published: October 2014

A bacterial-derived E3 ubiquitin ligase targets the human host protein glomulin, resulting in excess activation of the inflammasome and cell lysis.
In Vitro
Activity of wALADin Benzimidazoles against Different Life Cycle Stages of Plasmodium Parasites
Authors: Lentz Christian S. , Sattler Julia M. , Fendler Martina , Gottwalt Simon , Halls Victoria S. , Strassel Silke , Arriens Sandra , Hannam Jeffrey S. , Specht Sabine , Famulok Michael , Mueller Ann-Kristin , Hoerauf Achim , Pfarr Kenneth M.
Published: October 2014

wALADin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from
Wolbachia
endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage
Plasmodium falciparum
in vitro
(50% inhibitory concentrations, 39, 7.7, and 12.8 μM, respectively). One of these derivatives inhibited gliding motility of
Plasmodium berghei
ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates.
Impact on Resistance of the Use of Therapeutically Equivalent Generics: the Case of Ciprofloxacin
Authors: Rodriguez Carlos A. , Agudelo Maria , Zuluaga Andres F. , Vesga Omar
Published: October 2014

Therapeutic nonequivalence of generic antibiotics may lead to treatment failure and enrichment of resistance. However, there has been no demonstration that an equivalent generic displays the same resistance selection profile as the innovator drug. We aimed to test this hypothesis with five generic versions of ciprofloxacin by assessing their pharmaceutical equivalence with microbiological assays and their efficacy against
Pseudomonas aeruginosa
PAO1 in the neutropenic murine thigh infection model. One equivalent generic was selected for analysis by high-pressure liquid chromatography–tandem mass spectrometry (LC-MS/MS), to confirm chemical identity, and resistance selection experiments in a hollow-fiber (HF) system simulating two clinical dosing regimens. Total and resistant populations were measured, and the MICs of the resistant cells with and without an efflux pump inhibitor were determined. LC-MS/MS found no differences between products, and the innovator and the generic selected resistance with the same magnitude and mechanism after 7 days of treatment in the HF system, supporting the fact that a generic with demonstrated equivalence
in vivo
is also equivalent regarding resistance selection.
Mass Balance, Metabolite Profile, and
In Vitro-In Vivo
Comparison of Clearance Pathways of Deleobuvir, a Hepatitis C Virus Polymerase Inhibitor
Authors: Chen Lin-Zhi , Sabo John P. , Philip Elsy , Rowland Lois , Mao Yan , Latli Bachir , Ramsden Diane , Mandarino Debra A. , Sane Rucha S.
Published: October 2014

The pharmacokinetics, mass balance, and metabolism of deleobuvir, a hepatitis C virus (HCV) polymerase inhibitor, were assessed in healthy subjects following a single oral dose of 800 mg of [
14
C]deleobuvir (100 μCi). The overall recovery of radioactivity was 95.2%, with 95.1% recovered from feces. Deleobuvir had moderate to high clearance, and the half-life of deleobuvir and radioactivity in plasma were ∼3 h, indicating that there were no metabolites with half-lives significantly longer than that of the parent. The most frequently reported adverse events (in 6 of 12 subjects) were gastrointestinal disorders. Two major metabolites of deleobuvir were identified in plasma: an acyl glucuronide and an alkene reduction metabolite formed in the gastrointestinal (GI) tract by gut bacteria (CD 6168), representing ∼20% and 15% of the total drug-related material, respectively. Deleobuvir and CD 6168 were the main components in the fecal samples, each representing ∼30 to 35% of the dose. The majority of the remaining radioactivity found in the fecal samples (∼21% of the dose) was accounted for by three metabolites in which deleobuvir underwent both alkene reduction and monohydroxylation. In fresh human hepatocytes that form biliary canaliculi in sandwich cultures, the biliary excretion for these excretory metabolites was markedly higher than that for deleobuvir and CD 6168, implying that rapid biliary elimination upon hepatic formation may underlie the absence of these metabolites in circulation. The low
in vitro
clearance was not predictive of the observed
in vivo
clearance, likely because major deleobuvir biotransformation occurred by non-CYP450-mediated enzymes that are not well represented in hepatocyte-based
in vitro
models.
Molecular Characterization of
bla
NDM-5
Carried on an IncFII Plasmid in an Escherichia coli Isolate from a Nontraveler Patient in Spain
Authors: Pitart Cristina , Solé Mar , Roca Ignasi , Román Angely , Moreno Asunción , Vila Jordi , Marco Francesc
Published: October 2014

