bluuebunny/crossref_metadata_2025 huggingface dataset:
Determinants of Latin American Activism: Domestic and Transnational Political Opportunities and Threats
Authors: Shekha K. Russell
Published: August 2011

For decades Latin America has been and continues to be a vibrant source of activism as democracies emerge, civil societies strengthen, and movements turn an outward eye towards international forces. Social movements, organizations, and activists in Latin America mobilize around a diverse set of issues from neoliberalism to women’s rights and more. Yet, all groups must successfully navigate ever‐shifting domestic and transnational political opportunities and threats. This review first defines the political opportunity approach and discusses debates surrounding its utility and applicability at different phases of social movement activity, as well as growing debates about the importance of domestic versus transnational opportunities and threats for predicting movement mobilization, protests, and outcomes. Next the article discusses changing domestic and transnational political opportunities and threats throughout Latin America. It then turns to empirical application of the political opportunity model to various social movements, organizations, and activist groups working in Central and South America. This paper concludes with a brief revisit of the debate and points to future lines of inquiry. Additionally, it provides an interactive Google Map, which locates the prominent actors involved in Latin American activism, the international institutions that influence them, and Internet links for more information.
The Social Construction of Infertility
Authors: Greil Arthur , McQuillan Julia , Slauson‐Blevins Kathleen
Published: August 2011

Health and illness are not objective states but socially constructed categories. We focus here on infertility, a phenomenon that has shifted from being seen as a private problem of couples to being seen as a medical condition. Studying infertility provides an ideal vantage point from which to study such features of health care as inter‐societal and cross‐cultural disparities in health care, the relationship between identity and health, gender roles, and social and cultural variations in the process of medicalization. Infertility is stratified, both globally and within Western societies. Access to care is extremely limited for many women in developing societies and also for marginalized women in some highly industrialized societies. We also discuss the ways in which responses to infertility are influenced by the process of self‐definition. The experience of infertility is profoundly shaped by varying degrees of pronatalism and patriarchy. In advanced industrial societies, where voluntary childfree status is acknowledged, many women experience infertility as a ‘secret stigma’; in other cultures, where motherhood is normative for all women, infertility may be impossible to hide. In the West, acceptance of the medical model is virtually hegemonic, but in other societies medical interpretations of infertility coexist with traditional interpretations.
Politics and Esthetics
Authors: Tucker Ken
Published: August 2011

This essay examines the intersection and history of esthetics and politics. Esthetics now provides specific forms or categories of understanding for politics and public life; in the language of social movements, esthetics often supplies the ‘frames’ by which we perceive the world. I discuss the sociological literature on esthetics, and explore some of its connections to politics broadly conceived. I argue that an adequate sociological approach to esthetic politics must explore the history, characteristics, and intersection of the esthetic sphere and popular culture, for these two realms have influenced political ideas and practices.
SERUM CYSTATIN C VERSUS SERUM CREATININE IN THE ESTIMATION OF GLOMERULAR FILTRATION RATE IN RHABDOMYOLYSIS
Authors: Yap Michael , Lamarche Jorge , Peguero Alfredo , Courville Craig
Published: August 2011

Cystatin C has emerged as a possible, usable surrogate marker of renal function. We present a case that illustrates the clinical utility of cystatin C in the setting of acute kidney injury secondary to rhabdomyolysis. An African American male whose baseline cystatin C and serum creatinine levels taken a month prior to admission were compared against their daily values during his admission and at follow up. On admission, the patient's reduction in glomerular filtration rate (GFR) from baseline was much less when calculated with cystatin C than with serum creatinine. His clinical recovery was more reflective of the higher GFR with cystatin C than what would be assumed with his serum creatinine, which at its worst was 5 ml/min/1.73 m2. The patient was eventually discharged from the hospital with a GFR of 40 ml/min by cystatin C despite his GFR by the MDRD equation being 12. Cystatin C may be a more accurate marker of the both the amount of injury and the rate of resolution of acute kidney injury than serum creatinine in rhabdomyolysis.
Chinese Clinical Trial Registry: mission, responsibility and operation
Authors: Wu Taixiang , Li Youping , Liu Guanjian , Li Jing , Wang Li , Du Liang ,   on behalf of the Chinese Clinical Registry
Published: August 2011

As a national public clinical trial registry and a recognized Primary Registry of the WHO ICTRP, the Chinese Clinical Trial Registry (ChiCTR) has responsibility to disseminate knowledge about clinical trial transparency, which is an important ethical issue for healthcare studies involving humans, and to promote the quality of healthcare studies in China. This article describes the mission, policy and operation of the ChiCTR. We discuss the need to improve the quality of clinical trials and our ideas for new developments. The registration of clinical trials is an ethical responsibility and obligation for researchers. A clinical study is a public event itself, which needs the participation of the public, and its results should also be seen as a service to the public. Therefore, the public have the right to know how a study is progressing.
Why Moscow Has Escalated Its Territorial Dispute with Tokyo
Authors: Weitz Richard
Published: August 2011

