bluuebunny/crossref_metadata_2025 huggingface dataset:
HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells
Authors: Shi Lewis Z. , Wang Ruoning , Huang Gonghua , Vogel Peter , Neale Geoffrey , Green Douglas R. , Chi Hongbo
Published: June 2011

Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg cells) and controls cell fate determination. TH17 but not Treg cell–inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1α–dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1α resulted in diminished TH17 development but enhanced Treg cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
Diagnosis, Prevention, and Treatment of Catheter-Associated Urinary Tract Infection in Adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America
Authors: Hooton Thomas M. , Bradley Suzanne F. , Cardenas Diana D. , Colgan Richard , Geerlings Suzanne E. , Rice James C. , Saint Sanjay , Schaeffer Anthony J. , Tambayh Paul A. , Tenke Peter , Nicolle Lindsay E.
Published: June 2011

Guidelines for the diagnosis, prevention, and management of persons with catheter-associated urinary tract infection (CA-UTI), both symptomatic and asymptomatic, were prepared by an Expert Panel of the Infectious Diseases Society of America. The evidence-based guidelines encompass diagnostic criteria, strategies to reduce the risk of CA-UTIs, strategies that have not been found to reduce the incidence of urinary infections, and management strategies for patients with catheter-associated asymptomatic bacteriuria or symptomatic urinary tract infection. These guidelines are intended for use by physicians in all medical specialties who perform direct patient care, with an emphasis on the care of patients in hospitals and long-term care facilities.
Raman photoluminescence spectra of silicon nanowires synthesized by a vapor phase transport method
Authors: Chu Anh Tuan , Thi Thu Trang Nguyen , Tran Thanh Thuy , Vu Binh Nam , Pham Toan Thang , Pham Van Tuan , Pham Thanh Huy , Pham Hong Duong
Published: June 2011

Silicon nanowires were successfully synthesized by a thermal evaporation method. We have observed a strong and broad emission band centered at 670 nm, which is attributed to the quantum confinement effect related to Si nanostructures embedded in the complex SiO

x
matrix. By fitting an experimental Raman spectrum, we confirm that the as-received wires possess crystalline silicon cores whose sizes were around 5 nm. Furthermore, the abnormal dependence of integral photoluminescence intensity on measured temperature was investigated.
In silico analysis of phytoene synthase and its promoter reveals hints for regulation mechanisms of carotenogenesis in Duanliella bardawil
Authors: Lao Yong-Min , Xiao Lan , Ye Zhi−Wei , Jiang Jian-Guo , Zhou Shi-Shui
Published: June 2011

Motivation: Previous researches showed that phytoene synthase (Psy) from Dunaliella bardawil is the first regulatory point in carotenogenesis. We hypothesize certain interactions between the environmental stress factors and the regulatory sequences of Psy in D.bardawil (DbPsy). Consequently, LA PCR-based genomic walking approach was performed for isolation of psy promoter and terminator, respectively. The obtained nucleic acid sequences and the corresponding protein structure of DbPsy were analyzed and predicted using various bioinformatics tools. Finally, we presented some hints for the regulation mechanisms of DbPsy at the molecular level according to the computed results.

Results: LA PCR-based genomic walking results showed that the isolated sequences are the promoter and terminator of psy, correspondingly. Computational analysis demonstrated several candidate motifs of the promoter exhibiting hypothetic UV-B-, norglurzon- and salt-induced characteristics, as well as some typical domains universally discovered in promoter sequences, such as TATA-box, CCAAT-box and GATA-box, etc. Furthermore, the structure of Psy was also predicted and aligned along with many counterparts at the protein level. Low homology of N-terminus was found in D.bardawil, while a relatively conserved C-terminus was predicted to be involved in the catalytic activity and substrate recognization/binding. Phylogenic analysis classified the DbPsy into a cluster with other algae. These results implied that Psy may share similar regulation mechanisms among algae with respect to their C-termini; while the diversity in N-terminus among Psys, along with the predicted inducible motifs in psy promoter from D.bardawil, may confer the fine tuning differences between D.bardawil and other algae.

Conclusion: By means of computer techniques, we found in D.barawali that two interesting conserved motifs of psy promoter may involve in UV-B, norglurzon and salt regulation correspondingly; and that the diversity of Psy protein mainly lies in the N-termini among algae. These results indicate some hints for regulation mechanisms of carotenogenesis in D.bradawil.