A carbapenem-resistant
Escherichia coli
isolate (sequence type 448 [ST448]) was recovered from a urine culture of a female patient with no recent record of traveling. PCR screening identified the presence of
bla
NDM-5
,
bla
TEM-1
,
bla
OXA-1
,
bla
CMY-42
, and
rmtB. bla
NDM-5
was carried in a conjugative IncFII-type plasmid (90 kb) together with
bla
TEM-1
and
rmtB
. The genetic environment of
bla
NDM-5
showed a structure similar to those of pMC-NDM and pGUE-NDM, identified in Poland and France in
E. coli
of African and Indian origin, respectively.
Carboxymefloquine, the Major Metabolite of the Antimalarial Drug Mefloquine, Induces Drug-Metabolizing Enzyme and Transporter Expression by Activation of Pregnane X Receptor
Authors: Piedade Rita , Traub Stefanie , Bitter Andreas , Nüssler Andreas K. , Gil José P. , Schwab Matthias , Burk Oliver
Published: October 2014

Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether these
in vitro
findings are of
in vivo
relevance has to be addressed in future clinical drug-drug interaction studies.
Probing the Molecular Mechanism of Hypericin-Induced Parasite Death Provides Insight into the Role of Spermidine beyond Redox Metabolism in Leishmania donovani
Authors: Singh Shalini , Sarma Shyamali , Katiyar Shashank P. , Das Mousumi , Bhardwaj Ruchika , Sundar Durai , Dubey Vikash Kumar
Published: October 2014

Hypericin, a natural compound from
Hypericum perforatum
(St. John's wort), has been identified as a specific inhibitor of
Leishmania donovani
spermidine synthase (LdSS) using integrated computational and biochemical approaches. Hypericin showed
in vitro
inhibition of recombinant LdSS enzyme activity. The
in vivo
estimation of spermidine levels in
Leishmania
promastigotes after hypericin treatment showed significant decreases in the spermidine pools of the parasites, indicating target specificity of the inhibitor molecule. The inhibitor, hypericin, showed significant antileishmanial activity, and the mode of death showed necrosis-like features. Further, decreased trypanothione levels and increased glutathione levels with elevated reactive oxygen species (ROS) levels were observed after hypericin treatment. Supplementation with trypanothione in the medium with hypericin treatment restored
in vivo
trypanothione levels and ROS levels but could not prevent necrosis-like death of the parasites. However, supplementation with spermidine in the medium with hypericin treatment restored
in vivo
spermidine levels and parasite death was prevented to a large extent. The data overall suggest that the parasite death due to spermidine starvation as a result of LdSS inhibition is not related to elevated levels of reactive oxygen species. This suggests the involvement of spermidine in processes other than redox metabolism in
Leishmania
parasites. Moreover, the work provides a novel scaffold, i.e., hypericin, as a potent antileishmanial molecule.
Effects of Shiga Toxin Type 2 on a Bioengineered Three-Dimensional Model of Human Renal Tissue
Authors: DesRochers Teresa M. , Kimmerling Erica Palma , Jandhyala Dakshina M. , El-Jouni Wassim , Zhou Jing , Thorpe Cheleste M. , Leong John M. , Kaplan David L.
Published: October 2014

Shiga toxins (Stx) are a family of cytotoxic proteins that can cause hemolytic-uremic syndrome (HUS), a thrombotic microangiopathy, following infections by Shiga toxin-producing
Escherichia coli
(STEC). Renal failure is a key feature of HUS and a major cause of childhood renal failure worldwide. There are currently no specific therapies for STEC-associated HUS, and the mechanism of Stx-induced renal injury is not well understood primarily due to a lack of fully representative animal models and an inability to monitor disease progression on a molecular or cellular level in humans at early stages. Three-dimensional (3D) tissue models have been shown to be more
in vivo
-like in their phenotype and physiology than 2D cultures for numerous disease models, including cancer and polycystic kidney disease. It is unknown whether exposure of a 3D renal tissue model to Stx will yield a more
in vivo
-like response than 2D cell culture. In this study, we characterized Stx2-mediated cytotoxicity in a bioengineered 3D human renal tissue model previously shown to be a predictor of drug-induced nephrotoxicity and compared its response to Stx2 exposure in 2D cell culture. Our results demonstrate that although many mechanistic aspects of cytotoxicity were similar between 3D and 2D, treatment of the 3D tissues with Stx resulted in an elevated secretion of the kidney injury marker 1 (Kim-1) and the cytokine interleukin-8 compared to the 2D cell cultures. This study represents the first application of 3D tissues for the study of Stx-mediated kidney injury.
The Conserved Hypothetical Protein Rv0574c Is Required for Cell Wall Integrity, Stress Tolerance, and Virulence of Mycobacterium tuberculosis
Authors: Garg Rajni , Tripathi Deeksha , Kant Sashi , Chandra Harish , Bhatnagar Rakesh , Banerjee Nirupama
Published: October 2014