Four reasons likely explain why President Dmitry Medvedev and other Russian officials have decided to escalate their 65‐year‐old dispute with Japan over the Southern Kurils/ Northern Territories. First, Tokyo's relations with China, North Korea, and other countries are poor. Furthermore, Russia is eager to raise its profile in East Asia more generally. In addition, the Japanese have become increasingly open to expanding economic ties with Russia despite the dispute. Finally, Medvedev himself has domestic political reasons to adopt a more aggressive posture toward Japan regarding the disputed islands. Russia has succeeded during the past few months in solidifying Moscow's hold over the islands. In the long term, the Japanese will probably prove more amenable to making the most concessions because China's continuing rise is presenting a greater threat to Tokyo's interests.
Ties That Bind? Assessing the Impact of Economic Interdependence on East Asian Alliances*
Authors: Lee Dong Sun , Kim Sung Eun
Published: August 2011

This article investigates how commercial ties affect the cohesiveness of US alliances with East Asian nations. While the conventional wisdom views their effects as positive, we argue that economic interdependence does not markedly reinforce East Asian alliances because the alliances have an asymmetrical structure. To evaluate these competing arguments, we examine the impact of bilateral trade on the US alliances with Japan, Taiwan, the Philippines, and South Korea, over the past quarter‐century. Our empirical analysis provides little evidence for the conventional view, while supporting our argument. Based on this finding, the article offers some practical implications for the free trade agreement and the security alliance between South Korea and the USA.
Foreign Aid and Economic Development: The Success Story of South Korea*
Authors: Kim Jiyoung
Published: August 2011

By joining the Development Assistance Committee of the Organisation for Economic Co‐operation and Development in December 2009, South Korea became the first country to do so after having been a recipient of aid for about 50 years. Once one of the poorest nations in the world and a major aid recipient, South Korea has emerged as the thirteenth largest economy in the world and a major donor country. Throughout South Korea's rapid development period, foreign assistance played a critical role in producing the country's miraculous economic growth. In fact, South Korea is one of the very few cases in which foreign aid succeeded in promoting self‐supporting economic development of the recipient country. This article deals mainly with foreign assistance and economic development in South Korea and explains how foreign aid was used and how it contributed to the economic development of South Korea, focusing on the role of government ownership and commitment. In South Korea, foreign aid was employed successfully to overcome various national challenges and to support state‐led development projects, spurring economic development. In particular, this paper highlights the importance of strong government commitment and ownership, with which South Korea effectively managed foreign aid and minimized institutional cost. The South Korean case contrasts with many other developing countries in which foreign aid has been largely wasted and failed to bring about self‐supporting economic development of the recipient countries.
Fetal growth restriction and the programming of heart growth and cardiac insulin‐like growth factor 2 expression in the lamb
Authors: Wang Kimberley C. W. , Zhang Lei , McMillen I. Caroline , Botting Kimberley J. , Duffield Jaime A. , Zhang Song , Suter Catherine M. , Brooks Doug A. , Morrison Janna L.
Published: August 2011

Non‐Technical Summary  Cardiovascular disease is responsible for 30% of deaths worldwide and epidemiological data demonstrate that poor growth before birth is associated with an increased risk of heart disease in adult life. We show that in response to reduced placental substrate supply there is an increase in cardiac insulin‐like growth factor‐2 (IGF‐2) and the IGF‐2 receptor (IGF‐2R) in the fetus. Importantly, this effect is programmed because it is also present after birth in the lamb at 21 days of age. We also show that the increase in IGF‐2 and IGF‐2R gene expression is not epigenetically regulated through the IGF‐2/H19 or IGF‐2R methylation process. This study places the IGF‐2 receptor signalling pathway as a prime candidate for mediating cardiac hypertrophy in fetal growth restriction before and after birth.
Transcranial static magnetic field stimulation of the human motor cortex
Authors: Oliviero Antonio , Mordillo‐Mateos Laura , Arias Pablo , Panyavin Ivan , Foffani Guglielmo , Aguilar Juan
Published: August 2011

Non‐Technical Summary  Non‐invasive neuromodulation of the human brain – with pulsed magnetic fields or small direct currents – is becoming increasingly popular for treating a variety of neurological and neuropsychiatric disorders. In the present work we investigated in healthy humans the possibility of a non‐invasive modulation of motor cortex excitability by the application of static magnetic fields through the scalp. We found that transcranial static magnetic field stimulation (tSMS) can reduce the excitability of the motor cortex for a period that outlasts the time of the application of the magnetic field. Moreover, we demonstrated that these excitability changes take origin at the cortical level. These results suggest that tSMS using small static magnets may be a promising tool to modulate cerebral excitability in a non‐invasive, painless and reversible way.
1995 ASME Gas Turbine Award Paper: Development and Application of a Multistage Navier–Stokes Flow Solver: Part II—Application to a High-Pressure Compressor Design
Authors: LeJambre C. R. , Zacharias R. M. , Biederman B. P. , Gleixner A. J. , Yetka C. J.
Published: August 2011

Two versions of a three-dimensional multistage Navier–Stokes code were used to optimize the design of an eleven-stage high-pressure compressor. The first version of the code utilized a “mixing plane” approach to compute the flow through multistage machines. The effects due to tip clearances and flowpath cavities were not modeled. This code was used to minimize the regions of separation on airfoil and endwall surfaces for the compressor. The resulting compressor contained bowed stators and rotor airfoils with contoured endwalls. Experimental data acquired for the HPC showed that it achieved 2 percent higher efficiency than a baseline machine, but it had 14 percent lower stall margin. Increased stall margin of the HPC was achieved by modifying the stator airfoils without compromising the gain in efficiency as demonstrated in subsequent rig and engine tests. The modifications to the stators were defined by using the second version of the multistage Navier–Stokes code, which models the effects of tip clearance and endwall flowpath cavities, as well as the effects of adjacent airfoil rows through the use of “bodyforces” and “deterministic stresses.” The application of the Navier–Stokes code was assessed to yield up to 50 percent reduction in the compressor development time and cost.
An Analysis of Axial Compressor Fouling and a Blade Cleaning Method
Authors: Tarabrin A. P. , Schurovsky V. A. , Bodrov A. I. , Stalder J.-P.
Published: August 2011

