bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling of Ceramic Particle Heating and Melting in a Microwave Plasma
Authors: Saha Kaushik , Chaudhuri Swetaprovo , Cetegen Baki M.
Published: November 2010

A comprehensive model based on finite volume method was developed to analyze the heat-up and the melting of ceramic particles injected into a microwave excited laminar air plasma flow field. Plasma flow field was simulated as a hot gas flow generated by volumetric heat addition in the microwave coupling region, resulting in a temperature of 6000 K. Alumina and zirconia particles of different diameters were injected into the axisymmetric laminar plasma flow at different injection velocities and locations. Additionally, noncontinuum effects, variation of transport properties of plasma surrounding the spherical particles and absorption of microwave radiation in the ceramic particles were considered in the model. Model predictions suggest that zirconia and alumina particles with diameters less than 50 μm can be effectively melted in a microwave plasma and can produce more uniform melt states. Microwave plasma environment with the ability to inject particles into the plasma core provide the opportunity to create more uniform melt states as compared with dc arc plasmas that are influenced by characteristic arc root fluctuations and turbulent dispersions.
Modeling Transport in Porous Media With Phase Change: Applications to Food Processing
Authors: Halder Amit , Dhall Ashish , Datta Ashim K.
Published: November 2010

Fundamental, physics-based modeling of complex food processes is still in the developmental stages. This lack of development can be attributed to complexities in both the material and transport processes. Society has a critical need for automating food processes (both in industry and at home) while improving quality and making food safe. Product, process, and equipment designs in food manufacturing require a more detailed understanding of food processes that is possible only through physics-based modeling. The objectives of this paper are (1) to develop a general multicomponent and multiphase modeling framework that can be used for different thermal food processes and can be implemented in commercially available software (for wider use) and (2) to apply the model to the simulation of deep-fat frying and hamburger cooking processes and validate the results. Treating food material as a porous medium, heat and mass transfer inside such material during its thermal processing is described using equations for mass and energy conservation that include binary diffusion, capillary and convective modes of transport, and physicochemical changes in the solid matrix that include phase changes such as melting of fat and water and evaporation/condensation of water. Evaporation/condensation is considered to be distributed throughout the domain and is described by a novel nonequilibrium formulation whose parameters have been discussed in detail. Two complex food processes, deep-fat frying and contact heating of a hamburger patty, representing a large group of common food thermal processes with similar physics have been implemented using the modeling framework. The predictions are validated with experimental results from the literature. As the food (a porous hygroscopic material) is heated from the surface, a zone of evaporation moves from the surface to the interior. Mass transfer due to the pressure gradient (from evaporation) is significant. As temperature rises, the properties of the solid matrix change and the phases of frozen water and fat become transportable, thus affecting the transport processes significantly. Because the modeling framework is general and formulated in a manner that makes it implementable in commercial software, it can be very useful in computer-aided food manufacturing. Beyond its immediate applicability in food processing, such a comprehensive model can be useful in medicine (for thermal therapies such as laser surgery), soil remediation, nuclear waste treatment, and other fields where heat and mass transfer takes place in porous media with significant evaporation and other phase changes.
Thermal Processing of Tissue Engineering Scaffolds
Authors: Clyne Alisa Morss
Published: November 2010

Tissue engineering requires complex three-dimensional scaffolds that mimic natural extracellular matrix function. A wide variety of techniques have been developed to create both fibrous and porous scaffolds out of polymers, ceramics, metals, and composite materials. Existing techniques include fiber bonding, electrospinning, emulsion freeze drying, solvent casting/particulate leaching, gas foaming/particulate leaching, high pressure processing, and thermally induced phase separation. Critical scaffold properties, including pore size, porosity, pore interconnectivity, and mechanical integrity, are determined by thermal processing parameters in many of these techniques. In this review, each tissue engineering scaffold preparation method is discussed, including recent advancements as well as advantages and disadvantages of the technique, with a particular emphasis placed on thermal parameters. Improvements on these existing techniques, as well as new thermal processing methods for tissue engineering scaffolds, will be needed to provide tissue engineers with finer control over tissue and organ development.
Titania Nanotubes: Novel Nanostructures for Improved Osseointegration
Authors: Swami Nathan , Cui Zhanwu , Nair Lakshmi S.
Published: November 2010

Nanostructured one dimensional titanium oxides such as nanotubes and nanowires have raised interest lately due to their unique electronic and optical properties. These materials also have shown significant potential as biomaterials because of their ability to modulate protein and cellular interactions. In this review, synthesis and modification of titania nanotubes have been discussed with emphasis on electrochemical synthesis and wet chemical synthesis and their heat treatment of resulting titania nanotubes. The biomedical applications of titania nanotubes were subsequently discussed in detail with a focus on osseointegration. The areas discussed are cell responses to titania nanotubes, effects of titania nanotubes on stem cell proliferation and differentiation, titania nanotubes as drug delivery vehicles, surface modification of titania nanotubes, and in vivo studies using titania nanotubes. It is concluded that the in vitro and in vivo study clearly demonstrates the efficacy of titania nanotube in enhancing osseointegration of orthopedic implants and much of the future work is expected to focus on improving implant functions by modulating the physical and chemical properties of the nanotubes and by locally delivering bioactive molecules in a sustained manner.
Theoretical Analysis of Microwave Heating of Dielectric Materials Filled in a Rectangular Waveguide With Various Resonator Distances
Authors: Rattanadecho Phadungsak , Klinbun Waraporn
Published: November 2010

