bluuebunny/crossref_metadata_2025 huggingface dataset:
Population calcium imaging of spontaneous respiratory and novel motor activity in the facial nucleus and ventral brainstem in newborn mice
Authors: Persson Karin , Rekling Jens C.
Published: March 2011

Non‐technical summary  The brainstem contains neural circuits that control breathing. Groups of neurons produce the rhythm of inspiration and expiration, and other groups produce the motor output that controls respiratory muscles. One such group of neurons is the facial nucleus, which controls muscles in the face. Here we show, using electrical and calcium imaging techniques, that different subregions within the facial nucleus are particularly active during breathing, which suggest an involvement in keeping the airway open during inspiration. Furthermore, the experiments show that a novel rhythm generating circuit is present in the brainstem. These results may help us to a better understanding of how the brainstem controls breathing and other motor behaviours in the upper body.
Cerebellar motor learning versus cerebellar motor timing: the climbing fibre story
Authors: Llinás Rodolfo R.
Published: March 2011

Abstract  Theories concerning the role of the climbing fibre system in motor learning, as opposed to those addressing the olivocerebellar system in the organization of motor timing, are briefly contrasted. The electrophysiological basis for the motor timing hypothesis in relation to the olivocerebellar system is treated in detail.
Study of Fluid Effects on Dynamics of Composite Structures
Authors: Kwon Y. W.
Published: March 2011

This study investigated the effect of fluid-structure interaction on dynamic responses of submerged composite structures subjected to a mechanical impact loading. The research was focused on finding various parameters that affected the transient dynamic responses of the submerged composite structures. To this end, coupled fluid-structure interaction analyses of composite structures surrounded by a water medium were conducted numerically for various parametric studies and their results were compared with those of dry (i.e., in air) structures in order to understand the role of each parameter under study. Furthermore, modified dry structural models were developed to represent the dynamic responses of the same structures under water with a reasonable accuracy. Those models would be beneficial to predict the structural behaviors under water without an expensive computational or experimental cost.
Analytical Solution of the Thermoelasticity Problem in a Coke Drum With Cladding
Authors: Ning Z. H. , Liu R. H. , Huang S. Q. , Lu X. S.
Published: March 2011

Craze cracking and clad disbonding typically occur in cladding due to thermomechanical cycling and high property mismatch between dissimilar materials in a coke drum. The thermoelasticity problem in a coke drum with cladding is assumed quasi-static and solved analytically in this paper. The transient temperature distribution in both radial and axial directions is derived analytically based on the two-dimensional heat conduction theory. The iteration technique is applied to simulate the dynamic thermal boundary conditions caused by a fluid surface level rising continuously during both heated feed filling and water quench steps. Additionally, the classical laminated thin shell theory is applied to solve the quasi-static structural problem. The analytical results of the quasi-static thermoelasticity problem are compared with the finite element analysis. It is shown that during the water quench step, the maximum axial thermal gradient occurs at the inner surface of the clad, close to the water surface. The tension stresses occur in the clad due to its coefficient of thermal expansion smaller than that of the base metal material. Both the maximal axial stress and hoop stress occur at the cladding surface. These results may be helpful in explaining the formation mechanism of the clad disbonding and the shallow surface cracks at the inner surface of cladding.
A Comparison of Selected Strategies for Adaptive Control of Wave Energy Converters
Authors: Hals Jørgen , Falnes Johannes , Moan Torgeir
Published: March 2011

Wave-energy converters of the point-absorbing type (i.e., having small extension compared with the wavelength) are promising for achieving cost reductions and design improvements because of a high power-to-volume ratio and better possibilities for mass production of components and devices as compared with larger converter units. However, their frequency response tends to be narrow banded, which means that the performance in real seas (irregular waves) will be poor unless their motion is actively controlled. Only then the invested equipment can be fully exploited, bringing down the overall energy cost. In this work various control methods for point-absorbing devices are reviewed, and a representative selection of methods is investigated by numerical simulation in irregular waves, based on an idealized example of a heaving semisubmerged sphere. Methods include velocity-proportional control, approximate complex conjugated control, approximate optimal velocity tracking, phase control by latching and clutching, and model-predictive control, all assuming a wave pressure measurement as the only external input to the controller. The methods are applied for a single-degree-of-freedom heaving buoy. Suggestions are given on how to implement the controllers, including how to tune control parameters and handle amplitude constraints. Based on simulation results, comparisons are made on absorbed power, reactive power flow, peak-to-average power ratios, and implementation complexity. Identified strengths and weaknesses of each method are highlighted and explored. It is found that overall improvements in average absorbed power of about 100–330% are achieved for the investigated controllers as compared with a control strategy with velocity-proportional machinery force. One interesting finding is the low peak-to-average ratios resulting from clutching control for wave periods about 1.5 times the resonance period and above.
Reduction of the Sound Pressure Radiated by a Submarine by Isolation of the End Caps
Authors: Caresta Mauro , Kessissoglou Nicole J.
Published: March 2011