The paper describes the phenomenon of axial compressor fouling due to aerosols contained in the air. Key parameters having effect on the level of fouling are determined. A mathematical model of a progressive compressor fouling using the stage-by-stage calculation method is developed. Calculation results on the influence of fouling on the compressor performance are presented. A new index of sensitivity of axial compressors to fouling is suggested. The paper gives information about Turbotect’s deposit cleaning method of compressor blading and the results of its application on an operating industrial gas turbine. Regular on-line and off-line washings of the compressor flow path make it possible to maintain a high level of engine efficiency and output.
On the Interpretation of Measured Profile Losses in Unsteady Wake–Turbine Blade Interaction Studies
Authors: Hodson H. P. , Dawes W. N.
Published: August 2011

The interaction of wakes shed by a moving blade row with a downstream blade row causes unsteady flow. The meaning of the free-stream stagnation pressure and stagnation enthalpy in these circumstances has been examined using simple analyses, measurements, and CFD. The unsteady flow in question arises from the behavior of the wakes as so-called negative jets. The interactions of the negative jets with the downstream blades lead to fluctuations in static pressure, which in turn generate fluctuations in the stagnation pressure and stagnation enthalpy. It is shown that the fluctuations of the stagnation quantities created by unsteady effects within the blade row are far greater than those within the incoming wake. The time-mean exit profiles of the stagnation pressure and stagnation enthalpy are affected by these large fluctuations. This phenomenon of energy separation is much more significant than the distortion of the time-mean exit profiles that is caused directly by the cross-passage transport associated with the negative jet, as described by Kerrebrock and Mikolajczak. Finally, it is shown that if only time-averaged values of loss are required across a blade row, it is nevertheless sufficient to determine the time-mean exit stagnation pressure.
Flow Development Through Interturbine Diffusers
Authors: Dominy R. G. , Kirkham D. A. , Smith A. D.
Published: August 2011

Interturbine diffusers offer the potential advantage of reducing the flow coefficient in the following stages, leading to increased efficiency. The flows associated with these ducts differ from those in simple annular diffusers both as a consequence of their high-curvature S-shaped geometry and of the presence of wakes created by the upstream turbine. Experimental data and numerical simulations clearly reveal the generation of significant secondary flows as the flow develops through the diffuser in the presence of cross-passage pressure gradients. The further influence of inlet swirl is also demonstrated. Data from experimental measurements with and without an upstream turbine are discussed and computational simulations are shown not only to give a good prediction of the flow development within the diffuser but also to demonstrate the importance of modeling the fully three-dimensional nature of the flow.
LDA Study of the Flow Development Through an Orthogonally Rotating U-Bend of Strong Curvature and Rib-Roughened Walls
Authors: Iacovides H. , Jackson D. C. , Ji H. , Kelemenis G. , Launder B. E. , Nikas K.
Published: August 2011

This Paper reports laser-Doppler anemometry (LDA) and wall pressure measurements of turbulent flow in a square-sectioned, rotating U-bend, typical of coolant passages employed in modern gas turbine blades. In the upstream and downstream tangents, the pressure and suction (inner and outer) surfaces are roughened with discrete square-sectioned ribs in a staggered arrangement for a rib-height to duct-diameter ratio of 0.1. Three cases have been examined at a passage Reynolds number of 105: a stationary case; a case of positive rotation (the pressure side coinciding with the outer side of the U-bend) at a rotation number (Ro ≡ ΩD/Um) of 0.2; and a case of negative rotation at Ro = −0.2. Measurements have been obtained along the symmetry plane of the duct. In the upstream section, the separation bubble behind each rib is about 2.5 rib heights long. Rotation displaces the high-momentum fluid toward the pressure side, enhances turbulence along the pressure side, and suppresses turbulence along the suction side. The introduction of ribs in the straight sections reduces the size of the separation bubble along the inner wall of the U-bend, by raising turbulence levels at the bend entry; it also causes the formation of an additional separation bubble over the first rib interval along the outer wall, downstream of the bend exit. Rotation also modifies the mean flow development within the U-bend, with negative rotation speeding up the flow along the inner wall and causing a wider inner-wall separation bubble at exit. Turbulence levels within the bend are generally increased by rotation and, over the first two diameters downstream of the bend, negative rotation increases turbulence while positive rotation on the whole has the opposite effect.
Functionalization dependence of the electron beam sensitivity for a conformationally immobile calix[6]arene resist
Authors: Spencer Gregory , Ralls Daniel , Wolfe Stephen , Blanda Michael , Bandyopadhyay Anup
Published: August 2011