The virulence of
Mycobacterium tuberculosis
is intimately related to its distinctive cell wall. The biological significance of poly-α-
l
-glutamine (PLG), a component in the cell wall of virulent mycobacteria, has not been explored adequately. The focus of this study is to investigate the role of a locus, Rv0574c, coding for a polyglutamate synthase-like protein, in the synthesis of poly-α-
l
-glutamine in the context of mycobacterial virulence. Evaluation of Rv0574c gene expression in
M. tuberculosis
demonstrated its growth-phase-linked induction with concomitant accumulation of poly-α-
l
-glutamine in the cell wall. Rv0574c was activated under conditions prevalent in the tubercular granuloma, e.g., hypoxia, nitric oxide, and CO
2
. For functional characterization, we produced a deletion mutant of the Rv0574c gene by allelic exchange. The mutant produced smaller amounts of poly-α-
l
-glutamine in the cell wall than did the wild-type bacterium. Additionally, the increased sensitivity of the mutant to antitubercular drugs, SDS, lysozyme, and mechanical stress was accompanied by a drastic reduction in the ability to form biofilm. Growth of the ΔRv0574c strain was normal under
in vitro
conditions but was retarded in THP-1 macrophages and in the lungs and spleen of BALB/c mice. This was in agreement with histopathology of the lungs showing slow growth and less severe pathology than that of the wild-type strain. In summary, this study demonstrates that the protein encoded by the Rv0574c locus, by virtue of modulating PLG content in the cell wall, helps in maintaining cellular integrity in a hostile host environment. Also, its involvement in protecting the pathogen from host-generated lethal factors contributes to the infectious biology of
M. tuberculosis
.
In VivoMechanisms Involved in Enhanced Protection Utilizing an Fc Receptor-Targeted Mucosal Vaccine Platform in a Bacterial Vaccine and Challenge Model
Authors: Bitsaktsis Constantine , Babadjanova Zulfia , Gosselin Edmund J.
Published: October 2014

Targeting antigens (Ag) to Fcγ receptors (FcγR) intranasally (i.n.) enhances immunogenicity and protection against intracellular and extracellular pathogens. Specifically, we have demonstrated that targeting fixed (inactivated)Francisella tularensis(iFT) organisms to FcR in mice i.n., with MAb-iFT immune complexes, enhancesF. tularensis-specific immune responses and protection againstF. tularensischallenge. Furthermore, traditional adjuvant is not required. In addition, we have demonstrated that the increased immunogenicity following the targeting of iFT to FcR is due, in part, to enhanced dendritic cell (DC) maturation, enhanced internalization, and processing and presentation of iFT by DCs, as well as neonatal FcR (FcRn)-enhanced trafficking of iFT from the nasal passage to the nasal mucosa-associated lymphoid tissue (NALT). Using this immunization and challenge model, we expanded on these studies to identify specificin vivoimmune responses impacted and enhanced by FcR targeting of iFT i.n. Specifically, the results of this study demonstrate for the first time that targeting iFT to FcR increases the frequency of activated DCs within the lungs of MAb-iFT-immunized mice subsequent toF. tularensisLVS challenge. In addition, the frequency and number of gamma interferon (IFN-γ)-secreting effector memory (EM) CD4+T cells elicited byF. tularensisinfection (postimmunization) is increased in an interleukin 12 (IL-12)-dependent manner. In summary, these studies build significantly upon previously published work utilizing this vaccine platform. We have identified a number of additional mechanisms by which this novel, adjuvant-independent, FcR-targeted mucosal vaccine approach enhances immunity and protection against infection, while further validating its potential as a universal vaccine platform against mucosal pathogens.
Oral Streptococci and Nitrite-Mediated Interference of Pseudomonas aeruginosa
Authors: Scoffield Jessica A. , Wu Hui
Published: October 2014