A passive isolation approach to reduce the sound pressure radiated by a submarine is presented. The submerged vessel is modeled as a stiffened cylindrical hull partitioned by bulkheads and with two end caps of conical shape. Fluctuating forces from the propeller are transmitted to the hull through the shaft and a rigid foundation, resulting in axisymmetric excitation of the hull. The hull surface motion is mainly in the axial direction with a small radial component due to the coupling between the two orthogonal shell displacements. The sound pressure resulting from the axial motion is radiated from the end caps of the submarine. This work investigates reduction of the far field sound pressure by passive isolation of the end caps from the main hull. Isolation of the axial motion of the end caps from the cylindrical hull results in significant reduction of the radiated sound at low frequencies. The fluid loading approximation for a finite cylindrical shell in the low frequency range is also discussed.
System Analysis of Thermochemical-Based Biorefineries for Coproduction of Hydrogen and Electricity
Authors: Braun Robert J. , Hanzon Luke G. , Dean Jered H.
Published: March 2011

Fuels derived from biomass feedstocks are a particularly attractive energy resource pathway given their inherent advantages of energy security via domestic fuel crop production and their renewable status. However, there are numerous questions regarding how to optimally produce, distribute, and utilize biofuels such that they are economically, energetically, and environmentally sustainable. Comparative analyses of two conceptual 2000 tons/day thermochemical-based biorefineries are performed to explore the effects of emerging technologies on process efficiencies. System models of the biorefineries, created using ASPEN Plus®, include all primary process steps required to convert a biomass feedstock into hydrogen, including gasification, gas cleanup and conditioning, hydrogen purification, and thermal integration. The biorefinery concepts studied herein are representative of “near-term” (approximately 2015) and “future” (approximately 2025) plants. The near-term plant design serves as a baseline concept and incorporates currently available commercial technologies for all nongasifier processes. Gasifier technology employed in these analyses is centered on directly heated, oxygen-blown, fluidized-bed systems that are pressurized to nearly 25 bars. The future plant design employs emerging gas cleaning and conditioning technologies for both tar and sulfur removal unit operations. A 25% increase in electric power production is observed for the future case over the baseline configuration due to the improved thermal integration while realizing an overall plant efficiency improvement of 2 percentage points. Exergy analysis reveals that the largest inefficiencies are associated with the (i) gasification, (ii) steam and power production, and (iii) gas cleanup and purification processes. Additional suggestions for improvements in the biorefinery plant for hydrogen production are given.
Technoeconomic Analysis of Microalgae Cofiring Process for Fossil Fuel-Fired Power Plants
Authors: Ma Jian , Hemmers Oliver
Published: March 2011

The concept of cofiring (algal biomass burned together with coal or natural gas in existing utility power boilers) includes the utilization of CO2 from power plant for algal biomass culture and oxycombustion of using oxygen generated by biomass to enhance the combustion efficiency. As it reduces CO2 emission by recycling it and uses less fossil fuel, there are concomitant benefits of reduced greenhouse gas (GHG) emissions. The by-products (oxygen) of microalgal biomass can be mixed with air or recycled flue gas prior to combustion, which will have the benefits of lower nitrogen oxide concentration in flue gas, higher efficiency of combustion, and not too high temperature (avoided by available construction materials) resulting from coal combustion in pure oxygen. A technoeconomic analysis of microalgae cofiring process for fossil fuel-fired power plants is studied. A process with closed photobioreactor and artificial illumination is evaluated for microalgae cultivation, due to its simplicity with less influence from climate variations. The results from this process would contribute to further estimation of process performance and investment. Two case studies show that there are average savings about $0.264 million/MW/yr and $0.203 million/MW/yr for coal-fired and natural gas-fired power plants, respectively. These cost savings are economically attractive and demonstrate the promise of microalgae technology for reducing GHG emission from fossil fuel-fired power plants.
A Robotic Cadaveric Flatfoot Analysis of Stance Phase
Authors: Jackson Lyle T. , Aubin Patrick M. , Cowley Matthew S. , Sangeorzan Bruce J. , Ledoux William R.
Published: March 2011