This paper proposes mathematical models of the microwave heating process of dielectric materials filled in a rectangular waveguide with a resonator. A microwave system supplies a monochromatic wave in a fundamental mode (TE10 mode). A convection exchange at the upper surface of the sample is considered. The effects of resonator distance and operating frequency on distributions of electromagnetic fields inside the waveguide, temperature profile, and flow pattern within the sample are investigated. The finite-difference time-domain method is used to determine the electromagnetic field distribution in a microwave cavity by solving the transient Maxwell equations. The finite control volume method based on the SIMPLE algorithm is used to predict the heat transfer and fluid flow model. Two dielectric materials, saturated porous medium and water, are chosen to display microwave heating phenomena. The simulation results agree well with the experimental data. Based on the results obtained, the inserted resonator has a strong effect on the uniformity of temperature distributions, depending on the penetration depth of microwave. The optimum distances of the resonator depend greatly on the operating frequencies.
Interfering with Tolerance
Authors: Foley John F.
Published: November 2010

Interferon-γ promotes the activation of macrophages by facilitating chromatin remodeling of proinflammatory genes.
A Steady Beat
Authors: Hines Pamela J.
Published: November 2010

Optogenetics is applied to study development of the zebrafish pacemaker.
Calcium Signaling by STIM and Orai: Intimate Coupling Details Revealed
Authors: Wang Youjun , Deng Xiaoxiang , Gill Donald L.
Published: November 2010

Intramolecular interactions within STIM1 control activation of Orai1 channels.
Frizzled Signaling: Gα
o
and Rab5 at the Crossroads of the Canonical and PCP Pathways?
Authors: Strutt David , Vincent Jean-Paul
Published: November 2010

Rab5, a key effector of endocytosis, binds to Frizzled proteins, modulating their trafficking and signaling.
Peptide Antibiotic Sensing and Detoxification Modules of
Bacillus subtilis
Authors: Staroń Anna , Finkeisen Dora Elisabeth , Mascher Thorsten
Published: November 2010

Peptide antibiotics are produced by a wide range of microorganisms. Most of them target the cell envelope, often by inhibiting cell wall synthesis. One of the resistance mechanisms against antimicrobial peptides is a detoxification module consisting of a two-component system and an ABC transporter. Upon the detection of such a compound, the two-component system induces the expression of the ABC transporter, which in turn removes the antibiotic from its site of action, mediating the resistance of the cell. Three such peptide antibiotic-sensing and detoxification modules are present in
Bacillus subtilis
. Here we show that each of these modules responds to a number of peptides and confers resistance against them. BceRS-BceAB (BceRS-AB) responds to bacitracin, plectasin, mersacidin, and actagardine. YxdJK-LM is induced by a cationic antimicrobial peptide, LL-37. The PsdRS-AB (formerly YvcPQ-RS) system responds primarily to lipid II-binding lantibiotics such as nisin and gallidermin. We characterized the
psdRS-AB
operon and defined the regulatory sequences within the P

psdA

promoter. Mutation analysis demonstrated that P

psdA

expression is fully PsdR dependent. The features of both the P

bceA

and P

psdA

promoters make them promising candidates as novel whole-cell biosensors that can easily be adjusted for high-throughput screening.
Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management
Authors: Piret Jocelyne , Boivin Guy
Published: November 2010

Herpes simplex viruses (HSV) type 1 and type 2 are responsible for recurrent orolabial and genital infections. The standard therapy for the management of HSV infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valacyclovir and famciclovir. These compounds are phosphorylated by the viral thymidine kinase (TK) and then by cellular kinases. The triphosphate forms selectively inhibit the viral DNA polymerase (DNA pol) activity. Drug-resistant HSV isolates are frequently recovered from immunocompromised patients but rarely found in immunocompetent subjects. The gold standard phenotypic method for evaluating the susceptibility of HSV isolates to antiviral drugs is the plaque reduction assay. Plaque autoradiography allows the associated phenotype to be distinguished (TK-wild-type, TK-negative, TK-low-producer, or TK-altered viruses or mixtures of wild-type and mutant viruses). Genotypic characterization of drug-resistant isolates can reveal mutations located in the viral TK and/or in the DNA pol genes. Recombinant HSV mutants can be generated to analyze the contribution of each specific mutation with regard to the drug resistance phenotype. Most ACV-resistant mutants exhibit some reduction in their capacity to establish latency and to reactivate, as well as in their degree of neurovirulence in animal models of HSV infection. For instance, TK-negative HSV mutants establish latency with a lower efficiency than wild-type strains and reactivate poorly. DNA pol HSV mutants exhibit different degrees of attenuation of neurovirulence. The management of ACV- or PCV-resistant HSV infections includes the use of the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir. There is a need to develop new antiherpetic compounds with different mechanisms of action.
Raltegravir Is a Substrate for SLC22A6: a Putative Mechanism for the Interaction between Raltegravir and Tenofovir
Authors: Moss Darren M. , Kwan Wai San , Liptrott Neill J. , Smith Darren L. , Siccardi Marco , Khoo Saye H. , Back David J. , Owen Andrew
Published: November 2010