Calixarenes form a group of compounds that have been studied as high resolution negative electron beam resists. In this work, resists based on a conformationally immobile calix[6]arene molecule were synthesized and their sensitivities measured while the number of attached functional groups was systematically varied. This provided a direct test of the effect of the degree of functionalization on the electron beam resist sensitivity. The synthesis produced two basic molecular conformations: a cone conformer and a 1,2,3-alternate conformer. The number of attached allyl groups was deliberately varied from 0 to 8 allyls in steps of 2 allyls per synthesis. The resulting nine different resists were exposed and contrast curves were measured by atomic force microscopy. The least sensitive were the unfunctionalized calix[6]arenes with threshold doses of about 2 mC/cm2. The fully functionalized conformers had threshold doses around 0.1 mC/cm2. The sensitivities of both conformers were found to scale directly with the number of attached allyls for the sequence running from 0 to 8 attached functional groups. The molecular weight effect on sensitivity, seen by other groups, appeared only for the heaviest of the nine resists. This conformer, containing six attached functional groups had the highest sensitivity of all those tested. The presence of these two methods for improving sensitivity, partial functionalization of the conformers and higher conformer molecular weight, allows for the possibility of creating a single calixarene resist that is optimized simultaneously for more than one property, such as sensitivity for imaging and etch resistance for pattern transfer.
Schottky-barrier height modulation of metal/In0.53Ga0.47As interfaces by insertion of atomic-layer deposited ultrathin Al2O3
Authors: Wang Runsheng , Xu Min , Ye Peide D. , Huang Ru
Published: August 2011

The improvement of the metal/InGaAs interface is essential for the future application of InGaAs metal source/drain Schottky-barrier metal-oxide-semiconductor field-effect-transistors. In this article, on In0.53Ga0.47As, the authors examine the recently proposed method of inserting an ultrathin insulator to modulate the effective Schottky-barrier height (SBH) at the metal/semiconductor interface. Both n-type and p-type In0.53Ga0.47As are investigated by inserting an atomic-layer deposited Al2O3 interlayer. The results indicate that SBH modulation is more effective at the n-InGaAs interface than the p-InGaAs interface for the same Al2O3 thickness. However, the Fermi level at the metal/InGaAs interface is still weakly pinned even after inserting 2 nm Al2O3. The mechanism of the SBH modulation could be attributed to the creation of an electric dipole at the Al2O3/InGaAs interface, which induces a barrier shift.
Analysis of a dip-solder process for self-assembly
Authors: Rao M. , Lusth J. C. , Burkett S. L.
Published: August 2011

Dip-soldering is a crucial step in forming certain self-assembled metal structures. However, this particular use of dip-soldering is not well described in the literature. The goal of this work is to characterize the thickness and roughness of solder layers deposited by dipping metallic films into solder melt over a range of temperatures. Control of the solder thickness and roughness will improve the yield of structures whose self-assembly is driven by surface area minimization during solder reflow. Film thickness and overall film roughness for four solder alloys, each with different melting points, were measured on unpatterned and patterned copper films. Additionally, two variations in flux treatment were investigated: flux maintained at room temperature and flux heated to 98 °C. Findings include the determination of critical temperatures, particular to each alloy, above which the roughness and thickness of the deposited solder dramatically decreases. Preheating the flux improves the nature of the deposition below these critical points. Above the critical points, thickness and roughness of the solder vary little and heating the flux does not provide significant improvements. This study provides insight into designing a process flow that optimizes the folding characteristics of self-assembled metal polyhedra by controlling the volume and quality of the solder layer.
Structure of a Light-Activated LOV Protein Dimer That Regulates Transcription
Authors: Vaidya Anand T. , Chen Chen-Hui , Dunlap Jay C. , Loros Jennifer J. , Crane Brian R.
Published: August 2011

Light-induced conformational changes in a blue-light sensor facilitate its dimerization.
K2P Potassium Channels, Mysterious and Paradoxically Exciting
Authors: Goldstein Steve A. N.
Published: August 2011

K2P potassium channels become permeable to Na
+
with low extracellular K
+
concentrations and may increase the risk for cardiac arrhythmias.
A Nuclear Movement for Neuronal Death
Authors: Adler Elizabeth M.
Published: August 2011

The aberrant activation and nuclear translocation of AMPK-α1 decreases Bcl2 abundance and contributes to neuronal death in Huntington’s disease.
Body Homeostasis and Serotonin
Authors: Stern Peter R.
Published: August 2011

Inducible neuron inhibition reveals essential roles for serotonergic neurons in respiratory and body temperature homeostasis.
Carbapenem Susceptibility Testing Errors Using Three Automated Systems, Disk Diffusion, Etest, and Broth Microdilution and Carbapenem Resistance Genes in Isolates of Acinetobacter baumannii-calcoaceticus Complex
Authors: Markelz Ana Elizabeth , Mende Katrin , Murray Clinton K. , Yu Xin , Zera Wendy C. , Hospenthal Duane R. , Beckius Miriam L. , Calvano Tatjana , Akers Kevin S.
Published: August 2011