Contact:  jgjiang@scut.edu.cn
Poétique et éthique de la compilation médiévale: la conversion de saint Augustin dans quelques compilations du XIII
e
siècle
Authors: Coste Florent
Published: June 2011

Au treizième siècle les ordres mendiants avaient besoin, pour servir leur nouvelle mission pastorale, d'instruments de travail donnant matière à la prédication et à la confession. L’époque scolastique fut ainsi propice à l’émergence de grandes collections édifiantes comme les recueils de sermons, les légendiers ou les recueils d’
exempla
. Les compilateurs ont pris la régulière habitude au treizième siècle de légitimer leur démarche de rassemblement des textes en s'appuyant sur la conversion de saint Augustin. On se propose ici de relire cet épisode des
Confessions
comme une exemplification du travail du compilateur: la reconduction et l'enchâssement du discours rapporté qui s'y joue véhicule une éthique du témoignage et de l'imitation.
Collectionner les saints: hagiographie, identité et compilation dans les collections non-bollandistes (XVI
e
–XVII
e
siècles)
Authors: Gabriel Frédéric
Published: June 2011

Avant le monument bien connu des
Acta sanctorum
édités par les Bollandistes, énorme collection de dizaines d'in-folios commencée au dix-septième siècle par le jésuite Jean Bollandus, de très nombreuses compilations hagiographiques ont circulé, sous les formes et les titres les plus divers. Cette étude ne vise pas à décrire ces multiples éditions prenant l'aspect de récits miraculaires, d'anecdotes diverses, de biographies, de calendriers liturgiques, d'histoires de reliques, ou de litanies — autant d’éléments propices à la collection. Il s'agit de montrer la richesse conceptuelle de ces compilations pour une réflexion sur la collection. Par exemple, quant à l'objet de la collection, original, il s'agit d’
hommes
à la poursuite d'une identité trouvée uniquement dans l'imitation d'un modèle christique absolu. Ces biographies qui reflètent toutes La Référence se retrouvent dans le mode d’écriture et de compilation des séries hagiographiques: il s'agit d’œuvres écrites à plusieurs, remaniées, imitées, refondues. L'auteur-éditeur est avant tout un collecteur. Parallèlement à une rhétorique de l'exemplarité, ces collections sont en perpétuelle réécriture et réédition, et par là même, en perpétuelle multiplication, à l'image des saints eux-mêmes, multiplicité en expansion mais formant un seul Corps mystique. En un sens, la collection hagiographique crée ce corps, Corps textuel collectif et symbolique d'une infinité toujours à recenser.
Properties of elliptical guides for neutron beam transport and applications for new instrumentation concepts
Authors: Rodriguez Damian Martin , Kennedy Shane J. , Bentley Phillip M.
Published: June 2011

The use of nonlinear tapered guides is becoming more common in advanced neutron scattering facilities around the world. Elliptical guides offer the promise of high performance not only as focusing devices but as an efficient way to transport neutrons over long distances. Here, the analytical expressions to determine their performance are derived and discussed. Under certain conditions, an increase in flux delivery is observed with increasing guide length, due to an increase in the angular spread of the neutrons reflected in the guide. The performance is only limited by the distance between the source and the guide entrance, the dimensions of the instrument placed after it, and the supermirror coating. As an example of the potential of elliptical geometry in instrumentation, a new small-angle neutron scattering (SANS) instrument concept is proposed, in which the neutron source is directly coupled to a half-ellipse, and the instrumental performance is evaluated by means of analytical expressions. The results show that such an instrument may provide a viable alternative to conventional pinhole SANS for high-resolution measurements and small samples, being substantially more compact and simpler to operate. The main limitation comes from the coma aberration which is inevitable on extended sources. The extent of the coma problem is also analysed.
Exploring the structure of inter-platelet galleries in organically modified montmorillonite using the small-angle X-ray scattering interface distribution function approach
Authors: Rosenthal Martin , Anokhin Denis V. , Defaux Matthieu , Portale Giuseppe , Ivanov Dimitri A.
Published: June 2011

Small-angle X-ray scattering interface distribution function (IDF) analysis is successfully applied to evaluate the two- and three-phase inter-platelet gallery structure in synthetic montmorillonite (MMT) modified with a mixture of chemically grafted and physically adsorbed chains of a typical organic modifier, octadecyl trimethyl ammonium bromide. Two distinctly different states of adsorbed chains in the inter-platelet galleries are identified. The first one corresponds to a fully cation-exchanged structure with an inter-platelet distance of about 21 Å. In this case the organic modifier is in a liquid-like state, and the system does not exhibit any structural or thermal transitions between ambient temperature and 433 K. When the number of adsorbed chains exceeds the cation-exchange capacity of the MMT platelets the inter-platelet spacing is increased to 43 Å. In this case, the variable-temperature IDFs reveal partially crystalline order in the inter-platelet galleries, which vanishes at the melting point of the alkyl tails confined in the galleries.
A program to analyze the distributions of unmeasured reflections
Authors: Urzhumtseva Ludmila , Urzhumtsev Alexandre
Published: June 2011

Crystallographic Fourier maps may contain barely interpretable or non-interpretable regions if these maps are calculated with an incomplete set of diffraction data. Even a small percentage of missing data may be crucial if these data are distributed non-uniformly and form connected regions of reciprocal space. Significant time and effort can be lost trying to interpret poor maps, in improving them by phase refinement or in fighting against artefacts, whilst the problem could in fact be solved by completing the data set. To characterize the distribution of missing reflections, several types of diagrams have been suggested in addition to the usual plots of completeness in resolution shells and cumulative data completeness. A computer program,FOBSCOM, has been developed to analyze the spatial distribution of unmeasured diffraction data, to search for connected regions of unmeasured reflections and to obtain numeric characteristics of these regions. By performing this analysis, the program could help to save time during structure solution for a number of projects. It can also provide information about a possible overestimation of the map quality and model-biased features when calculated values are used to replace unmeasured data.
Analysis of multiple solutions in powder pattern indexing: the common reciprocal metric tensor approach
Authors: Kroll Herbert , Stöckelmann Diedrich , Heinemann Rolf
Published: June 2011