The identification of transporters of the HIV integrase inhibitor raltegravir could be a factor in an understanding of the pharmacokinetic-pharmacodynamic relationship and reported drug interactions of raltegravir. Here we determined whether raltegravir was a substrate for ABCB1 or the influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A1, SLC22A6, SLC10A1, SLC15A1, and SLC15A2. Raltegravir transport by ABCB1 was studied with CEM, CEM
VBL100
, and Caco-2 cells. Transport by uptake transporters was assessed by using a
Xenopus laevis
oocyte expression system, peripheral blood mononuclear cells, and primary renal cells. The kinetics of raltegravir transport and competition between raltegravir and tenofovir were also investigated using SLC22A6-expressing oocytes. Raltegravir was confirmed to be an ABCB1 substrate in CEM, CEM
VBL100
, and Caco-2 cells. Raltegravir was also transported by SLC22A6 and SLC15A1 in oocyte expression systems but not by other transporters studied. The

K
m

and
V
max
for SLC22A6 transport were 150 μM and 36 pmol/oocyte/h, respectively. Tenofovir and raltegravir competed for SLC22A6 transport in a concentration-dependent manner. Raltegravir inhibited 1 μM tenofovir with a 50% inhibitory concentration (IC
50
) of 14.0 μM, and tenofovir inhibited 1 μM raltegravir with an IC
50
of 27.3 μM. Raltegravir concentrations were not altered by transporter inhibitors in peripheral blood mononuclear cells or primary renal cells. Raltegravir is a substrate for SLC22A6 and SLC15A1 in the oocyte expression system. However, transport was limited compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir pharmacokinetics.
Molecular Assessment of
Plasmodium falciparum
Resistance to Antimalarial Drugs in Papua New Guinea Using an Extended Ligase Detection Reaction Fluorescent Microsphere Assay
Authors: Wong Rina P. M. , Karunajeewa Harin , Mueller Ivo , Siba Peter , Zimmerman Peter A. , Davis Timothy M. E.
Published: November 2010

Surveillance for
Plasmodium falciparum
drug resistance mutations is becoming an established tool for assessing antimalarial treatment effectiveness. We used an extended version of a high-throughput post-PCR multiplexed ligase detection reaction fluorescent microsphere assay (LDR-FMA) to detect single-nucleotide
P. falciparum
drug resistance polymorphisms in 402 isolates from children in Papua New Guinea (PNG) participating in an antimalarial treatment trial. There was a fixation of
P. falciparum crt
(
pfcrt
) K76T,
pfdhfr
C59R and S108N, and
pfmdr1
mutations (92%, 93%, 95%, and 91%, respectively). Multiple mutations were frequent. Eighty-eight percent of isolates possessed a quintuple mutation (underlined),
S
VMN
T
, N
RN
I, KAA, and
Y
YSND, in codons 72 to 76 for
pfcrt
; 51, 59, 108, and 164 for
pfdhfr
; 540, 581, and 613 for
pfdhps
; and 86, 184, 1034, 1042, and 1246 for
pfmdr1
, and four of these carried the K540E
pfdhps
allele. The
pfmdr1
D1246Y mutation was associated with PCR-corrected day 42
in vivo
treatment failure in children allocated piperaquine-dihydroartemisinin (
P
= 0.004). Although the
pfmdr1
NFSDD haplotype was found in only four isolates, it has been associated with artemether-lumefantrine treatment failure in Africa. LDR-FMA allows the large-scale assessment of resistance-associated single-nucleotide polymorphisms (SNPs). Our findings reflect previous heavy 4-aminoquinoline/sulfadoxine-pyrimethamine use in PNG. Since artemether-lumefantrine and piperaquine-dihydroartemisinin will become first- and second-line treatments, respectively, the monitoring of
pfmdr1
SNPs appears to be a high priority.
Human Tissue Distribution of Voriconazole
Authors: Weiler Stefan , Fiegl David , MacFarland Róisín , Stienecke Eva , Bellmann-Weiler Rosa , Dunzendorfer Stefan , Joannidis Michael , Bellmann Romuald
Published: November 2010

Voriconazole concentrations were determined in autopsy samples of eight patients who had been treated for a median of 7 days (interquartile range [IQR], 5 days). Voriconazole penetrates well into various tissues, with median levels of 6.26 μg/g ((interquartile range [IQR], 7.87 μg/g) in the lung, 3.41 μg/g (IQR, 16.72 μg/g) in the brain, 6.89 μg/g (IQR, 24.16 μg/g) in the liver, 6.47 μg/g (IQR, 6.19 μg/g) in the kidneys, 5.60 μg/g (IQR, 11.49 μg/g) in the spleen, and 7.55 μg/g (IQR, 16.91 μg/g) in the myocardium.
rmtD2
, a New Allele of a 16S rRNA Methylase Gene, Has Been Present in
Enterobacteriaceae
Isolates from Argentina for More than a Decade
Authors: Tijet Nathalie , Andres Patricia , Chung Catherine , Lucero Celeste , Low Donald E. , Galas Marcelo , Corso Alejandra , Petroni Alejandro , Melano Roberto G.
Published: November 2010