The oral cavity harbors a diverse community of microbes that are physiologically unique. Oral microbes that exist in this polymicrobial environment can be pathogenic or beneficial to the host. Numerous oral microbes contribute to the formation of dental caries and periodontitis; however, there is little understanding of the role these microbes play in systemic infections. There is mounting evidence that suggests that oral commensal streptococci are cocolonized with
Pseudomonas aeruginosa
during cystic fibrosis pulmonary infections and that the presence of these oral streptococci contributes to improved lung function. The goal of this study was to examine the underlying mechanism by which
Streptococcus parasanguinis
antagonizes pathogenic
P. aeruginosa
. In this study, we discovered that oral commensal streptococci, including
Streptococcus parasanguinis
,
Streptococcus sanguinis
, and
Streptococcus gordonii
, inhibit the growth of
P. aeruginosa
and that this inhibition is mediated by the presence of nitrite and the production of hydrogen peroxide (H
2
O
2
) by oral streptococci. The requirement of both H
2
O
2
and nitrite for the inhibition of
P. aeruginosa
is due to the generation of reactive nitrogenous intermediates (RNI), including peroxynitrite. Transposon mutagenesis showed that a
P. aeruginosa
mutant defective in a putative ABC transporter permease is resistant to both streptococcus/nitrite- and peroxynitrite-mediated killing. Furthermore,
S. parasanguinis
protects
Drosophila melanogaster
from killing by
P. aeruginosa
in a nitrite-dependent manner. Our findings suggest that the combination of nitrite and H
2
O
2
may represent a unique anti-infection strategy by oral streptococci during polymicrobial infections.
CD4+T Cells Promote Antibody Production but Not Sustained Affinity Maturation during Borrelia burgdorferi Infection
Authors: Elsner Rebecca A. , Hastey Christine J. , Baumgarth Nicole
Published: October 2014

CD4 T cells are crucial for enhancing B cell-mediated immunity, supporting the induction of high-affinity, class-switched antibody responses, long-lived plasma cells, and memory B cells. Previous studies showed that the immune response toBorrelia burgdorferiappears to lack robust T-dependent B cell responses, as neither long-lived plasma cells nor memory B cells form for months after infection, and nonswitched IgM antibodies are produced continuously during this chronic disease. These data prompted us to evaluate the induction and functionality ofB. burgdorferiinfection-induced CD4 TFHcells. We report that CD4 T cells were effectively primed and TFHcells induced afterB. burgdorferiinfection. These CD4 T cells contributed to the control ofB. burgdorferiburden and supported the induction ofB. burgdorferi-specific IgG responses. However, while affinity maturation of antibodies against a prototypic T-dependentB. burgdorferiprotein, Arthritis-related protein (Arp), were initiated, these increases were reversed later, coinciding with the previously observed involution of germinal centers. The cessation of affinity maturation was not due to the appearance of inhibitory or exhausted CD4 T cells or a strong induction of regulatory T cells.In vitroT-B cocultures demonstrated that T cells isolated fromB. burgdorferi-infected but notB. burgdorferi-immunized mice supported the rapid differentiation of B cells into antibody-secreting plasma cells rather than continued proliferation, mirroring the induction of rapid short-lived instead of long-lived T-dependent antibody responsesin vivo. The data further suggest thatB. burgdorferiinfection drives the humoral response away from protective, high-affinity, and long-lived antibody responses and toward the rapid induction of strongly induced, short-lived antibodies of limited efficacy.
A Moraxella catarrhalis Two-Component Signal Transduction System Necessary for Growth in Liquid Media Affects Production of Two Lysozyme Inhibitors
Authors: Joslin Stephanie N. , Pybus Christine , Labandeira-Rey Maria , Evans Amanda S. , Attia Ahmed S. , Brautigam Chad A. , Hansen Eric J.
Published: October 2014