Powder pattern indexing routines frequently yield multiple solutions,i.e.different reciprocal lattices and unit cells. Here, a method is suggested that reveals whether or not there are numerical and geometric relationships between the solutions. It is based on the detection of a reciprocal vector triplet that is common to two or more proposed reciprocal lattices. Hence, the method can be termed a common reciprocal metric tensor approach. If no such common tensor exists, the different reciprocal lattices are unrelated, but if one exists the lattices are either in a sublattice/superlattice or in a coincidence-site lattice relationship, depending on the character of the respective orientation matrix. Furthermore, the approach can also be used to generate, from a given indexing solution, further valid indexing solutions that could also be produced by indexing routines.
Amdahl's law and parallelization of theFMLSQprogram on the Intel Nehalem architecture
Authors: Strokopytov Boris V. , Dorovatovsky Pavel V. , Trofimov Anton A. , Polyakov Konstantin M.
Published: June 2011

This paper highlights a parallelization of theFMLSQprogram, which allows full-matrix least-squares refinement of large macromolecular structures. The detailed elapsed time profiling ofFMLSQand analysis of its execution on two different Intel architectures has led to a dramatic speedup due to parallelization of all stages of the algorithm. Amdahl's law proved to be very useful during this analysis. It has been shown that processor memory bandwidth may be more important than raw processing power for parallel crystallographic calculations. The new parallelized version of the program has been tested on several protein structures at high resolution. Requirements for a computing architecture intended for full-matrix refinement are discussed in detail.
Decomposition of W(CO)6at high pressures and temperatures
Authors: Rademacher Nadine , Bayarjargal Lkhamsuren , Friedrich Alexandra , Morgenroth Wolfgang , Avalos-Borja Miguel , Vogel Sven C. , Proffen Thomas , Winkler Björn
Published: June 2011

The decomposition of hexacarbonyltungsten, W(CO)6, has been studied. The decomposition was induced by heating W(CO)6in an autoclave at 523 K and pressures up to 1.8 MPa, and by laser heating in a diamond anvil cell at pressures between 5 and 18 GPa. The products have been characterized using synchrotron X-ray diffraction, pair distribution function analysis, Raman spectroscopy and scanning electron microscopy. Decomposition in the autoclave at the lower pressures resulted in the formation of a metastable tungsten carbide, W2C, with an average particle size of 1–2 nm, and an unidentified nanocrystalline tungsten oxide and nanocrystalline graphite with average particle sizes of 1–2 and 11 nm, respectively. The existence of nanocrystalline graphite was deduced from micro-Raman spectra and the graphite particle size was extracted from the intensities of the Raman modes. The high-pressure decomposition products obtained in the diamond anvil cell are the monoclinic tungsten oxide phase WO2and the high-pressure phase W3O8(I). The approximate average size of the graphite particles formed here was 6–8 nm. The bulk modulus of W(CO)6isB0≃ 13 GPa.
Subjective experiences of family caregivers of patients with dementia as predictive factors of quality of life
Authors: TAKAI Michiko , TAKAHASHI Megumi , IWAMITSU Yumi , OISHI Satoru , MIYAOKA Hitoshi
Published: June 2011

Background:  The aim of the present study was to investigate predictive factors of quality of life (QOL) in home caregivers of patients with dementia.

Methods:  A total of 118 home caregivers (48 male, 70 female) were asked to complete the World Health Organization (WHO) Quality of Life 26 (WHO/QOL‐26) questionnaire, the Pines Burnout Measure (BM), and the Beck Depression Inventory, second edition (BDI‐II). Patient demographics and clinical data regarding cognitive impairment, neuropsychiatric symptoms, and dementia severity were obtained from medical records.

Results:  Spearman rank correlation coefficients revealed that caregiver QOL was significantly correlated with patients' neuropsychiatric symptoms (r=−0.19; P < 0.05), as well as depressive symptoms (r=−0.59, P < 0.01) and burnout (r=−0.59, P < 0.01) in caregivers. Stepwise multiple regression analysis revealed that depressive symptoms in caregivers was the strongest predictor for caregiver QOL (R2= 0.37, P < 0.001) and that caregiver QOL was best predicted by the combination of depressive symptoms, burnout, and the cognitive impairment of patients (R2= 0.46, P < 0.05).