The
Acinetobacter baumannii-calcoaceticus
complex (ABC) is associated with increasing carbapenem resistance, necessitating accurate resistance testing to maximize therapeutic options. We determined the accuracy of carbapenem antimicrobial susceptibility tests for ABC isolates and surveyed them for genetic determinants of carbapenem resistance. A total of 107 single-patient ABC isolates from blood and wound infections from 2006 to 2008 were evaluated. MICs of imipenem, meropenem, and doripenem determined by broth microdilution (BMD) were compared to results obtained by disk diffusion, Etest, and automated methods (the MicroScan, Phoenix, and Vitek 2 systems). Discordant results were categorized as very major errors (VME), major errors (ME), and minor errors (mE). DNA sequences encoding OXA beta-lactamase enzymes (
bla
OXA-23-like
,
bla
OXA-24-like
,
bla
OXA-58-like
, and
bla
OXA-51-like
) and metallo-β-lactamases (MBLs) (IMP, VIM, and SIM1) were identified by PCR, as was the
KPC2
carbapenemase gene. Imipenem was more active than meropenem and doripenem. The percentage of susceptibility was 37.4% for imipenem, 35.5% for meropenem, and 3.7% for doripenem. Manual methods were more accurate than automated methods.
bla
OXA-23-like
and
bla
OXA-24-like
were the primary resistance genes found.
bla
OXA-58-like
, MBLs, and
KPC2
were not present. Both automated testing and manual testing for susceptibility to doripenem were very inaccurate, with VME rates ranging between 2.8 and 30.8%. International variability in carbapenem breakpoints and the absence of CLSI breakpoints for doripenem present a challenge in susceptibility testing.
Gentamicin Improves the Activities of Daptomycin and Vancomycin against Enterococcus faecalis In Vitro and in an Experimental Foreign-Body Infection Model
Authors: Furustrand Tafin Ulrika , Majic Ivana , Zalila Belkhodja Cyrine , Betrisey Bertrand , Corvec Stéphane , Zimmerli Werner , Trampuz Andrej
Published: August 2011

For enterococcal implant-associated infections, the optimal treatment regimen has not been defined. We investigated the activity of daptomycin, vancomycin, and gentamicin (and their combinations) against
Enterococcus faecalis in vitro
and in a foreign-body infection model. Antimicrobial activity was investigated by time-kill and growth-related heat production studies (microcalorimetry) as well as with a guinea pig model using subcutaneously implanted cages. Infection was established by percutaneous injection of
E. faecalis
in the cage. Antibiotic treatment for 4 days was started 3 h after infection. Cages were removed 5 days after end of treatment to determine the cure rate. The MIC, the minimal bactericidal concentration (MBC) in the logarithmic phase, and the MBC in the stationary phase were 1.25, 5, and >20 μg/ml for daptomycin, 1, >64, and >64 μg/ml for vancomycin, and 16, 32, and 4 μg/ml for gentamicin, respectively.
In vitro
, gentamicin at subinhibitory concentrations improved the activity against
E. faecalis
when combined with daptomycin or vancomycin in the logarithmic and stationary phases. In the animal model, daptomycin cured 25%, vancomycin 17%, and gentamicin 50% of infected cages. In combination with gentamicin, the cure rate for daptomycin increased to 55% and that of vancomycin increased to 33%. In conclusion, daptomycin was more active than vancomycin against adherent
E. faecalis
, and its activity was further improved by the addition of gentamicin. Despite a short duration of infection (3 h), the cure rates did not exceed 55%, highlighting the difficulty of eradicating
E. faecalis
from implants already in the early stage of implant-associated infection.
Dolutegravir (S/GSK1349572) Exhibits Significantly Slower Dissociation than Raltegravir and Elvitegravir from Wild-Type and Integrase Inhibitor-Resistant HIV-1 Integrase-DNA Complexes
Authors: Hightower Kendra E. , Wang Ruolan , DeAnda Felix , Johns Brian A. , Weaver Kurt , Shen Yingnian , Tomberlin Ginger H. , Carter H. Luke , Broderick Timothy , Sigethy Scott , Seki Takahiro , Kobayashi Masanori , Underwood Mark R.
Published: August 2011

The integrase inhibitor (INI) dolutegravir (DTG; S/GSK1349572) has significant activity against HIV-1 isolates with raltegravir (RAL)- and elvitegravir (ELV)-associated resistance mutations. As an initial step in characterizing the different resistance profiles of DTG, RAL, and ELV, we determined the dissociation rates of these INIs with integrase (IN)-DNA complexes containing a broad panel of IN proteins, including IN substitutions corresponding to signature RAL and ELV resistance mutations. DTG dissociates slowly from a wild-type IN-DNA complex at 37°C with an off-rate of 2.7 × 10
−6
s
−1
and a dissociative half-life (
t
1/2
) of 71 h, significantly longer than the half-lives for RAL (8.8 h) and ELV (2.7 h). Prolonged binding (
t
1/2
, at least 5 h) was observed for DTG with IN-DNA complexes containing E92, Y143, Q148, and N155 substitutions. The addition of a second substitution to either Q148 or N155 typically resulted in an increase in the off-rate compared to that with the single substitution. For all of the IN substitutions tested, the off-rate of DTG from IN-DNA complexes was significantly slower (from 5 to 40 times slower) than the off-rate of RAL or ELV. These data are consistent with the potential for DTG to have a higher genetic barrier to resistance, provide evidence that the INI off-rate may be an important component of the mechanism of INI resistance, and suggest that the slow dissociation of DTG may contribute to its distinctive resistance profile.
Pharmacokinetic/Pharmacodynamic (PK/PD) Indices of Antibiotics Predicted by a Semimechanistic PKPD Model: a Step toward Model-Based Dose Optimization
Authors: Nielsen Elisabet I. , Cars Otto , Friberg Lena E.
Published: August 2011