There are a paucity of data concerning gene products that could contribute to the ability of
Moraxella catarrhalis
to colonize the human nasopharynx. Inactivation of a gene (
mesR
) encoding a predicted response regulator of a two-component signal transduction system in
M. catarrhalis
yielded a mutant unable to grow in liquid media. This
mesR
mutant also exhibited increased sensitivity to certain stressors, including polymyxin B, SDS, and hydrogen peroxide. Inactivation of the gene (
mesS
) encoding the predicted cognate sensor (histidine) kinase yielded a mutant with the same inability to grow in liquid media as the
mesR
mutant. DNA microarray and real-time reverse transcriptase PCR analyses indicated that several genes previously shown to be involved in the ability of
M. catarrhalis
to persist in the chinchilla nasopharynx were upregulated in the
mesR
mutant. Two other open reading frames upregulated in the
mesR
mutant were shown to encode small proteins (LipA and LipB) that had amino acid sequence homology to bacterial adhesins and structural homology to bacterial lysozyme inhibitors. Inactivation of both
lipA
and
lipB
did not affect the ability of
M. catarrhalis
O35E to attach to a human bronchial epithelial cell line
in vitro
. Purified recombinant LipA and LipB fusion proteins were each shown to inhibit human lysozyme activity
in vitro
and in saliva. A
lipA lipB
deletion mutant was more sensitive than the wild-type parent strain to killing by human lysozyme in the presence of human apolactoferrin. This is the first report of the production of lysozyme inhibitors by
M. catarrhalis
.
Mutational Analysis of the Shigella flexneri O-Antigen Polymerase Wzy: Identification of Wzz-Dependent Wzy Mutants
Authors: Nath Pratiti , Tran Elizabeth Ngoc Hoa , Morona Renato
Published: October 2014

The O-antigen (Oag) component of lipopolysaccharide (LPS) is a major virulence determinant of
Shigella flexneri
and is synthesized by the O-antigen polymerase, Wzy
Sf
. Oag chain length is regulated by chromosomally encoded Wzz
Sf
and pHS-2 plasmid-encoded Wzz
pHS2
. To identify functionally important amino acid residues in Wzy
Sf
, random mutagenesis was performed on the

wzy
Sf

gene in a pWaldo-TEV-GFP plasmid, followed by screening with colicin E2. Analysis of the LPS conferred by mutated Wzy
Sf
proteins in the

wzy
Sf

-deficient (Δ
wzy
) strain identified 4 different mutant classes, with mutations found in periplasmic loop 1 (PL1), PL2, PL3, and PL6, transmembrane region 2 (TM2), TM4, TM5, TM7, TM8, and TM9, and cytoplasmic loop 1 (CL1) and CL5. The association of Wzy
Sf
and Wzz
Sf
was investigated by transforming these mutated

wzy
Sf

plasmids into a

wzy
Sf

- and

wzz
Sf

-deficient (Δ
wzy Δwzz
) strain. Comparison of the LPS profiles in the Δ
wzy
and Δ
wzy Δwzz
backgrounds identified Wzy
Sf
mutants whose polymerization activities were Wzz
Sf
dependent. Colicin E2 and bacteriophage Sf6c sensitivities were consistent with the LPS profiles. Analysis of the expression levels of the Wzy
Sf
-GFP mutants in the Δ
wzy
and Δ
wzy Δwzz
backgrounds identified a role for Wzz
Sf
in Wzy
Sf
stability. Hence, in addition to its role in regulating Oag modal chain length, Wzz
Sf
also affects Wzy
Sf
activity and stability.
Interaction of the C-Terminal Tail of FliF with FliG from the Na
+
-Driven Flagellar Motor of Vibrio alginolyticus
Authors: Ogawa Ryo , Abe-Yoshizumi Rei , Kishi Takaaki , Homma Michio , Kojima Seiji
Published: October 2014