Conclusion:  The results of the present study demonstrate that subjective experiences of caregivers are more strongly correlated with caregiver QOL than patient‐related variables and are thus powerful determinants of caregiver QOL. These findings suggest that caregiver intervention, which aims to increase QOL, may benefit from the incorporation of strategies to reduce depressive symptoms and burnout.
Protein kinase C stabilizes X‐linked inhibitor of apoptosis protein (XIAP) through phosphorylation at Ser87 to suppress apoptotic cell death
Authors: KATO Kiyoko , TANAKA Toshihisa , SADIK Golam , BABA Miyako , MARUYAMA Daisuke , YANAGIDA Kanta , KODAMA Takashi , MORIHARA Takashi , TAGAMI Shinji , OKOCHI Masayasu , KUDO Takashi , TAKEDA Masatoshi
Published: June 2011

Background:  Multiple protein kinases have been shown to be involved in the apoptotic neuronal loss of Alzheimer's disease (AD). Although some studies support the role of protein kinase C (PKC) in amyloid precursor protein processing as well as in tau phosphorylation, a direct role for PKC in apoptotic neuronal death remains to be clarified. In the present study, we report on the possible role of PKC in cell survival during conditions of stress through phosphorylation of the X‐linked inhibitor of apoptosis protein (XIAP).

Methods:  Phosphorylation of XIAP at Ser87 was confirmed by western blot analysis employing phosphorylation dependent anti‐XIAP antibody after incubation of recombinant XIAP with active PKC in vitro. And increased phosphorylation of XIAP at the site was also confirmed in SH‐SY5Y cells treated with PKC activator, phorbol 12‐myristate 13‐acetate (PMA). A mutant XIAP construct in which Ser87 was substituted by Ala, was prepared, and transfected to cells. After the transfection of wild or mutant XIAP, cells viability was evaluated by counting living and dead cells treated with PMA during etoposide‐induced apoptosis.

Results:  Recombinant XIAP was phosphorylated at Ser87 by PKC in vitro and treatment of XIAP‐transfected SH‐SY5Y cells with a PKC activator, phorbol 12‐myristate 13‐acetate (PMA) induced phosphorylation of XIAP at Ser87. Pulse chase experiments revealed that, when phosphorylated at Ser87, wild‐type XIAP is more stable than XIAP with a Ser87Ala substitution, which is degraded faster. Importantly, the phosphorylation of XIAP at the site by PKC significantly increased cell survival up to approximately 2.5 times under the condition of apoptosis induced by 25 µg/ml etoposide.

Conclusion:  The findings of the present study indicate a role for PKC, through phosphorylation of XIAP at Ser87 and its stabilization, in cell survival under conditions of stress and lend strength to the idea that PKC is crucial in regulating neuronal homeostasis, which may be impaired in AD.
Effects of Combination of Proliferative Agents and Erythropoietin on Left Ventricular Remodeling Post–Myocardial Infarction
Authors: Kanashiro‐Takeuchi Rosemeire M. , Takeuchi Lauro M. , Hatzistergos Konstantinos , Quevedo Henry , Selem Sarah M. , Treuer Adriana V. , Premer Courtney , Balkan Wayne , Margitich Irene , Song Yun , Hu Qinghua , Hare Joshua M.
Published: June 2011

Erythropoietin (EPO) has the potential to improve ischemic tissue by mobilizing endothelial progenitor cells and enhancing neovascularization. We hypothesized that combining EPO with human chorionic gonadotrophin (hCG) would improve post–myocardial infarction (MI) effects synergistically.

Methods: After MI, five to seven animals were randomly assigned to each of the following treatments: control; hCG; EPO; hCG + EPO, and prolactin (PRL) + EPO. Follow‐up echocardiograms were performed to assess cardiac structure and function. Apoptosis was determined by terminal deoxynucleotidyl transferase‐mediated dUTP nick end‐labeling (TUNEL) assay and western blot analysis for apoptosis‐related proteins, and cell proliferation by immunostaining for Ki67 and c‐kit cells.

Results: The MI‐mediated increased chamber systolic dimension (p < 0.05 in controls) was attenuated by hCG, EPO, and hCG + EPO (p < 0.05 vs. control) but not PRL + EPO. Similarly all treatment groups, except PRL + EPO, reduced MI‐induced increases (p < 0.05 vs. control) in ejection fraction (EF). The functional improvement in the EPO‐treated groups was accompanied by increased capillary density. Apoptosis was markedly reduced in all treated groups. Significantly more cardiac c‐kit+ cells were found in the hCG + EPO group.

Conclusion: Our findings revealed that EPO, hCG, or their combination ameliorate cardiac remodeling post‐MI. Whereas EPO stimulates neovascularization only and hCG + EPO stimulates c‐kit+ cell proliferation. These data suggest that combining mobilizing and proliferative agents adds to the durability and sustainability of cytokine‐based therapies for remodeling post‐MI. Clin Trans Sci 2011; Volume 4: 168–174
Evaluating Translational Research: A Process Marker Model
Authors: Trochim William , Kane Cathleen , Graham Mark J. , Pincus Harold A.
Published: June 2011