A pharmacokinetic-pharmacodynamic (PKPD) model that characterizes the full time course of
in vitro
time-kill curve experiments of antibacterial drugs was here evaluated in its capacity to predict the previously determined PK/PD indices. Six drugs (benzylpenicillin, cefuroxime, erythromycin, gentamicin, moxifloxacin, and vancomycin), representing a broad selection of mechanisms of action and PK and PD characteristics, were investigated. For each drug, a dose fractionation study was simulated, using a wide range of total daily doses given as intermittent doses (dosing intervals of 4, 8, 12, or 24 h) or as a constant drug exposure. The time course of the drug concentration (PK model) as well as the bacterial response to drug exposure (
in vitro
PKPD model) was predicted. Nonlinear least-squares regression analyses determined the PK/PD index (the maximal unbound drug concentration [
fC
max
]/MIC, the area under the unbound drug concentration-time curve [
f
AUC]/MIC, or the percentage of a 24-h time period that the unbound drug concentration exceeds the MIC [
fT
>MIC
]) that was most predictive of the effect. The
in silico
predictions based on the
in vitro
PKPD model identified the previously determined PK/PD indices, with
fT
>MIC
being the best predictor of the effect for β-lactams and
f
AUC/MIC being the best predictor for the four remaining evaluated drugs. The selection and magnitude of the PK/PD index were, however, shown to be sensitive to differences in PK in subpopulations, uncertainty in MICs, and investigated dosing intervals. In comparison with the use of the PK/PD indices, a model-based approach, where the full time course of effect can be predicted, has a lower sensitivity to study design and allows for PK differences in subpopulations to be considered directly. This study supports the use of PKPD models built from
in vitro
time-kill curves in the development of optimal dosing regimens for antibacterial drugs.
OmpK26, a Novel Porin Associated with Carbapenem Resistance in Klebsiella pneumoniae
Authors: García-Sureda Laura , Doménech-Sánchez Antonio , Barbier Mariette , Juan Carlos , Gascó Joan , Albertí Sebastián
Published: August 2011

Clinical isolates of
Klebsiella pneumoniae
resistant to carbapenems are being isolated with increasing frequency. Loss of the expression of the major nonspecific porins OmpK35/36 is a frequent feature in these isolates. In this study, we looked for porins that could compensate for the loss of the major porins in carbapenem-resistant organisms. Comparison of the outer membrane proteins from two
K. pneumoniae
clinical isogenic isolates that are susceptible (KpCS-1) and resistant (KpCR-1) to carbapenems revealed the absence of OmpK35/36 and the presence of a new 26-kDa protein in the resistant isolate. An identical result was obtained when another pair of isogenic isolates that are homoresistant (Kpn-3) and heteroresistant (Kpn-17) to carbapenems were compared. Mass spectrometry and DNA sequencing analysis demonstrated that this new protein, designated OmpK26, is a small monomeric oligogalacturonate-specific porin that belongs to the KdgM family of porins. Insertion-duplication mutagenesis of the OmpK26 coding gene,
yjhA
, in the carbapenem-resistant, porin-deficient isolate KpCR-1 caused the expression of OmpK36 and the reversion to the carbapenem-susceptible phenotype, suggesting that OmpK26 is indispensable for KpCR-1 to lose OmpK36 and become resistant to these antibiotics. Moreover, loss of the major porin and expression of OmpK26 reduced
in vitro
fitness and attenuated virulence in a murine model of acute systemic infection. Altogether, these results indicate that expression of the oligogalacturonate-specific porin OmpK26 compensates for the absence of OmpK35/36 and allows carbapenem resistance in
K. pneumoniae
but cannot restore the fitness of the microorganism.
Endocytosis-Mediated Vacuolar Accumulation of the Human ApoE Apolipoprotein-Derived ApoEdpL-W Antimicrobial Peptide Contributes to Its Antifungal Activity in Candida albicans
Authors: Rossignol Tristan , Kelly Bridie , Dobson Curtis , d'Enfert Christophe
Published: August 2011

The 18-amino-acid cationic, tryptophan-rich ApoEdpL-W peptide derived from human ApoE apolipoprotein was shown to have antifungal activity against pathogenic yeasts of the
Candida
genus (except
C. glabrata
). ApoEdpL-W was active against planktonic cells and early-stage biofilms but less active against mature biofilms, possibly because of its affinity for extracellular matrix beta-glucans. Moreover, ApoEdpL-W absorbed to medically relevant materials partially prevented the formation of biofilms on these materials. The exposure of
C. albicans
cells to sublethal doses of ApoEdpL-W triggered a transcriptional response reminiscent of that associated with the inactivation of the
MYO5
gene required for endocytosis as well as the upregulation of amino acid transporter genes. A fluorescent derivative of ApoEdpL-W accumulated at the cytoplasmic membrane and subsequently was translocated to the vacuole. Strikingly, the inactivation of
MYO5
or addition of latrunculin, an inhibitor of endocytosis, prevented the vacuolar accumulation of fluorescein-labeled ApoEdpL-W and reduced the antifungal activity of ApoEdpL-W. This, together with the insensitivity of ApoEdpL-W to alterations in membrane fluidity and high salt, suggested that the ApoEdpL-W mode of action was dependent upon vacuolar targeting and differed significantly from that of other antifungal peptides, such as Histatin-5 and Magainin 2.
Bacteriophages Carrying Antibiotic Resistance Genes in Fecal Waste from Cattle, Pigs, and Poultry
Authors: Colomer-Lluch Marta , Imamovic Lejla , Jofre Juan , Muniesa Maite
Published: August 2011