Rotation of the polar flagellum of
Vibrio alginolyticus
is driven by a Na
+
-type flagellar motor. FliG, one of the essential rotor proteins located at the upper rim of the C ring, binds to the membrane-embedded MS ring. The MS ring is composed of a single membrane protein, FliF, and serves as a foundation for flagellar assembly. Unexpectedly, about half of the
Vibrio
FliF protein produced at high levels in
Escherichia coli
was found in the soluble fraction. Soluble FliF purifies as an oligomer of ∼700 kDa, as judged by analytical size exclusion chromatography. By using fluorescence correlation spectroscopy, an interaction between a soluble FliF multimer and FliG was detected. This binding was weakened by a series of deletions at the C-terminal end of FliF and was nearly eliminated by a 24-residue deletion or a point mutation at a highly conserved tryptophan residue (W575). Mutations in FliF that caused a defect in FliF-FliG binding abolish flagellation and therefore confer a nonmotile phenotype. As data from
in vitro
binding assays using the soluble FliF multimer correlate with data from
in vivo
functional analyses, we conclude that the C-terminal region of the soluble form of FliF retains the ability to bind FliG. Our study confirms that the C-terminal tail of FliF provides the binding site for FliG and is thus required for flagellation in
Vibrio
, as reported for other species. This is the first report of detection of the FliF-FliG interaction in the Na
+
-driven flagellar motor, both
in vivo
and
in vitro
.
Radical prostatectomy in the presence of ongoing refractory ESBLEscherichia colibacterial prostatitis
Authors: McLoughlin Louise Catherine , McDermott T E D , Thornhill John Alan
Published: October 2014

A 44-year-old Indian national with a prostate-specific antigen of 5.4 ng/mL underwent 12-core transrectal ultrasound-guided prostate biopsies. Following this, he had three hospital admissions with severe urosepsis secondary to extended spectrum β lactamase (ESBL) producingEscherichia coli. He had recurrent sepsis immediately after discontinuation of intravenous meropenem to which the ESBL was sensitive. He proceeded to radical prostatectomy for intermediate-high risk Gleason 7 prostate cancer, while still on intravenous meropenem, 2 months after his biopsy. His prostatectomy involved a difficult dissection due to inflammatory changes and fibrosis after multiple septic episodes. He had complete resolution of infection after surgery with discontinuation of antibiotics on the third postoperative day, without any recurrence of sepsis.
Specimen size effects on behavior of loose sand in triaxial compression tests
Authors: Omar Tarek , Sadrekarimi Abouzar
Published: October 2014

Triaxial tests are often used to determine the behavior and strength characteristics of soils without due attention to the differences in specimen size. Several drained and undrained monotonic triaxial compression shear tests are performed in this study on three different specimen sizes of the same sand to investigate the influence of specimen size and scale effect on sand compression and shear behavior. The behavior of a sand specimen is strongly influenced by shear banding and specimen boundary conditions, which are manifested as specimen size effects in the test results of this study. The measured sand compressibility and shear strength parameters are employed to describe scale effects, and investigate specimen size effects in liquefaction triggering analysis. The results show that while larger specimens exhibit a less compressible behavior during isotropic compression, larger shear strengths and effective friction angles are mobilized in the smaller specimens during shearing. A number of geotechnical analyses can be significantly affected by variations in strength parameters of the same soil determined from different specimen sizes. While using small size specimens for determining shear strength parameters might result in an unconservative design, a large specimen size provides a more accurate representation of different soil strength conditions and field deformations.
Scaling law of static liquefaction mechanism in geocentrifuge and corresponding hydromechanical characterization of an unsaturated silty sand having a viscous pore fluid
Authors: Askarinejad Amin , Beck Alexander , Springman Sarah M.
Published: October 2014

Fast landslides induced by rainfall impose considerable damage on infrastructure and cause major casualties worldwide. Static liquefaction is one of the triggering mechanisms mentioned frequently in the literature as a cause of this type of landslide. The scaling laws required to model this mechanism in the geotechnical centrifuge are developed, and it is shown that either a reduction in the soil pore size or use of a viscous pore fluid is needed to unify the time scaling factors of contractive volume change of the saturated voids and dissipation of the excess pore pressure generated. The latter option was used in this research; therefore, the influences of the viscous pore fluid on the hydromechanical characteristics of a silty sand were investigated. Subsequently, geocentrifuge tests were conducted to compare the behaviour of a slope having a viscous solution as the pore fluid with that of a model with water as the pore fluid. Both slopes were subjected to rainfall, and the evolution of the pore pressure and surface movements were monitored.
Recognition- and defense-related gene expression at 3 resynthesis stages in lichen symbionts
Authors: Athukorala Sarangi N.P. , Piercey-Normore Michele D.
Published: October 2014