Objective: We examine the concept of translational research from the perspective of evaluators charged with assessing translational efforts. One of the major tasks for evaluators involved in translational research is to help assess efforts that aim to reduce the time it takes to move research to practice and health impacts. Another is to assess efforts that are intended to increase the rate and volume of translation. Methods: We offer an alternative to the dominant contemporary tendency to define translational research in terms of a series of discrete “phases.”Results: We contend that this phased approach has been confusing and that it is insufficient as a basis for evaluation. Instead, we argue for the identification of key operational and measurable markers along a generalized process pathway from research to practice. Conclusions: This model provides a foundation for the evaluation of interventions designed to improve translational research and the integration of these findings into a field of translational studies. Clin Trans Sci 2011; Volume 4: 153–162
Mitochondria: isolation, structure and function
Authors: Picard Martin , Taivassalo Tanja , Gouspillou Gilles , Hepple Russell T.
Published: June 2011

Abstract  Mitochondria are complex organelles constantly undergoing processes of fusion and fission, processes that not only modulate their morphology, but also their function. Yet the assessment of mitochondrial function in skeletal muscle often involves mechanical isolation of the mitochondria, a process which disrupts their normally heterogeneous branching structure and yields relatively homogeneous spherical organelles. Alternatively, methods have been used where the sarcolemma is permeabilized and mitochondrial morphology is preserved, but both methods face the downside that they remove potential influences of the intracellular milieu on mitochondrial function. Importantly, recent evidence shows that the fragmented mitochondrial morphology resulting from routine mitochondrial isolation procedures used with skeletal muscle alters key indices of function in a manner qualitatively similar to mitochondria undergoing fission in vivo. Although these results warrant caution when interpreting data obtained with mitochondria isolated from skeletal muscle, they also suggest that isolated mitochondrial preparations might present a useful way of interrogating the stress resistance of mitochondria. More importantly, these new findings underscore the empirical value of studying mitochondrial function in minimally disruptive experimental preparations. In this review, we briefly discuss several considerations and hypotheses emerging from this work.
Effects of a Realistically Rough Surface on Vane Heat Transfer Including the Influence of Turbulence Condition and Reynolds Number
Authors: Erickson E. L. , Ames F. E. , Bons J. P.
Published: June 2011

Heat transfer distributions are experimentally acquired and reported for a vane with both a smooth and a realistically rough surface. Surface heat transfer is investigated over a range of turbulence levels (low (0.7%), grid (8.5%), aerocombustor (13.5%), and aerocombustor with decay (9.5%)) and a range of chord Reynolds numbers (ReC=500,000, 1,000,000, and 2,000,000). The realistically rough surface distribution was generated by Brigham Young University’s accelerated deposition facility. The surface is intended to represent a TBC surface that has accumulated 7500 h of operation with particulate deposition due to a mainstream concentration of 0.02 ppmw. The realistically rough surface was scaled by 11 times for consistency with the vane geometry and cast using a high thermal conductivity epoxy (k=2.1 W/m/K) to comply with the vane geometry. The surface was applied over the foil heater covering the vane pressure surface and about 10% of the suction surface. The 958×573 roughness array generated by Brigham Young on a 9.5×5.7 mm2 region was averaged to a 320×191 array for fabrication. The calculated surface roughness parameters of this scaled and averaged array included the maximum roughness, Rt=1.99 mm, the average roughness, Ra=0.25 mm, and the average forward facing angle, αf=3.974 deg. The peak to valley roughness, Rz, was determined to be 0.784 mm. The sand grain roughness of the surface (kS=0.466 mm) was estimated using a correlation offered by Bons (2005, “A Critical Assessment of Reynolds Analogy for Turbine Flows,” ASME J. Turbomach., 127, pp. 472–485). Based on estimates of skin friction coefficient using a turbulence correlation with the vane chord Reynolds numbers representative values for the surface’s roughness Reynolds number are 23, 43, and 80 for the three exit condition Reynolds numbers tested. Smooth vane heat transfer distributions exhibited significant laminar region augmentation with the elevated turbulence levels. Turbulence also caused early transition on the pressure surface for the higher Reynolds numbers. The rough surface had no significant effect on heat transfer in the laminar regions but caused early transition on the pressure surface in every case.
Estimating the Loss Associated With Film Cooling for a Turbine Stage
Authors: Lim Chia Hui , Pullan Graham , Northall John
Published: June 2011

A methodology is presented to allow designers to estimate the penalty for turbine efficiency associated with film cooling. The approach is based on the control volume analysis of Hartsel and the entropy-based formulations of Young and Wilcock. The present work extends these techniques to include flow ejected at compound angles and uses three-dimensional computational fluid dynamics (CFD) to provide the mainstream flow properties. The method allows the loss contribution from each hole to be identified separately. The proposed method is applied to an aeroengine high-pressure turbine stage. It is found that, if the efficiency definition includes all irreversibilities, the penalty associated with film cooling would be 8.0%. However, if the pragmatic approach is adopted whereby the unavoidable entropy generated due to the equilibration of coolant and mainstream static temperatures is ignored, the efficiency penalty is 0.7%. Finally, a series of case studies is used to quantify the impact of changes to the local mainstream flow direction and coolant ejection angle on the predicted turbine efficiency. It is shown, quantitatively, that reducing the angle between the directions of the coolant and mainstream flows offers the greatest potential for the designer to improve film-cooled turbine efficiency.
Experimental comparison of seven commercial dosimetry diodes for measurement of stereotactic radiosurgery cone factors
Authors: Dieterich Sonja , Sherouse George W.
Published: June 2011

Purpose:

The purpose of this work is to assess the variation in performance of various commercially available dosimetry diodes for quantitative small field dosimetry, specifically by intercomparing measurements of SRS cone factors.