The first allele of a 16S rRNA methyltransferase gene,
rmtD2
, conferring very high resistance to all clinically available aminoglycosides, was detected in 7/1,064 enterobacteria collected in 2007.
rmtD2
was located on a conjugative plasmid in a Tn
2670
-like element inside a structure similar to that of
rmtD1
but probably having an independent assembly.
rmtD2
has been found since 1996 to 1998 mainly in
Enterobacter
and
Citrobacter
isolates, suggesting a possible reservoir in these genera. This presumption deserves monitoring by continuous surveillance.
An A643V Amino Acid Substitution in Upc2p Contributes to Azole Resistance in Well-Characterized Clinical Isolates of
Candida albicans
Authors: Hoot Samantha J. , Smith Adam R. , Brown Ryan P. , White Theodore C.
Published: November 2010

The
Candida albicans
Upc2p transcription factor regulates
ERG11
, encoding the target of azole drugs. Gain-of-function mutations that contribute to resistance were recently identified in a series of sequential clinical isolates (N. Dunkel, T. T. Liu, K. S. Barker, R. Homayouni, J. Morschhauser, and P. D. Rogers, Eukaryot. Cell 7:1180-1190, 2008). In the present study,
UPC2
was sequenced from a matched set of 17 isolates. An A643V substitution was present in all of the isolates in the series that overexpressed
ERG11
. Azole susceptibility, ergosterol levels, and expression of
ERG
genes were elevated in the A643V clinical isolates and in reconstructed strains.
Herb-Drug Interaction betweenEchinacea purpureaand Darunavir-Ritonavir in HIV-Infected Patients
Authors: Moltó José , Valle Marta , Miranda Cristina , Cedeño Samandhy , Negredo Eugenia , Barbanoj Manuel José , Clotet Bonaventura
Published: November 2010

The aim of this open-label, fixed-sequence study was to investigate the potential ofEchinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included.E. purpurearoot extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration ofE. purpureawith darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.
Recent Exposure to Caspofungin or Fluconazole Influences the Epidemiology of Candidemia: a Prospective Multicenter Study Involving 2,441 Patients
Authors: Lortholary Olivier , Desnos-Ollivier Marie , Sitbon Karine , Fontanet Arnaud , Bretagne Stéphane , Dromer Françoise
Published: November 2010

A prospective multicenter surveillance program on yeast bloodstream infections was implemented in the Paris, France, area without restrictions on ward of hospitalization (intensive care unit, hematology, and surgery) or age (adults and children). The present analysis concerns 2,618 isolates collected over 7 years from 2,441 patients. Centralized species identification and antifungal susceptibility testing using the EUCAST methodology were performed. Almost 10% (232/2,441) of the patients had recently (≤30 days) been treated with antifungal drugs. We analyzed the effect of recent exposure to fluconazole (
n
= 159) or caspofungin (
n
= 61) on the proportions of the five major
Candida
species. For both drugs, preexposure was associated with a decreased prevalence of
Candida albicans
in favor of less drug-susceptible species (
C. glabrata
and
C. krusei
for the former and
C. parapsilosis
and, to a lesser extent,
C. glabrata
and
C. krusei
for the latter;
P
= 0.001). In the multivariate analysis, the risk of being infected with an isolate with decreased susceptibility to fluconazole was independently associated with an age of ≥15 years (odds ratio [OR] = 2.45; 95% confidence interval [CI] = 1.39 to 4.31;
P
= 0.002) and with recent exposure to fluconazole (OR = 2.17; 95% CI = 1.51 to 3.13;
P
< 0.001), while the risk of being infected with an isolate with decreased susceptibility to caspofungin was independently associated with an age <15 years (OR = 2.53; 95% CI = 1.43 to 4.48;
P
= 0.001) and with recent exposure to caspofungin (OR = 4.79; 95% CI = 2.47 to 9.28;
P
< 0.001). These findings could influence future recommendations for the management of candidemia.
Amiodarone Inhibits
Trypanosoma cruzi
Infection and Promotes Cardiac Cell Recovery with Gap Junction and Cytoskeleton Reassembly
In Vitro
Authors: Adesse Daniel , Meirelles Azzam Eduardo , de Nazareth L. Meirelles Maria , Urbina Julio A. , Garzoni Luciana R.
Published: November 2010

We present the results of the first detailed study of the antiproliferative and ultrastructural effects of amiodarone on
Trypanosoma cruzi
, the causative agent of Chagas' disease. Moreover, we report the effects of this compound on the recovery of F-actin fibrils, connexin43, and contractility in
T. cruzi
-infected cardiac myocytes. Amiodarone is the most prescribed class III antiarrhythmic agent and is frequently used for the symptomatic treatment of Chagas' disease patients with cardiac compromise. In addition, recent studies identified its antifungal and antiprotozoal activities, which take place through Ca
2+
homeostasis disruption and ergosterol biosynthesis blockade. We tested different concentrations of amiodarone (2.5 to 10 μM) on infected primary cultures of heart muscle cells and observed a dose- and time-dependent effect on growth of the clinically relevant intracellular amastigote form of
T. cruzi
. Ultrastructural analyses revealed that amiodarone had a profound effect on intracellular amastigotes, including mitochondrial swelling and disorganization of reservosomes and the kinetoplast and a blockade of amastigote-trypomastigote differentiation. Amiodarone showed no toxic effects on host cells, which recovered their F-actin fibrillar organization, connexin43 distribution, and spontaneous contractility concomitant with the drug-induced eradication of the intracellular parasites. Amiodarone is, therefore, a promising compound for the development of new drugs against
T. cruzi
.
Pre-Steady-State Kinetic Analysis of the Incorporation of Anti-HIV Nucleotide Analogs Catalyzed by Human X- and Y-Family DNA Polymerases
Authors: Brown Jessica A. , Pack Lindsey R. , Fowler Jason D. , Suo Zucai
Published: November 2010