The symptomatic flatfoot deformity (pes planus with peri-talar subluxation) can be a debilitating condition. Cadaveric flatfoot models have been employed to study the etiology of the deformity, as well as invasive and noninvasive surgical treatment strategies, by evaluating bone positions. Prior cadaveric flatfoot simulators, however, have not leveraged industrial robotic technologies, which provide several advantages as compared with the previously developed custom fabricated devices. Utilizing a robotic device allows the researcher to experimentally evaluate the flatfoot model at many static instants in the gait cycle, compared with most studies, which model only one to a maximum of three instances. Furthermore, the cadaveric tibia can be statically positioned with more degrees of freedom and with a greater accuracy, and then a custom device typically allows. We created a six degree of freedom robotic cadaveric simulator and used it with a flatfoot model to quantify static bone positions at ten discrete instants over the stance phase of gait. In vivo tibial gait kinematics and ground reaction forces were averaged from ten flatfoot subjects. A fresh frozen cadaveric lower limb was dissected and mounted in the robotic gait simulator (RGS). Biomechanically realistic extrinsic tendon forces, tibial kinematics, and vertical ground reaction forces were applied to the limb. In vitro bone angular position of the tibia, calcaneus, talus, navicular, medial cuneiform, and first metatarsal were recorded between 0% and 90% of stance phase at discrete 10% increments using a retroreflective six-camera motion analysis system. The foot was conditioned flat through ligament attenuation and axial cyclic loading. Post-flat testing was repeated to study the pes planus deformity. Comparison was then made between the pre-flat and post-flat conditions. The RGS was able to recreate ten gait positions of the in vivo pes planus subjects in static increments. The in vitro vertical ground reaction force was within ±1 standard deviation (SD) of the in vivo data. The in vitro sagittal, coronal, and transverse plane tibial kinematics were almost entirely within ±1 SD of the in vivo data. The model showed changes consistent with the flexible flatfoot pathology including the collapse of the medial arch and abduction of the forefoot, despite unexpected hindfoot inversion. Unlike previous static flatfoot models that use simplified tibial degrees of freedom to characterize only the midpoint of the stance phase or at most three gait positions, our simulator represented the stance phase of gait with ten discrete positions and with six tibial degrees of freedom. This system has the potential to replicate foot function to permit both noninvasive and surgical treatment evaluations throughout the stance phase of gait, perhaps eliciting unknown advantages or disadvantages of these treatments at other points in the gait cycle.
Characterizing Heterogeneous Properties of Cerebral Aneurysms With Unknown Stress-Free Geometry: A Precursor to In Vivo Identification
Authors: Zhao Xuefeng , Raghavan Madhavan L. , Lu Jia
Published: March 2011

Knowledge of elastic properties of cerebral aneurysms is crucial for understanding the biomechanical behavior of the lesion. However, characterizing tissue properties using in vivo motion data presents a tremendous challenge. Aside from the limitation of data accuracy, a pressing issue is that the in vivo motion does not expose the stress-free geometry. This is compounded by the nonlinearity, anisotropy, and heterogeneity of the tissue behavior. This article introduces a method for identifying the heterogeneous properties of aneurysm wall tissue under unknown stress-free configuration. In the proposed approach, an accessible configuration is taken as the reference; the unknown stress-free configuration is represented locally by a metric tensor describing the prestrain from the stress-free configuration to the reference configuration. Material parameters are identified together with the metric tensor pointwisely. The paradigm is tested numerically using a forward-inverse analysis loop. An image-derived sac is considered. The aneurysm tissue is modeled as an eight-ply laminate whose constitutive behavior is described by an anisotropic hyperelastic strain-energy function containing four material parameters. The parameters are assumed to vary continuously in two assigned patterns to represent two types of material heterogeneity. Nine configurations between the diastolic and systolic pressures are generated by forward quasi-static finite element analyses. These configurations are fed to the inverse analysis to delineate the material parameters and the metric tensor. The recovered and the assigned distributions are in good agreement. A forward verification is conducted by comparing the displacement solutions obtained from the recovered and the assigned material parameters at a different pressure. The nodal displacements are found in excellent agreement.
Differential Passive and Active Biaxial Mechanical Behaviors of Muscular and Elastic Arteries: Basilar Versus Common Carotid
Authors: Wagner H. P. , Humphrey J. D.
Published: March 2011