Methods:

Measurements were made in 6 MV photon beams with fixed SRS cones for two accelerator‐based SRS systems: a Varian Clinac iX (Varian/Zmed cones) at 600 MU/min and a CyberKnife model G4 at 800 MU/min. Measurements were made at 1.5 cm depth in water using the IBA Dosimetry “blue phantom” 3D scanning system, controlled byomnipro‐accept software. Source‐to‐detector distance was 100 cm for the Clinac, 80 cm for the CyberKnife. Two normalization methods were used for the Clinac, one directly referenced to diode measurements in a 10 cm × 10 cm square field and the other indirectly by “daisy‐chaining” diode measurements to ion chamber measurement in the 10 cm × 10 cm reference field through an intermediate 4 cm × 4 cm square field. CyberKnife factors were referenced directly to measurements in the 60 mm reference field. Seven commercial diodes were evaluated: PTW TN60008, TN60012, TN60016, TN60017; IBA Dosimetry SFD; Sun Nuclear EDGE; Exradin SD1 (first generation prototype).

Results:

With the exception of the SFD, all the evaluated devices yielded surprisingly consistent results. Standard deviations of Clinac factors for four diodes (SD1, EDGE, TN60008, and TN60012) ranged from approximately 0.50% at 30 mm to 2.0% at 5 mm cones size when referenced directly to the 10 cm × 10 cm measurement. The daisy‐chaining strategy reduced the standard deviation to approximately 0.30% at 30 mm and 1.9% at 5 mm. Standard deviations for the same four diodes in the CyberKnife beam ranged up to approximately 1.0% at 5 mm.

Conclusions:

The inter‐detector variation is small and appears to be systematic with detector packaging, more inherent filtration producing flatter curves for both the relatively hard Clinac beam and the softer CyberKnife beam. The daisy‐chain strategy appears to be of limited value for most of the diodes, but does bring the SFD results into significantly better agreement with the others.
The invariance of the total direct DNA strand break yield
Authors: Bernal M. A. , deAlmeida C. E. , Sampaio C. , Incerti S. , Champion C. , Nieminen P.
Published: June 2011

Purpose:

The invariance of the total direct strand break yield when DNA is irradiated by different types of particles and energies has been reported by previous works. This study is intended to explain the physical causes of this behavior.

Methods:

Thegeant4‐dna extension of the geant4 general purpose Monte Carlo simulation toolkit has been used to determine direct strand break yields induced by protons and alpha particles impacting on a B‐DNA geometrical model, including five organization levels of the human genetic material. The linear energy transfer (LET) of such particles ranges from 4.8 keV/μm (10 MeV protons) to about 235 keV/μm (2 MeV alpha particles), at 5.225 μm depth (near the center of the region of interest). Direct total, single and double strand break probabilities have been determined in a liquid water homogeneous medium with a 1.06 g/cm density. The energetic spectra of single strand breaks (SSB), the number of energy deposition events, and the SSB/event ratio were determined.

Results:

The target‐hit probability was found to be independent of both the type and the energy of the incident particle, even if this latter is a secondary electron. This probability is determined by the geometrical properties of the system. The total strand break yield and the number of energy deposition events required to reach a certain absorbed dose were found nearly independent of the type and energy of the incident ion (proton or alpha). In contrast, the double strand break (DSB) yield was found strongly dependent on the LET of the incident radiation.

Conclusions:

The SSB generation process is homogeneous and independent of the LET of the particles involved, at least within the proton and alpha particle energy range here studied. The target‐hit probability is only determined by the ratio between the total volume occupied by targets and that of the ROI where the radiation deposits its energy. The maximum separation distance between two adjacent SSBs to produce a DSB is the parameter that breaks the homogeneity of the target‐hit process, making the DSB production process strongly heterogeneous.
Daptomycin Antibiotic Lock Therapy in a Rat Model of Staphylococcal Central Venous Catheter Biofilm Infections
Authors: Van Praagh Andrew D. G. , Li Tongchuan , Zhang Shuxin , Arya Anu , Chen Liping , Zhang Xi-Xian , Bertolami Shellie , Mortin Lawrence I.
Published: June 2011