Nucleoside reverse transcriptase inhibitors (NRTIs) are an important class of antiviral drugs used to manage infections by human immunodeficiency virus, which causes AIDS. Unfortunately, these drugs cause unwanted side effects, and the molecular basis of NRTI toxicity is not fully understood. Putative routes of NRTI toxicity include the inhibition of human nuclear and mitochondrial DNA polymerases. A strong correlation between mitochondrial toxicity and NRTI incorporation catalyzed by human mitochondrial DNA polymerase has been established bothin vitroandin vivo. However, it remains to be determined whether NRTIs are substrates for the recently discovered human X- and Y-family DNA polymerases, which participate in DNA repair and DNA lesion bypassin vivo. Using pre-steady-state kinetic techniques, we measured the substrate specificity constants for human DNA polymerases β, λ, η, ι, κ, and Rev1 incorporating the active, 5′-phosphorylated forms of tenofovir, lamivudine, emtricitabine, and zidovudine. For the six enzymes, all of the drug analogs were incorporated less efficiently (40- to >110,000-fold) than the corresponding natural nucleotides, usually due to a weaker binding affinity and a slower rate of incorporation for the incoming nucleotide analog. In general, the 5′-triphosphate forms of lamivudine and zidovudine were better substrates than emtricitabine and tenofovir for the six human enzymes, although the substrate specificity profile depended on the DNA polymerase. Our kinetic results suggest NRTI insertion catalyzed by human X- and Y-family DNA polymerases is a potential mechanism of NRTI drug toxicity, and we have established a structure-function relationship for designing improved NRTIs.
Using Bioluminescence To Monitor Treatment Response in Real Time in Mice with
Mycobacterium ulcerans
Infection
Authors: Zhang Tianyu , Li Si-Yang , Converse Paul J. , Almeida Deepak V. , Grosset Jacques H. , Nuermberger Eric L.
Published: November 2010

Mycobacterium ulcerans
causes Buruli ulcer, a potentially disabling ulcerative skin disease. Only recently was antimicrobial therapy proven effective. Treatment for 2 months with rifampin plus streptomycin was first proposed after experiments in the mouse footpad model demonstrated bactericidal activity. This treatment is now considered the treatment of choice, although larger ulcers may require adjunctive surgery. Shorter, oral regimens are desired, but evaluating drug activity in mice is hampered by the very slow growth of
M. ulcerans
, which takes 3 months to produce countable colonies. We created a recombinant bioluminescent
M. ulcerans
strain expressing
luxAB
from
Vibrio harveyi
for real-time evaluation of antimicrobial effects
in vivo
. Mouse footpads were injected with wild-type
M. ulcerans
1059 (WtMu) or the recombinant bioluminescent strain (rMu). Two weeks later, mice received rifampin plus streptomycin, kanamycin alone (to which rMu is resistant), or streptomycin alone for 4 weeks and were observed for footpad swelling (preventive model). Untreated controls and kanamycin-treated rMu-infected mice received rifampin plus streptomycin for 4 weeks after developing footpad swelling (curative model). Compared to WtMu, rMu exhibited similar growth and virulence
in vivo
and similar drug susceptibility. A good correlation was observed between luminescence (measured as relative light units) and number of viable bacteria (measured by CFU) in footpad homogenates. Proof of concept was also shown for serial real-time evaluation of drug activity in live mice. These results indicate the potential of bioluminescence as a real-time surrogate marker for viable bacteria in mouse footpads to accelerate the identification of new treatments for Buruli ulcer.
Role of
Tannerella forsythia
NanH Sialidase in Epithelial Cell Attachment
Authors: Honma Kiyonobu , Mishima Elina , Sharma Ashu
Published: November 2010