Cerebrovascular disease continues to be responsible for significant morbidity and mortality. There is, therefore, a pressing need to understand better the biomechanics of both intracranial arteries and the extracranial arteries that feed these vessels. We used a validated four-fiber family constitutive relation to model passive biaxial stress-stretch behaviors of basilar and common carotid arteries and we developed a new relation to model their active biaxial responses. These data and constitutive relations allow the first full comparison of circumferential and axial biomechanical behaviors between a muscular (basilar) and an elastic (carotid) artery from the same species. Our active model describes the responses by both types of vessels to four doses of the vasoconstrictor endothelin-1 (10−10M, 10−9M, 10−8M, and 10−7M) and predicts levels of smooth muscle cell activation associated with basal tone under specific in vitro testing conditions. These results advance our understanding of the biomechanics of intracranial and extracranial arteries, which is needed to understand better their differential responses to similar perturbations in hemodynamic loading.
Single-crystalline aluminum grown on MgAl2O4 spinel using molecular-beam epitaxy
Authors: Lin Y. , Norman A. G. , McMahon W. E. , Moutinho H. R. , Jiang C.-S. , Ptak A. J.
Published: March 2011

Al thin films were grown on MgAl2O4 spinel substrates using solid-source molecular-beam epitaxy. The structural properties of Al layers were systematically investigated as a function of substrate orientation and growth temperature. Scanning electron microscopy and atomic force microscopy show that low growth temperatures lead to smoother and more coalesced Al films. X-ray diffraction and electron backscatter diffraction (EBSD) measurements demonstrate that Al layers are single crystalline and coherently grown on both (100)- and (111)-oriented spinel substrates. EBSD data also clearly reveal a high density of twin domain structures in Al films grown on (111) spinel substrates, and all twin boundaries were determined to be Σ3 boundaries. High-resolution transmission electron microscopy was used to confirm the presence of twin structures. Al grown on (001) spinel roughens more easily than Al grown on (111) spinel at higher growth temperatures. It is suggested that Al surface energy and thermal expansion mismatch play a critical role in the evolution of surface morphology of Al thin films grown on MgAl2O4 spinel.
Reflection high energy electron diffraction investigation and comparison of the initial stage during molecular beam epitaxy of AlN on Si(111) and Si(110) substrates
Authors: Mansurov Vladimir , Xu Xiaoyan , Pandikunta Mahesh , Uddin Rakib , Nikishin Sergey
Published: March 2011

The onset of AlN nucleation on Si(111) and Si(110) surfaces during gas source molecular beam epitaxy with ammonia was carried out by reflection high energy electron diffraction. Exposing the clean Si surfaces to NH3 flux at 600 °C yields the formation of crystalline Si3N4 on both (111) and (110) surfaces. An 8×8 Si3N4 structure was observed for the Si(111) surface. On the Si(110) surface a 2.87 Å periodic structure was observed for electron beam directed along [001] azimuth and 2.46 Å periodic structure for the [1¯12] azimuth. Together, these periodic structures confirm the formation of Si3N4 (0001) plane on both Si(111) and Si(110) surfaces.
Improvement in the performance of ZnO thin film transistors by using ultralow-pressure sputtering
Authors: Huh Myung Soo , Won Seok-Jun , Yang Bong Seob , Oh Seungha , Oh Myeong Sook , Jeong Jae Kyeong , Kim Hyeong Joon
Published: March 2011

Thin film transistors (TFTs) were fabricated with a zinc oxide (ZnO) channel deposited by ultralow-pressure sputtering (ULPS) at a pressure less than 1.3×10−3 Pa. The field-effect mobility (μFE) and the subthreshold gate swing (SS) of the ULPS-ZnO TFTs were dramatically improved up to 8.5 cm2/V s and 0.31 V/decade, respectively, compared to 1.6 cm2/V s and 1.31 V/decade for the ZnO TFTs fabricated by a conventional sputtering pressure (CSP) of 6.7×10−1 Pa. The improved characteristics of the ULPS-ZnO TFTs compared to the CSP-ZnO one can be attributed to the greater densification of the ZnO semiconductor film at the lower deposition pressure.
Effect of UV wavelength on the hardening process of porogen-containing and porogen-free ultralow-k plasma-enhanced chemical vapor deposition dielectrics
Authors: Urbanowicz Adam M. , Vanstreels Kris , Verdonck Patrick , Van Besien Els , Christos Trompoukis , Shamiryan Denis , De Gendt Stefan , Baklanov Mikhail R.
Published: March 2011