Antibiotic lock therapy (ALT) is an adjunctive procedure to prevent or treat central venous catheter infections, ensuing catheter-related bacteremia, and catheter-related metastatic infections. Daptomycin is a cyclic lipopeptide that is rapidly bactericidal against methicillin-susceptible and -resistant
Staphylococcus aureus
. The efficacies of daptomycin against central venous catheter biofilms, catheter-related bacteremia, and catheter-related metastatic infections were evaluated by adapting a previously reported central venous catheter biofilm model in rats. Combined daptomycin ALT and systemic dosing resulted in the clearance of an established
in vivo S. aureus
central venous catheter biofilm after just two daily ALT treatments (30 min with daptomycin at 5 mg/ml) with concurrent systemic daptomycin dosing (40 mg/kg of body weight/day subcutaneously [s.c.]; equivalent exposure of 6 mg/kg/day in people). Daptomycin ALT solutions formulated in either saline or lactated Ringer's solution were equally fast in eradicating established
in vivo
methicillin-resistant
Staphylococcus epidermidis
(MRSE) central venous catheter biofilms. However, the lactated Ringer's formulation was superior to that of saline in sustaining the bacterial clearance of treated central venous catheters (83% versus 50%). In MRSE-infected central venous catheter studies, 3 days of daptomycin or vancomycin ALT (18 h at 5 mg/ml) with systemic s.c. dosing (40 mg/kg/day daptomycin or 100 mg/kg/day vancomycin) was equally effective 1 week posttherapy in maintaining cleared central venous catheters (90% [
n
= 10] versus 100% [
n
= 8]). These results suggest that daptomycin ALT, along with systemic dosing, could be an effective treatment option for the prevention or eradication of staphylococcal central venous catheter biofilm infections, thereby reducing the occurrence of catheter-related bacteremia or catheter-related metastatic infections.
Novel Trichomonacidal Spermicides
Authors: Jain Ashish , Lal Nand , Kumar Lokesh , Verma Vikas , Kumar Rajeev , Kumar Lalit , Singh Vishal , Mishra Raghav K. , Sarswat Amit , Jain S. K. , Maikhuri J. P. , Sharma V. L. , Gupta Gopal
Published: June 2011

Metronidazole, the U.S. Food and Drug Administration-approved drug against trichomoniasis, is nonspermicidal and thus cannot offer pregnancy protection when used vaginally. Furthermore, increasing resistance of
Trichomonas vaginalis
to 5-nitro-imidazoles is a cause for serious concern. On the other hand, the vaginal spermicide nonoxynol-9 (N-9) does not protect against sexually transmitted diseases and HIV in clinical situations but may in fact increase their incidence due to its nonspecific, surfactant action. We therefore designed dually active, nonsurfactant molecules that were capable of killing
Trichomonas vaginalis
(both metronidazole-susceptible and -resistant strains) and irreversibly inactivating 100% human sperm at doses that were noncytotoxic to human cervical epithelial (HeLa) cells and vaginal microflora (lactobacilli)
in vitro
. Anaerobic energy metabolism, cell motility, and defense against reactive oxygen species, which are key to survival of both sperm and
Trichomonas
in the host after intravaginal inoculation, depend crucially on availability of free thiols. Consequently, molecules were designed with carbodithioic acid moiety as the major pharmacophore, and chemical variations were incorporated to provide high excess of reactive thiols for interacting with accessible thiols on sperm and
Trichomonas
. We report here the
in vitro
activities, structure-activity relationships, and safety profiles of these spermicidal antitrichomonas agents, the most promising of which was more effective than N-9 (the OTC spermicide) in inactivating human sperm and more efficacious than metronidazole in killing
Trichomonas vaginalis
(including metronidazole-resistant strain). It also significantly reduced the available free thiols on human sperm and inhibited the cytoadherence of
Trichomonas
on HeLa cells. Experimentally
in vitro
, the new compounds appeared to be safer than N-9 for vaginal use.
Melatonin Attenuates Colistin-Induced Nephrotoxicity in Rats
Authors: Yousef Jumana M. , Chen Gong , Hill Prue A. , Nation Roger L. , Li Jian
Published: June 2011

Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (
n
= 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary
N
-acetyl-β-
d
-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (
P
< 0.0001). Plasma creatinine increased significantly (
P
= 0.023) only in the colistin group on day 6. Significant histological abnormalities (
P
< 0.0001) were detected only in the kidneys of the colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 ± 0.26 ml/min/kg) was lower than in the colistin group (4.28 ± 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic.
Polymorphisms in Isoniazid and Prothionamide Resistance Genes of the Mycobacterium tuberculosis Complex
Authors: Projahn Michaela , Köser Claudio U. , Homolka Susanne , Summers David K. , Archer John A. C. , Niemann Stefan
Published: June 2011

Sequence analyses of 74 strains that encompassed major phylogenetic lineages of the
Mycobacterium tuberculosis
complex revealed 10 polymorphisms in
mshA
(
Rv0486
) and four polymorphisms in
inhA
(
Rv1484
) that were not responsible for isoniazid or prothionamide resistance. Instead, some of these mutations were phylogenetically informative. This genetic diversity must be taken into consideration for drug development and for the design of molecular tests for drug resistance.
Coresistance to Isoniazid and Ethionamide Maps to Mycothiol Biosynthetic Genes in Mycobacterium bovis
Authors: Vilchèze Catherine , Av-Gay Yossef , Barnes S. Whitney , Larsen Michelle H. , Walker John R. , Glynne Richard J. , Jacobs William R.
Published: June 2011