Tannerella forsythia
is a Gram-negative oral anaerobe which contributes to the development of periodontitis, an inflammatory disease of the tooth-supporting tissues leading to tooth loss. The mechanisms by which this bacterium colonizes the oral cavity are poorly understood. The bacterium has been shown to express two distinct sialidases, namely, SiaHI and NanH, with the latter being the major sialidase. Bacterial sialidases can play roles in pathogenesis by cleaving sialic acids on host glycoproteins, destroying their integrity, and/or unmasking hidden epitopes on host surfaces for colonization. In the present study, we investigated the roles of the SiaHI and NanH sialidases by generating and characterizing specific deletion mutants. Our results showed that the NanH deficiency resulted in a total loss of sialidase activity associated with the outer-membrane and secreted fractions. On the other hand, the SiaHI deficiency resulted in only a slight reduction in the total sialidase activity, with no significant differences in the levels of sialidase activity in the outer membrane or secreted fractions compared to that in the wild-type strain. The results demonstrated that NanH is both surface localized and secreted. The NanH-deficient mutant but not the SiaHI-deficient mutant was significantly attenuated in epithelial cell binding and invasion abilities compared to the wild-type strain. Moreover, the NanH-deficient mutant alone was impaired in cleaving surface sialic acids on epithelial cells. Thus, our study suggests that NanH sialidase might play roles in bacterial colonization by exposing sialic acid-hidden epitopes on epithelial cells.
Proinflammatory Cytokine Gene Expression in the Stomach Correlates with Vaccine-Induced Protection against
Helicobacter pylori
Infection in Mice: an Important Role for Interleukin-17 during the Effector Phase
Authors: Flach Carl-Fredrik , Östberg Anna Karin , Nilsson Anne-Therese , Malefyt Rene De Waal , Raghavan Sukanya
Published: November 2010

CD4
+
T cells have been shown to be essential for vaccine-induced protection against
Helicobacter pylori
infection in mice. Less is known about the relative contributions of individual cell subpopulations, such as T
h
1 and T
h
17 cells, and their associated cytokines. The aim of the present study was to find immune correlates to vaccine-induced protection and further study their role in protection against
H. pylori
infection. Immunized and unimmunized mice were challenged with
H. pylori
, and immune responses were compared. Vaccine-induced protection was assessed by measuring
H. pylori
colonization in the stomach. Gastric gene expression of T
h
1- and/or T
h
17-associated cytokines was analyzed by quantitative PCR, and contributions of individual cytokines to protection were evaluated by antibody-mediated
in vivo
neutralization. By analyzing immunized and unimmunized mice, a significant inverse correlation between the levels of interleukin-12p40 (IL-12p40), tumor necrosis factor alpha (TNF), gamma interferon (IFN-γ), and IL-17 gene expression and the number of
H. pylori
bacteria in the stomachs of individual animals after challenge could be demonstrated. In a kinetic study, upregulation of TNF, IFN-γ, and IL-17 coincided with vaccine-induced protection at 7 days after
H. pylori
challenge and was sustained for at least 21 days.
In vivo
neutralization of these cytokines during the effector phase of the immune response revealed a significant role for IL-17, but not for IFN-γ or TNF, in vaccine-induced protection. In conclusion, although both T
h
1- and T
h
17-associated gene expression in the stomach correlate with vaccine-induced protection against
H. pylori
infection, our study indicates that mainly T
h
17 effector mechanisms are of critical importance to protection.
Characterization of Avian γδ T-Cell Subsets afterSalmonella entericaSerovar Typhimurium Infection of Chicks
Authors: Pieper Jana , Methner Ulrich , Berndt Angela
Published: November 2010

Avian γδ T lymphocytes are frequently found in blood and organs and are assumed to be crucial to the immune defense againstSalmonellainfections of chicks. To elucidate the so-far-unknown immunological features of subpopulations of avian γδ T cells in the course of infection, day-old chicks were infected orally withSalmonella entericaserovar Typhimurium. Until 11 days after infection, the occurrence as well as transcription of the CD8 antigen and immunologically relevant protein genes of CD8α−and CD8α+high(CD8αα+CD8αβ+) γδ cells were analyzed using flow cytometry and quantitative real-time reverse transcription-PCR (RT-PCR) with blood, spleen, thymus, and cecum samples. After infection, an increased percentage of CD8α+highγδ T lymphocytes was found in blood, in spleen, and, with the highest values and most rapidly, in cecum. Within the CD8α+highsubset, a significant rise in the number of CD8αα+cells was accompanied by enhanced CD8α antigen expression and reduced gene transcription of the CD8β chain. CD8αα+and CD8αβ+cells showed elevated transcription for Fas, Fas ligand (FasL), interleukin-2 receptor α (IL-2Rα), and gamma interferon (IFN-γ). While the highest fold changes in mRNA levels were observed in CD8αβ+cells, the mRNA expression rates of CD8αβ+cells never significantly exceeded those of the CD8αα+cells. In conclusion, both CD8α+highγδ T-cell subpopulations (CD8αα+and CD8αβ+) might be a potential source of IFN-γ inSalmonella-infected chicks. However, due to their prominent frequency in blood and organs after infection, the avian CD8αα+γδ T-cell subset seems to be unique and of importance in the course ofSalmonellaTyphimurium infection of very young chicks.
Identification of a Family of Effectors Secreted by the Type III Secretion System That Are Conserved in Pathogenic Chlamydiae
Authors: Muschiol Sandra , Boncompain Gaelle , Vromman François , Dehoux Pierre , Normark Staffan , Henriques-Normark Birgitta , Subtil Agathe
Published: November 2010