This study evaluates the occurrence of bacteriophages carrying antibiotic resistance genes in animal environments.
bla
TEM
,
bla
CTX-M
(clusters 1 and 9), and
mecA
were quantified by quantitative PCR in 71 phage DNA samples from pigs, poultry, and cattle fecal wastes. Densities of 3 to 4 log
10
gene copies (GC) of
bla
TEM
, 2 to 3 log
10
GC of
bla
CTX-M
, and 1 to 3 log
10
GC of
mecA
per milliliter or gram of sample were detected, suggesting that bacteriophages can be environmental vectors for the horizontal transfer of antibiotic resistance genes.
Virological Response after Short-Term CCR5 Antagonist Exposure in HIV-Infected Patients: Frequency of Subjects with Virological Response and Associated Factors
Authors: Ruiz-Mateos Ezequiel , González-Serna Alejandro , Genebat Miguel , Machmach Kawthar , Vidal Francesc , Muñoz-Fernández Ángeles , Ferrando-Martinez Sara , Leal Manuel
Published: August 2011

The virological response after an 8-day maraviroc monotherapy has been proposed to be an alternative method to determine whether an CCR5 antagonist should be prescribed to HIV-infected patients. The frequency of patients eligible for a combined antiretroviral therapy which includes maraviroc on the basis of the result of this clinical test is not well-known at the moment. In the same way, clinical and immunovirological factors associated with the virological response after antagonist exposure need to be determined. Ninety consecutive HIV-infected patients were exposed to an 8-day maraviroc monotherapy. The virological response was considered positive if either a reduction of ≥1-log
10
HIV RNA copies/ml or an undetectable viral load (<40 HIV RNA copies/ml) was achieved. CXCR4- and CCR5-tropic virus levels were determined by using patients' viral isolates and multiple rounds of infection of indicator cell lines (U87-CXCR4 and U87-CCR5). The frequency of patients with a positive virological response was 72.2% (94.7% and 66.2% for treatment-naïve and pretreated patients, respectively). The positive response rates dramatically decreased in patients with lower CD4
+
T-cell counts. The CXCR4-tropic virus level was the only variable independently associated with the virological response after short-term maraviroc exposure. Lower CD4
+
T-cell strata were associated with higher CXCR4-tropic virus levels. These results support the suggestion that CCR5 antagonists should be an early treatment option before the expansion of CXCR4-tropic strains.
Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy
Authors: Capela Rita , Cabal Ghislain G. , Rosenthal Philip J. , Gut Jiri , Mota Maria M. , Moreira Rui , Lopes Francisca , Prudêncio Miguel
Published: August 2011

It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The “magic bullet” thought to be necessary to reach eradication should not only provide treatment for all
Plasmodium
spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared
in vitro
and
in vivo
with those of the parent compounds. Both hybrids displayed enhanced
in vitro
activities, relative to those of the parent compounds, against
Plasmodium berghei
liver stages. Both compounds were about as potent as artemisinin against cultured
Plasmodium falciparum
(50% inhibitory concentration [IC
50
], ∼10 nM). When used to treat a murine
P. berghei
infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.
Tricomponent Immunopotentiating System as a Novel Molecular Design Strategy for Malaria Vaccine Development
Authors: Miyata Takeshi , Harakuni Tetsuya , Tsuboi Takafumi , Sattabongkot Jetsumon , Ikehara Ayumu , Tachibana Mayumi , Torii Motomi , Matsuzaki Goro , Arakawa Takeshi
Published: August 2011

The creation of subunit vaccines to prevent malaria infection has been hampered by the intrinsically weak immunogenicity of the recombinant antigens. We have developed a novel strategy to increase immune responses by creating genetic fusion proteins to target specific antigen-presenting cells (APCs). The fusion complex was composed of three physically linked molecular entities: (i) a vaccine antigen, (ii) a multimeric α-helical coiled-coil core, and (iii) an APC-targeting ligand linked to the core via a flexible linker. The vaccine efficacy of the tricomponent complex was evaluated using an ookinete surface protein ofPlasmodium vivax, Pvs25, and merozoite surface protein-1 ofPlasmodium yoelii. Immunization of mice with the tricomponent complex induced a robust antibody response and conferred substantial levels ofP. vivaxtransmission blockade as evaluated by a membrane feed assay, as well as protection from lethalP. yoeliiinfection. The observed effect was strongly dependent on the presence of all three components physically integrated as a fusion complex. This system, designated the tricomponent immunopotentiating system (TIPS), onto which any recombinant protein antigens or nonproteinaceous substances could be loaded, may be a promising strategy for devising subunit vaccines or adjuvants against various infectious diseases, including malaria.
Population Dynamics and Niche Distribution of Uropathogenic Escherichia coli during Acute and Chronic Urinary Tract Infection
Authors: Schwartz Drew J. , Chen Swaine L. , Hultgren Scott J. , Seed Patrick C.
Published: August 2011