The effect of narrow-band 172 nm and broad-band >200 nm UV sources in the new curing scheme of the plasma-enhanced chemical vapor deposition (PECVD) dielectrics is studied. The new curing scheme is based on porogen removal (organic sacrificial phase introduced to generate open porosity) from PECVD dielectric before its final UV curing. The results are compared with the PECVD films fabricated in the conventional scheme in which porogen is still present during the UV curing. The same curing time of porogen-containing conventional PECVD films with 172 nm and >200 nm UV sources results in only 10% difference in their Young’s modulus (YM): 5.84 and 5.32 GPa, respectively. However, the porogen-free films cured with 172 nm UV source show a YM of 6.64 GPa (k100 kHz∼2.2, 44% open porosity), approximately twice as large as those cured with >200 nm UV having a YM of 3.38 GPa (k100 kHz∼2.0, 48% open porosity). The mechanical properties, optical properties in the range of 150–800 nm, dielectric constants at 100 kHz and 4 GHz, porosities, pore size distributions, and bonding structure are evaluated. The impact of porogen on optical characteristics and, therefore, on the photochemical UV-hardening mechanism is discussed. The achieved mechanical properties are explained on a basis of the percolation of rigidity theory and random network concepts.
Collimator design for experimental minibeam radiation therapy
Authors: Babcock Kerry , Sidhu Narinder , Kundapur Vijayananda , Ali Kaiser
Published: March 2011

Purpose:

To design and optimize a minibeam collimator for minibeam radiation therapy studies using a 250 kVp x‐ray machine as a simulated synchrotron source.

Methods:

A Philips RT250 orthovoltage x‐ray machine was modeled using the EGSnrc/BEAMnrc Monte Carlo software. The resulting machine model was coupled to a model of a minibeam collimator with a beam aperture of 1 mm. Interaperture spacing and collimator thickness were varied to produce a minibeam with the desired peak‐to‐valley ratio.

Results:

Proper design of a minibeam collimator with Monte Carlo methods requires detailed knowledge of the x‐ray source setup. For a cathode‐ray tube source, the beam spot size, target angle, and source shielding all determine the final valley‐to‐peak dose ratio.

Conclusions:

A minibeam collimator setup was created, which can deliver a 30 Gy peak dose minibeam radiation therapy treatment at depths less than 1 cm with a valley‐to‐peak dose ratio on the order of 23%.
Dosimetric validation of Acuros® XB with Monte Carlo methods for photon dose calculations
Authors: Bush K. , Gagne I. M. , Zavgorodni S. , Ansbacher W. , Beckham W.
Published: March 2011

Purpose:

The dosimetric accuracy of the recently released Acuros® XB advanced dose calculation algorithm (Varian Medical Systems, Palo Alto, CA) is investigated for single radiation fields incident on homogeneous and heterogeneous geometries, and a comparison is made to the analytical anisotropic algorithm (AAA).

Methods:

Ion chamber measurements for the 6 and 18 MV beams within a range of field sizes (from to ) are used to validate Acuros® XB dose calculations within a unit density phantom. The dosimetric accuracy of Acuros® XB in the presence of lung, low‐density lung, air, and bone is determined using BEAMnrc/DOSXYZnrc calculations as a benchmark. Calculations using the AAA are included for reference to a current superposition/convolution standard.

Results:

Basic open field tests in a homogeneous phantom reveal an Acuros® XB agreement with measurement to within ±1.9% in the inner field region for all field sizes and energies. Calculations on a heterogeneous interface phantom were found to agree with Monte Carlo calculations to within ±2.0% in lung and within ±2.9% in low‐density lung . In comparison, differences of up to 10.2% and 17.5% in lung and low‐density lung were observed in the equivalent AAA calculations. Acuros® XB dose calculations performed on a phantom containing an air cavity were found to be within the range of ±1.5% to ±4.5% of the BEAMnrc/DOSXYZnrc calculated benchmark in the tissue above and below the air cavity. A comparison of Acuros® XB dose calculations performed on a lung CT dataset with a BEAMnrc/DOSXYZnrc benchmark shows agreement within ±2%/2mm and indicates that the remaining differences are primarily a result of differences in physical material assignments within a CT dataset.

Conclusions:

By considering the fundamental particle interactions in matter based on theoretical interaction cross sections, the Acuros® XB algorithm is capable of modeling radiotherapy dose deposition with accuracy only previously achievable with Monte Carlo techniques.
Global Phosphoproteomics Reveals Crosstalk Between Bcr-Abl and Negative Feedback Mechanisms Controlling Src Signaling
Authors: Rubbi Liudmilla , Titz Björn , Brown Lauren , Galvan Erica , Komisopoulou Evangelia , Chen Sharon S. , Low Tracey , Tahmasian Martik , Skaggs Brian , Müschen Markus , Pellegrini Matteo , Graeber Thomas G.
Published: March 2011