Chlamydiae are Gram-negative, obligate intracellular pathogens that replicate within a membrane-bounded compartment termed an inclusion. Throughout their development, they actively modify the eukaryotic environment. The type III secretion (TTS) system is the main process by which the bacteria translocate effector proteins into the inclusion membrane and the host cell cytoplasm. Here we describe a family of type III secreted effectors that are present in all pathogenic chlamydiae and absent in the environment-related species. It is defined by a common domain of unknown function, DUF582, that is present in four or five proteins in each
Chlamydiaceae
species. We show that the amino-terminal extremity of DUF582 proteins functions as a TTS signal. DUF582 proteins from
C. trachomatis
CT620, CT621, and CT711 are expressed at the middle and late phases of the infectious cycle. Immunolocalization further revealed that CT620 and CT621 are secreted into the host cell cytoplasm, as well as within the lumen of the inclusion, where they do not associate with bacterial markers. Finally, we show that DUF582 proteins are present in nuclei of infected cells, suggesting that members of the DUF582 family of effector proteins may target nuclear cell functions. The expansion of this family of proteins in pathogenic chlamydiae and their conservation among the different species suggest that they play important roles in the infectious cycle.
Francisella tularensisSchu S4 O-Antigen and Capsule Biosynthesis Gene Mutants Induce Early Cell Death in Human Macrophages
Authors: Lindemann Stephen R. , Peng Kaitian , Long Matthew E. , Hunt Jason R. , Apicella Michael A. , Monack Denise M. , Allen Lee-Ann H. , Jones Bradley D.
Published: November 2010

Francisella tularensisis capable of rampant intracellular growth and causes a potentially fatal disease in humans. Whereas many mutational studies have been performed with avirulent strains ofFrancisella, relatively little has been done with strains that cause human disease. We generated a near-saturating transposon library in the virulent strain Schu S4, which was subjected to high-throughput screening by transposon site hybridization through primary human macrophages, negatively selecting 202 genes. Of special note were genes in a locus of theFrancisellachromosome,FTT1236,FTT1237, andFTT1238. Mutants with mutations in these genes demonstrated significant sensitivity to complement-mediated lysis compared with wild-type Schu S4 and exhibited marked defects in O-antigen and capsular polysaccharide biosynthesis. In the absence of complement, these mutants were phagocytosed more efficiently by macrophages than wild-type Schu S4 and were capable of phagosomal escape but exhibited reduced intracellular growth. Microscopic and quantitative analyses of macrophages infected with mutant bacteria revealed that these macrophages exhibited signs of cell death much earlier than those infected with Schu S4. These data suggest thatFTT1236,FTT1237, andFTT1238are important for polysaccharide biosynthesis and that theFrancisellaO antigen, capsule, or both are important for avoiding the early induction of macrophage death and the destruction of the replicative niche.
CsrA Modulates Levels of Lipoproteins and Key Regulators of Gene Expression Critical for Pathogenic Mechanisms of
Borrelia burgdorferi
Authors: Karna S. L. Rajasekhar , Sanjuan Eva , Esteve-Gassent Maria D. , Miller Christine L. , Maruskova Mahulena , Seshu J.
Published: November 2010

Carbon storage regulator A (CsrA) is an RNA binding protein that has been characterized in many bacterial species to play a central regulatory role by modulating several metabolic processes. We recently showed that a homolog of CsrA in
Borrelia burgdorferi
(CsrA
Bb
, BB0184) was upregulated in response to propagation of
B. burgdorferi
under mammalian host-specific conditions. In order to further delineate the role of CsrA
Bb
, we generated a deletion mutant designated ES10 in a linear plasmid 25-negative isolate of
B. burgdorferi
strain B31 (ML23). The deletion mutant was screened by PCR and Southern blot hybridization, and a lack of synthesis of CsrA
Bb
in ES10 was confirmed by immunoblot analysis. Analysis of ES10 propagated at pH 6.8/37°C revealed a significant reduction in the levels of OspC, DbpA, BBK32, and BBA64 compared to those for the parental wild-type strain propagated under these conditions, while there were no significant changes in the levels of either OspA or P66. Moreover, the levels of two regulatory proteins, RpoS and BosR, were also found to be lower in ES10 than in the control strain. Quantitative real-time reverse transcription-PCR analysis of total RNA extracted from the parental strain and

csrA
Bb

mutant revealed significant differences in gene expression consistent with the changes at the protein level. Neither the

csrA
Bb

mutant nor the
trans
-complemented strain was capable of infection following intradermal needle inoculation in C3H/HeN mice at either 10
3
or 10
5
spirochetes per mouse. The further characterization of molecular basis of regulation mediated by CsrA
Bb
will provide significant insights into the pathophysiology of
B. burgdorferi.
RECENT DEVELOPMENTS IN DYNAMICAL SYSTEMS: THREE PERSPECTIVES
Authors: BALIBREA F. , CARABALLO T. , KLOEDEN P. E. , VALERO J.
Published: November 2010

This paper aims to an present account of some problems considered in the past years in Dynamical Systems, new research directions and also provide some open problems.
ESCAPING DYNAMICS IN THE PRESENCE OF DISSIPATION AND NOISE IN SCATTERING SYSTEMS
Authors: SEOANE JESÚS M. , SANJUÁN MIGUEL A. F.
Published: November 2010