Urinary tract infections (UTIs) have complex dynamics, with uropathogenic
Escherichia coli
(UPEC), the major causative agent, capable of colonization from the urethra to the kidneys in both extracellular and intracellular niches while also producing chronic persistent infections and frequent recurrent disease. In mouse and human bladders, UPEC invades the superficial epithelium, and some bacteria enter the cytoplasm to rapidly replicate into intracellular bacterial communities (IBCs) comprised of ∼10
4
bacteria each. Through IBC formation, UPEC expands in numbers while subverting aspects of the innate immune response. Within 12 h of murine bladder infection, half of the bacteria are intracellular, with 3 to 700 IBCs formed. Using mixed infections with green fluorescent protein (GFP) and wild-type (WT) UPEC, we discovered that each IBC is clonally derived from a single bacterium. Genetically tagged UPEC and a multiplex PCR assay were employed to investigate the distribution of UPEC throughout urinary tract niches over time. In the first 24 h postinfection (hpi), the fraction of tags dramatically decreased in the bladder and kidney, while the number of CFU increased. The percentage of tags detected at 6 hpi correlated to the number of IBCs produced, which closely matched a calculated multinomial distribution based on IBC clonality. The fraction of tags remaining thereafter depended on UTI outcome, which ranged from resolution of infection with or without quiescent intracellular reservoirs (QIRs) to the development of chronic cystitis as defined by persistent bacteriuria. Significantly more tags remained in mice that developed chronic cystitis, arguing that during the acute stages of infection, a higher number of IBCs precedes chronic cystitis than precedes QIR formation.
Comparative Genomics ofesxGenes from Clinical Isolates of Mycobacterium tuberculosis Provides Evidence for Gene Conversion and Epitope Variation
Authors: Uplekar Swapna , Heym Beate , Friocourt Véronique , Rougemont Jacques , Cole Stewart T.
Published: August 2011

The 23-membered Esx protein family is involved in the host-pathogen interactions ofMycobacterium tuberculosis. These secreted proteins are among the most immunodominant antigens recognized by the human immune system and have thus been used to develop vaccines and immunodiagnostic tests for tuberculosis (TB). Gene pairs for 10 Esx proteins are contained in the ESX-1 to ESX-5 loci, encoding type VII secretion systems. A subset of Esx proteins can be further classified into the Mtb9.9, QILSS, and TB10.4 subfamilies. To survey genetic diversity in the Esx family and its potential for antigenic variation, we sequenced allesxgenes from 108 clinical isolates ofM. tuberculosisfrom different clades by using a targeted approach. A total of 109 unique single nucleotide polymorphisms (SNPs) were observed, and 59 of these were nonsynonymous. Some of the resultant amino acid substitutions affect known Esx epitopes, including two in the EsxB (CFP-10) and EsxH (TB10.4) antigens. Assessment of the SNP distribution across the Esx proteins revealed high genetic variability, especially in the Mtb9.9 and QILSS subfamilies, and more conservation in the ESX-1 to ESX-4 loci. Comparison of the DNA sequences of variableesxgenes provided clear evidence for recombination events between different genes in the same strain, some of which are predicted to truncate the corresponding protein. Many of these polymorphisms escape detection by ultrahigh-throughput sequencing using short sequence reads, as such approaches cannot distinguish between closely related genes. Theesxgene family is dynamic, and sequence changes likely lead to immune variation.
Neutrophils Produce Interleukin 17A (IL-17A) in a Dectin-1- and IL-23-Dependent Manner during Invasive Fungal Infection
Authors: Werner Jessica L. , Gessner Melissa A. , Lilly Lauren M. , Nelson Michael P. , Metz Allison E. , Horn Dawn , Dunaway Chad W. , Deshane Jessy , Chaplin David D. , Weaver Casey T. , Brown Gordon D. , Steele Chad
Published: August 2011

We have previously reported that compromised interleukin 17A (IL-17A) production in the lungs increased susceptibility to infection with the invasive fungal pathogenAspergillus fumigatus. Here we have shown that culturing lung cells fromA. fumigatus-challenged miceex vivodemonstrated Dectin-1-dependent IL-17A production. In this system, neutralization of IL-23 but not IL-6, IL-1β, or IL-18 resulted in attenuated IL-17A production.Il23mRNA expression was found to be lower in lung cells fromA. fumigatus-challenged Dectin-1-deficient mice, whereas bone marrow-derived dendritic cells from Dectin-1-deficient mice failed to produce IL-23 in response toA. fumigatusin vitro. Addition of recombinant IL-23 augmented IL-17A production by wild-type (WT) and Dectin-1-deficient lung cells, although the addition of IL-6 or IL-1β did not augment the effect of IL-23. Intracellular cytokine staining of lung cells revealed lower levels of CD11b+IL-17A+and Ly-6G+IL-17A+cells inA. fumigatus-challenged Dectin-1-deficient mice. Ly-6G+neutrophils purified from the lungs ofA. fumigatus-challenged Dectin-1-deficient mice displayed lowerIl17amRNA expression but surprisingly had intactRorcandRoramRNA expression. We further demonstrated that Ly-6G+neutrophils required the presence of myeloid cells for IL-17A production. Finally, uponin vitrostimulation withA. fumigatus, thioglycolate-elicited peritoneal neutrophils were positive for intracellular IL-17A expression and produced IL-17A in a Dectin-1- and IL-23-dependent manner. In summary, Dectin-1-dependent IL-17A production in the lungs during invasive fungal infection is mediated in part by CD11b+Ly-6G+neutrophils in an IL-23-dependent manner.