Negative feedback fails to limit Src family kinase activity in the presence of Bcr-Abl, an oncoprotein that drives leukemia.
Amplification of the Driving Oncogene,
KRAS
or
BRAF
, Underpins Acquired Resistance to MEK1/2 Inhibitors in Colorectal Cancer Cells
Authors: Little Annette S. , Balmanno Kathryn , Sale Matthew J. , Newman Scott , Dry Jonathan R. , Hampson Mark , Edwards Paul A. W. , Smith Paul D. , Cook Simon J.
Published: March 2011

Resistance to cancer therapeutics targeting the second kinase in a three-kinase cascade involves amplification of the upstream kinase, not the inhibited kinase.
Science Signaling
Podcast: 29 March 2011
Authors: Graeber Thomas G. , VanHook Annalisa M.
Published: March 2011

Negative feedback mechanisms fail to limit Src family kinase activity in leukemias driven by the oncoprotein Bcr-Abl.
MYC, PARP1, and Chemoresistance: BIN There, Done That?
Authors: Ganesan Shridar
Published: March 2011

Enhanced capacity for DNA repair may contribute to chemoresistance in cancers with dysregulated c-MYC.
Inhibition of Hepatitis C Virus Replicon RNA Synthesis by PSI-352938, a Cyclic Phosphate Prodrug of β-d-2′-Deoxy-2′-α-Fluoro-2′-β-C-Methylguanosine
Authors: Lam Angela M. , Espiritu Christine , Murakami Eisuke , Zennou Veronique , Bansal Shalini , Micolochick Steuer Holly M. , Niu Congrong , Keilman Meg , Bao Haiying , Bourne Nigel , Veselenak Ronald L. , Reddy P. Ganapati , Chang Wonsuk , Du Jinfa , Nagarathnam Dhanapalan , Sofia Michael J. , Otto Michael J. , Furman Phillip A.
Published: March 2011

PSI-352938 is a novel cyclic phosphate prodrug of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylguanosine 5′-monophosphate that has potent activity against hepatitis C virus (HCV)in vitro. The studies described here characterize thein vitroanti-HCV activity of PSI-352938, alone and in combination with other inhibitors of HCV, and the cross-resistance profile of PSI-352938. The effective concentration required to achieve 50% inhibition for PSI-352938, determined using genotype 1a-, 1b-, and 2a-derived replicons stably expressed in the Lunet cell line, were 0.20, 0.13, and 0.14 μM, respectively. The active 5′-triphosphate metabolite, PSI-352666, inhibited recombinant NS5B polymerase from genotypes 1 to 4 with comparable 50% inhibitory concentrations. In contrast, PSI-352938 did not inhibit the replication of hepatitis B virus or human immunodeficiency virusin vitro. PSI-352666 did not significantly affect the activity of human DNA and RNA polymerases. PSI-352938 and its cyclic phosphate metabolites did not affect the cyclic GMP-mediated activation of protein kinase G. Clearance studies using replicon cells demonstrated that PSI-352938 cleared cells of HCV replicon RNA and prevented replicon rebound. An additive to synergistic effect was observed when PSI-352938 was combined with other classes of HCV inhibitors, including alpha interferon, ribavirin, NS3/4A inhibitors, an NS5A inhibitor, and nucleoside/nucleotide and nonnucleoside inhibitors. Cross-resistance studies showed that PSI-352938 remained fully active against replicons containing the S282T or the S96T/N142T amino acid alteration. Replicons that contain mutations conferring resistance to various classes of nonnucleoside inhibitors also remained sensitive to inhibition by PSI-352938. PSI-352938 is currently being evaluated in a phase I clinical study in genotype 1-infected individuals.
The Kinetic Effects on Thymidine Kinase 2 by Enzyme-Bound dTTP May Explain the Mitochondrial Side Effects of Antiviral Thymidine Analogs
Authors: Wang Liya , Sun Ren , Eriksson Staffan
Published: March 2011