Chaotic scattering in open Hamiltonian systems is a problem of fundamental interest with applications in several branches of physics. In this paper we analyze the effects of adding external perturbations such as dissipation and noise in chaotic scattering phenomena. Our main result is the exponential decay rate of the particles in the scattering region when the system is affected by dissipation and noise. In the case of dissipation the particles escape more slowly from the scattering region than in the conservative case. However, in the noisy case, the particles escape faster from the scattering region as compared to the noiseless case. Moreover, we analyze the fractal dimension of the set of singularities of the scattering function for the dissipative and the conservative cases. As a result of our analysis we have found that a scaling law exists between the exponential decay rate of the particles and the dissipative parameter, and that the fractal dimension for the noisy case is the unity.
BIMODAL PIECEWISE LINEAR DYNAMICAL SYSTEMS: REDUCED FORMS
Authors: FERRER JOSEP , MAGRET M. DOLORS , PEÑA MARTA
Published: November 2010

Piecewise linear systems constitute a class of nonlinear systems which have recently attracted the interest of researchers because of their interesting properties and the wide range of applications from which they arise. Different authors have used reduced forms when studying these systems, mostly in the case where they are observable. In this work, we focus on bimodal continuous dynamical systems (those consisting of two linear systems on each side of a given hyperplane, having continuous dynamics along that hyperplane) depending on two or three state variables, which are the most common piecewise linear systems found in practice. Reduced forms are obtained for general systems, not necessarily observable. As an application, we calculate the dimension of the equivalence classes.
EMPTY INTERIOR RECURRENCE FOR CONTINUOUS FLOWS ON SURFACES
Authors: LÓPEZ VÍCTOR JIMÉNEZ , LÓPEZ GABRIEL SOLER
Published: November 2010

In this paper we characterize topologically the empty interior subsets of a compact surface S which can be ω-limit sets of recurrent orbits (but not of nonrecurrent ones) of continuous flows on S. This culminates the classification of ω-limit sets for surface flows initiated in [Jiménez & Soler, 2001; Soler, 2003; Jiménez & Soler, 2004a, 2004b].

We also show that this type of ω-limit sets can always be realized (up to topological equivalence) by smooth flows but cannot be realized by analytic flows.
SELF-SYNCHRONIZING STREAM CIPHERS AND DYNAMICAL SYSTEMS: STATE OF THE ART AND OPEN ISSUES
Authors: MILLERIOUX G. , GUILLOT P.
Published: November 2010

Dynamical systems play a central role in the design of symmetric cryptosystems. Their use has been widely investigated both in "chaos-based" private communications and in stream ciphers over finite fields. In the former case, they take the form of automata named Moore or Mealy machines. The main charateristic of stream ciphers lies in that they require synchronization of complex sequences generated by the dynamical systems involved both at the transmitter and the receiver ends. In this paper, we focus on a special class of symmetric ciphers, namely the Self-Synchronizing Stream Ciphers. Indeed, such ciphers have not been seriously explored so far although they show interesting properties of synchronization which could make them very appealing in practice. We review and compare different design approaches which have been proposed in the open literature, and fully-specified algorithms are detailed for illustration purposes. Open issues related to the validation and the implementation of Self-Synchronizing Stream Ciphers are developed. We highlight the reason why some concepts borrowed from control theory appear to be useful to this end.
Oxygen-isotope dating the Yilgarn regolith
Authors: Chivas Allan. R. , Atlhopheng Julius. R.
Published: November 2010

The broad-scale distribution of δ
18
O values of kaolinite developed in weathering profiles in the Yilgarn Craton is interpreted as reflecting their age. As Australia progressively moved from a near-polar latitude in the Permian to lower latitude, with most translation during the past 60 Ma, the imprint of varying oxygen-isotope composition of meteoric water (rainwater and groundwater) has been preserved in weathering minerals such as clays and iron oxides. This correlation, namely δ
18
O values of kaolinite v. palaeo-latitude (and therefore, age), is well understood for eastern Australia. We have applied the same approach to samples widely spaced across the entire Yilgarn Craton and find that kaolinite from the majority of partially dissected weathering profiles displays Neogene δ
18
O ages. There are older profiles, some seemingly of pre-late Mesozoic age, and these are predominantly in the north and east of the craton. There is no evidence within the δ
18
O-derived age pattern for a northern older plateau and a younger southern plateau, at least in terms of their primary age of deep weathering as equated to planation. Instead, the difference between northern and southern areas is that the southern area is more dissected and displays more deeply stripped weathering profiles.
A theory (involving tropical cyclones) on the formation of coarse-grained sand beach ridges in NE Australia
Authors: Nott Jonathan
Published: November 2010

A theory is presented that coarse-grained sand beach ridge plains in northeastern Australia have developed their final form (i.e. the height of the ridges above sea level) as a result of marine inundations generated by intense tropical cyclones. Although winds generated during such tempests are of more than sufficient velocity to transport coarse-grained sands the beach is typically inundated by the storm surge and waves during these events and hence there is no viable source for aeolian sand transport. Numerical storm surge and shallow water wave models are run for two sites (Cairns and Cowley Beach) and the results indicate that only wave run-ups generated by category 3 or more intense tropical cyclones can deposit the final units of sediment onto the sand beach ridges at these locations. It is suggested that as a sand beach ridge increases in height, via successive deposition of units of sand, progressively higher marine inundations are required to reach the ridge crest. The final height of the sand beach ridge is dependent upon the interplay of sediment supply rates to the coastal system and the intensity and frequency of tropical cyclones. If tropical cyclones are responsible for the final form of the sand beach ridges then these sequences can be used to assess the long-term climatology of intense tropical cyclones over this broad geographical region.