Recognition and defense responses are early events in plant–pathogen interactions and between lichen symbionts. The effect of elicitors on responses between lichen symbionts is not well understood. The objective of this study was to compare the difference in recognition- and defense-related gene expression as a result of culture extracts (containing secreted water-soluble elicitors) from compatible and incompatible interactions at each of 3 resynthesis stages in the symbionts of Cladonia rangiferina. This study investigated gene expression by quantitative PCR in cultures of C. rangiferina and its algal partner, Asterochloris glomerata/irregularis, after incubation with liquid extracts from cultures of compatible and incompatible interactions at 3 early resynthesis stages. Recognition-related genes were significantly upregulated only after physical contact, demonstrating symbiont recognition in later resynthesis stages than expected. One of 3 defense-related genes, chit, showed significant downregulation in early resynthesis stages and upregulation in the third resynthesis stage, demonstrating a need for the absence of chitinase early in thallus formation and a need for its presence in later stages as an algal defense reaction. This study revealed that recognition- and defense-related genes are triggered by components in culture extracts at 3 stages of resynthesis, and some defense-related genes may be induced throughout thallus growth. The parasitic nature of the interaction shows parallels between lichen symbionts and plant pathogenic systems.
An Iterated Local Search Algorithm for the Lot-Streaming Flow Shop Scheduling Problem
Authors: Sang Hongyan , Gao Liang , Li Xinyu
Published: October 2014

The lot-streaming flow shop scheduling problem plays an important role in modern industry. This paper addresses this problem with the objective of minimizing the total weighted earliness and tardiness penalties and then proposes a simple but effective iterated local search (ILS) algorithm. In the proposed ILS algorithm, an adapted Nawaz–Enscore–Ham (NEH) heuristic is used to generate an initial solution. A local search procedure based on the insertion neighborhood is employed to perform local exploitation. A simulated-annealing-typed acceptance criterion is utilized to determine the start point for next iteration. Extensive experiments are conducted to compare the proposed ILS algorithm with some existing algorithms. The computational results and comparisons demonstrate the effectiveness of the proposed ILS algorithm.
DEA Models for Parallel Systems: Game-Theoretic Approaches
Authors: Du Juan , Zhu Joe , Cook Wade D. , Huo Jiazhen
Published: October 2014

In many settings, systems are composed of a group of independent sub-units. Each sub-unit produces the same set of outputs by consuming the same set of inputs. Conventional data envelopment analysis (DEA) views such a system as a "black-box", and uses the sum of the respective inputs and outputs of all relevant component units to calculate the system efficiency. Various DEA-based models have been developed for decomposing the overall efficiency. This paper further investigates this kind of structure by using the cooperative (or centralized) and non-cooperative (Stackelberg or leader–follower) game theory concepts. We show that the existing DEA approaches can be viewed as a centralized model that optimizes the efficiency scores of all sub-units jointly. The proposed leader–follower model will be useful when the priority sequence is available for sub-units. Consider, for example, the evaluation of relative efficiencies of a set of manufacturing facilities where multiple work shifts are operating. Management may wish to determine not only the overall plant efficiency, but as well, the performance of each shift in some priority sequence. The relationship between the system efficiency and component efficiencies is also explored. Our approaches are demonstrated with an example whose data set involves the national forests of Taiwan.
Bouncing scalar field cosmology in the polymeric minisuperspace picture
Authors: Vakili B. , Nozari K. , Hosseinzadeh V. , Gorji M. A.
Published: October 2014

We study a cosmological setup consisting of a FRW metric as the background geometry with a massless scalar field in the framework of classical polymerization of a given dynamical system. To do this, we first introduce the polymeric representation of the quantum operators. We then extend the corresponding process to reach a transformation which maps any classical variable to its polymeric counterpart. It is shown that such a formalism has also an analogue in terms of the symplectic structure, i.e. instead of applying polymerization to the classical Hamiltonian to arrive its polymeric form, one can use a new set of variables in terms of which Hamiltonian retains its form but now the corresponding symplectic structure gets a new deformed functional form. We show that these two methods are equivalent and by applying them to the scalar field FRW cosmology see that the resulting scale factor exhibits a bouncing behavior from a contraction phase to an expanding era. Since the replacing of the big bang singularity by a bouncing behavior is one of the most important predictions of the quantum cosmological theories, we may claim that our polymerized classical model brings with itself some signals from quantum theory.
Towards Improvement of Analogy-Based Software Development Effort Estimation: A Review
Authors: Bardsiri Vahid Khatibi , Abang Jawawi Dayang Norhayati , Khatibi Elham
Published: October 2014