Mitochondrial thymidine kinase 2 (TK2) is a key enzyme in the salvage of pyrimidine deoxynucleosides needed for mitochondrial DNA synthesis. TK2 phosphorylates thymidine (dThd), deoxycytidine (dCyd), and many other antiviral pyrimidine nucleoside analogs. Zidovudine (AZT) is the first nucleoside analog approved for anti-HIV therapy, and it is still used in combination with other drugs. One of the side effects of long-term treatment with nucleoside analogs is mitochondrial DNA depletion, which has been ascribed to competition by AZT for the endogenous dThd phosphorylation carried out by TK2. Here we studied the kinetics of AZT and 3′-fluorothymidine phosphorylation by recombinant human TK2 and the effects of these and other pyrimidine nucleoside analogs on the phosphorylation of dThd and dCyd. Thymidine analogs strongly inhibited dThd phosphorylation but not dCyd phosphorylation, which instead was stimulated ∼30%. We found that recombinant human TK2 contained the feedback inhibitor dTTP in a 1:1 molar ratio and that incubation with dThd and AZT could completely remove the enzyme-bound dTTP, but dCyd was less efficient in this regard. The release of feedback inhibitor by dThd and dThd analogs most likely accounts for the observed kinetics. Similar effects were also observed with native rat liver mitochondrial TK2, strongly indicating a physiologic role for this process, which most likely is an important factor in the mitochondrial toxicity observed with antiviral nucleoside analogs.
Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection
Authors: Cathcart George R. A. , Quinn Derek , Greer Brett , Harriott Pat , Lynas John F. , Gilmore Brendan F. , Walker Brian
Published: March 2011

Pseudomonas elastase (LasB), a metalloprotease virulence factor, is known to play a pivotal role in pseudomonal infection. LasB is secreted at the site of infection, where it exerts a proteolytic action that spans from broad tissue destruction to subtle action on components of the host immune system. The former enhances invasiveness by liberating nutrients for continued growth, while the latter exerts an immunomodulatory effect, manipulating the normal immune response. In addition to the extracellular effects of secreted LasB, it also acts within the bacterial cell to trigger the intracellular pathway that initiates growth as a bacterial biofilm. The key role of LasB in pseudomonal virulence makes it a potential target for the development of an inhibitor as an antimicrobial agent. The concept of inhibition of virulence is a recently established antimicrobial strategy, and such agents have been termed “second-generation” antibiotics. This approach holds promise in that it seeks to attenuate virulence processes without bactericidal action and, hence, without selection pressure for the emergence of resistant strains. A potent inhibitor of LasB,N-mercaptoacetyl-Phe-Tyr-amide (Ki= 41 nM) has been developed, and its ability to block these virulence processes has been assessed. It has been demonstrated that thes compound can completely block the action of LasB on protein targets that are instrumental in biofilm formation and immunomodulation. The novel LasB inhibitor has also been employed in bacterial-cell-based assays, to reduce the growth of pseudomonal biofilms, and to eradicate biofilm completely when used in combination with conventional antibiotics.
Prospective, Open-Label Investigation of the Pharmacokinetics of Daptomycin during Cardiopulmonary Bypass Surgery
Authors: Nguyen Megan H. , Eells Samantha J. , Tan Jennifer , Sheth Corinne T. , Omari Bassam , Flores Margarita , Wang Jeffrey , Miller Loren G.
Published: March 2011

As methicillin-resistant
Staphylococcus aureus
(MRSA) becomes more prevalent, vancomycin is becoming increasingly used as a prophylaxis against surgical-site infections for cardiothoracic surgeries. However, vancomycin administration can be challenging, and the pharmacokinetics of alternative antibiotics in this setting are poorly understood. The primary objective of this investigation was to describe the pharmacokinetics of daptomycin in patients undergoing coronary artery bypass graft surgery. We enrolled 15 patients undergoing coronary artery bypass surgery requiring cardiopulmonary bypass. Each subject was administered a single open-label dose of daptomycin (8 mg/kg of body weight) for surgical prophylaxis. Fourteen daptomycin plasma samples were collected. Safety outcomes between subjects who received daptomycin and 15 control subjects who received the standard-of-care antibiotic were compared. The mean maximal concentration of daptomycin (
C
max
) was 84.4 ± 27.1 μg/ml; the mean daptomycin concentration during the cardiopulmonary bypass procedure was 33.2 ± 11.4 μg/ml and was 30.9 ± 12.7 μg/ml at sternum closure. Mean daptomycin concentrations at 12, 18, 24, and 48 h were 22.7 ± 9.7, 16.2 ± 8.2, 12.0 ± 4.7, and 3.5 ± 2.3 μg/ml, respectively. Mean daptomycin concentrations were consistently above the MIC at which 90% of the tested isolates are inhibited (MIC
90
) for
S. aureus
and
S. epidermidis
during the cardiopulmonary bypass procedure. Daptomycin was not associated with surgical-site infections or differences in adverse events compared to findings for control subjects. We found that a single dose of daptomycin at 8 mg/kg was well tolerated and achieved adequate plasma concentrations against common pathogens associated with surgical-site infections after cardiothoracic surgery. Daptomycin may be considered an alternative surgical prophylaxis antibiotic for patients undergoing cardiothoracic bypass surgery who are unable to receive vancomycin.
Polyphasic Identification and Susceptibility to Seven Antifungals of 102 Aspergillus Isolates Recovered from Immunocompromised Hosts in Greece
Authors: Arabatzis Michael , Kambouris Manousos , Kyprianou Miltiades , Chrysaki Aikaterini , Foustoukou Maria , Kanellopoulou Maria , Kondyli Lydia , Kouppari Georgia , Koutsia-Karouzou Chrysa , Lebessi Evangelia , Pangalis Anastasia , Petinaki Efthimia , Stathi Ageliki , Trikka-Graphakos Eleftheria , Vartzioti Erriketi , Vogiatzi Aliki , Vyzantiadis Timoleon-Achilleas , Zerva Loukia , Velegraki Aristea
Published: March 2011