A search to identify new mechanisms of isoniazid resistance in
Mycobacterium bovis
led to the isolation of mutants defective in mycothiol biosynthesis due to mutations in genes coding for the glycosyltransferase (
mshA
) or the cysteine ligase (
mshC
). These mutants showed low-level resistance to isoniazid but were highly resistant to ethionamide. This study further illustrates that mutations in mycothiol biosynthesis genes may contribute to isoniazid or ethionamide resistance across mycobacterial species.
Identification of a Novel Benzimidazole That Inhibits Bacterial Biofilm Formation in a Broad-Spectrum Manner
Authors: Sambanthamoorthy Karthik , Gokhale Ankush A. , Lao Weiwei , Parashar Vijay , Neiditch Matthew B. , Semmelhack Martin F. , Lee Ilsoon , Waters Christopher M.
Published: June 2011

Bacterial biofilm formation causes significant industrial economic loss and high morbidity and mortality in medical settings. Biofilms are defined as multicellular communities of bacteria encased in a matrix of protective extracellular polymers. Because biofilms have a high tolerance for treatment with antimicrobials, protect bacteria from immune defense, and resist clearance with standard sanitation protocols, it is critical to develop new approaches to prevent biofilm formation. Here, a novel benzimidazole molecule, named antibiofilm compound 1 (ABC-1), identified in a small-molecule screen, was found to prevent bacterial biofilm formation in multiple Gram-negative and Gram-positive bacterial pathogens, including
Pseudomonas aeruginosa
and
Staphylococcus aureus
, on a variety of different surface types. Importantly, ABC-1 itself does not inhibit the growth of bacteria, and it is effective at nanomolar concentrations. Also, coating a polystyrene surface with ABC-1 reduces biofilm formation. These data suggest ABC-1 is a new chemical scaffold for the development of antibiofilm compounds.
In Vitro
Spectrum of Activity of Finafloxacin, a Novel, pH-Activated Fluoroquinolone, under Standard and Acidic Conditions
Authors: Stubbings Will , Leow Pamela , Yong Goh Chee , Goh Falicia , Körber-Irrgang Barbara , Kresken Michael , Endermann Rainer , Labischinski Harald
Published: June 2011

Finafloxacin is a novel fluoroquinolone that exhibits enhanced antibacterial activity under acidic conditions. The aim of this study was to define the
in vitro
pH-activity relationship. Finafloxacin exhibited optimal antibacterial activity between pH 5.0 and 6.0 at which MICs were 4- to 8-fold lower than those determined at neutral pH. These observations were then confirmed against a larger collection of bacteria. These data suggest that finafloxacin could potentially offer a therapeutic advantage within acidic foci of infection.
The
SLCO1B1
rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications
Authors: Chigutsa Emmanuel , Visser Marianne E. , Swart Elizabeth C. , Denti Paolo , Pushpakom Sudeep , Egan Deirdre , Holford Nicholas H. G. , Smith Peter J. , Maartens Gary , Owen Andrew , McIlleron Helen
Published: June 2011

Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the
ABCB1
gene) and organic anion-transporting polypeptide 1B1 (coded for by
SLCO1B1
). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for
ABCB1
,
SLCO1B1
,
PXR
, and
CAR
polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the
SLCO1B1
rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (
C
max
) below 8 mg/liter from 63% to 31%.
ABCB1
,
PXR
, and
CAR
polymorphisms were not associated with differences in rifampin pharmacokinetics.
SLCO1B1
rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.
Complement-Mediated Bactericidal Activity of Anti-Factor H Binding Protein Monoclonal Antibodies against the Meningococcus Relies upon Blocking Factor H Binding
Authors: Giuntini Serena , Reason Donald C. , Granoff Dan M.
Published: June 2011

Binding of the complement-downregulating protein factor H (fH) to the surface of the meningococcus is important for survival of the organism in human serum. The meningococcal vaccine candidate factor H binding protein (fHbp) is an important ligand for human fH. While some fHbp-specific monoclonal antibodies (MAbs) block binding of fH to fHbp, the stoichiometry of blocking in the presence of high serum concentrations of fH and its effect on complement-mediated bactericidal activity are unknown. To investigate this question, we constructed chimeric antibodies in which the human IgG1 constant region was paired with three murine fHbp-specific binding domains designated JAR 3, JAR 5, and MAb502. By surface plasmon resonance, the association rates for binding of all three MAbs to immobilized fHbp were >50-fold higher than that for binding of fH to fHbp, and the MAb dissociation rates were >500-fold lower than that for fH. While all three MAbs elicited similar C1q-dependent C4b deposition on live bacteria (classical complement pathway), only those antibodies that inhibited binding of fH to fHbp (JAR 3 and JAR 5) had bactericidal activity with human complement. MAb502, which did not inhibit fH binding, had complement-mediated bactericidal activity only when tested with fH-depleted human complement. When an IgG1 anti-fHbp MAb binds to sparsely exposed fHbp on the bacterial surface, there appears to be insufficient complement activation for bacteriolysis unless fH binding also is inhibited. The ability of fHbp vaccines to elicit protective antibodies, therefore, is likely to be enhanced if the antibody repertoire is of high avidity and includes fH-blocking activity.