In this paper a systematic review is conducted to investigate the structure, components, techniques, evaluation procedure, and comparison scope related to prior ABE-based studies. The undeniable role of accurate development effort estimation in the success of software project management has attracted the attention of researchers over the past few years. Among various algorithmic and non-algorithmic estimation methods, analogy based estimation (ABE) is a widely accepted method due to its simplicity and estimation capability. This paper investigates the improvement process of ABE method during 2000 to 2012. Six research questions are defined to be addressed through evaluation of prior ABE-based studies. The review domain includes 24 papers selected through a tough filtration process. The results show that improvement of ABE can be performed through adjustment, grey theory, attribute weighting and attribute selection techniques. Moreover, ABE configurations can significantly affect the results.
A Clustering-Based Bipartite Graph Privacy-Preserving Approach for Sharing High-Dimensional Data
Authors: Wang Li-e , Li Xianxian
Published: October 2014

Driven by mutual benefits, there is a demand for transactional data sharing among organizations or parties for research or business analysis purpose. It becomes an essential concern to provide privacy-preserving data sharing and meanwhile maintain data utility, due to the fact that transactional data may contain sensitive personal information. Existing privacy-preserving methods, such as k-anonymity and l-diversity, cannot handle high-dimensional sparse data well, since they would bring about much data distortion in the anonymization process. In this paper, we use bipartite graphs with node attributes to model high-dimensional sparse data, and then propose a privacy-preserving approach for sharing transactional data in a new vision, in which the bipartite graph is anonymized into a weighted bipartite graph by clustering node attributes. Our approach can maintain privacy of the associations between entities and resist certain attackers with knowledge of partial items. Experiments have been performed on real-life data sets to measure the information loss and the accuracy of answering aggregate queries. Experimental results show that the approach improves the balance of performance between privacy protection and data utility.
KEY DIFFERENCES AND SIMILARITIES IN WAYS OF MANAGING AND SUPPORTING RADICAL PHARMACEUTICAL FRONT END INNOVATION — A CASE STUDY OF THE PHARMACEUTICAL INDUSTRY
Authors: AAGAARD ANNABETH
Published: October 2014

The purpose of this paper is to explore how Front End Innovation (FEI) is supported and managed among companies of different nationality within the context of pharmaceutical R&D. The present study is carried out in order to contribute to the development of a clearer understanding of active facilitation of innovation management and FEI in theory and in practice across international borders. I aim to show how different aspects of Pharma and nationality affect the way innovation management and radical FEI are supported within organisations. This is examined through an in-depth case study of the Danish and US based pharmaceutical company, H. Lundbeck A/S, and a comparative study including five European and American pharmaceutical companies. The findings from the study reveal a number of similarities and differences in innovation management and FEI support of radical projects and among the different nationalities. This presents propositions of important aspects to consider in facilitation of radical FEI in general and in multinational pharmaceutical companies. In addition, proposals are made for a global study of innovation management and FEI support including Chinese and other Asian pharmaceutical companies, which represent a growing market. The value added and the contribution of this paper to the existing FEI literature is therefore in the specificity of the empirical setting in which the issue is investigated.
4D Graphical representation research of DNA sequences
Authors: Tan Chengjie , Li Shanshan , Zhu Ping
Published: October 2014

Graphical representation of DNA sequences is a key component in studying biological problems. In order to gain new insights in DNA sequences, this paper combined the digitized methods of single-base, base pairs and coding in triplet bases with the times of base appearing, and then a novel 4D graphical representation method of DNA sequences was put forward. It was a one-to-one correspondence of the arbitrary DNA sequence and 4D graphical representation, that avoided causing non-unique 4D graphical representation and overlapping lines. The method could reflect the biological information features of DNA sequence more comprehensively and effectively without any losses. Based on the 4D graphical representation, we used the geometric center of 4D graphical representation as eigenvalue of DNA sequences analyses, which kept the original features of the data, and then established the Euclidean distances and included angles between vectors' terminal point for similarity analyses of the first extron of the beta-globulin gene among 11 species. Finally, we established the graph of systematic hierarchical cluster analysis of 11 species to observe more easily the relationship between species. A positive outcome was reached, and the results were in accord with biological taxonomy, which also supported the rationality and effectiveness of the novel 4D graphical representation.