In this study, the first such study in Greece, we used polyphasic identification combined with antifungal susceptibility study to analyze
Aspergillus
clinical isolates comprising 102 common and rare members of sections Fumigati, Flavi, Terrei, Nidulantes, Nigri, Circumdati, Versicolores, and Usti. High amphotericin B MICs (>2 μg/ml) were found for 17.6% of strains. Itraconazole, posaconazole, and voriconazole MICs of >4 μg/ml were shown in 1%, 5%, and 0% of the isolates, respectively. Anidulafungin, micafungin, and caspofungin minimum effective concentrations (MECs) of ≥2 μg/ml were correspondingly recorded for 4%, 9%, and 33%, respectively, of the strains.
Emergence of Escherichia coli Sequence Type ST131 Carrying both the
bla
GES-5
and
bla
CTX-M-15
Genes
Authors: Kim Juwon , Hong Seong Geun , Bae Il Kwon , Kang Ji Roung , Jeong Seok Hoon , Lee Wookeun , Lee Kyungwon
Published: March 2011

Escherichia coli
clinical isolate BD07372 of sequence type ST131 recovered from a bed sore specimen exhibited high-level resistance to ceftazidime and cefotaxime but exhibited susceptibility to imipenem and meropenem. The isolate harbored two β-lactamase genes, the
bla
CTX-M-15
gene carried by an ∼250-kbp plasmid carrying the FIA and FIC replicons and the
bla
GES-5
gene carried by a class 1 integron in the chromosome.
Induction of Antimalaria Immunity by Pyrimethamine Prophylaxis during Exposure to Sporozoites Is Curtailed by Parasite Resistance
Authors: Friesen Johannes , Borrmann Steffen , Matuschewski Kai
Published: March 2011

Each year, infections with the protozoan parasite
Plasmodium falciparum
kill 1 million people, mostly children in Africa. Intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) reduces the incidence of malaria and aims to prevent mortality in infants, children, and pregnant women. There is contradictory evidence as to whether this strategy may generate additional protection against reinfection beyond the limited duration of the intervention. Previous work established that ablation of either liver-stage maturation or subsequent life cycle conversion by causal prophylactic drugs elicits protective immune responses against reinfections when drugs are no longer present. Here we show in the rodent malaria model that pyrimethamine, a component of SP, inhibits liver-stage development
in vitro
and
in vivo
, confirming the causal prophylactic activity of pyrimethamine. Repeated exposure to high doses of
Plasmodium berghei
sporozoites during pyrimethamine prophylaxis induced complete protection in C57BL/6 mice against challenge with high doses of sporozoites delivered intravenously 35 to 199 days later. Immunizations by infectious mosquito bites induced limited, inoculation-dependent protection against subsequent challenge by infected mosquito bites but provided partial protection against experimental cerebral malaria. Short-term pyrimethamine prophylaxis during intravenous transmission of sporozoites from a pyrimethamine-resistant strain delayed, but did not prevent, blood-stage infection. Our data provide a rationale for the notion of sustained protective efficacy of IPT based on the capacity of arrested, drug-sensitive liver-stage and/or suppressed blood-stage parasites to mount lasting protection.
Characteristics of NDM-1-Producing Escherichia coli Isolates That Belong to the Successful and Virulent Clone ST131
Authors: Peirano Gisele , Schreckenberger Paul C. , Pitout Johann D. D.
Published: March 2011

An NDM-1 carbapenemase-producing
Escherichia coli
isolate of sequence type 131 (ST131) that belonged to phylogenetic group B2 was obtained from a patient with a urinary tract infection who returned to the United States after a recent hospitalization while visiting India. NDM-1-producing
E. coli
ST131 had significantly more virulence factors than NDM-1-producing
E. coli
ST101, previously isolated from a patient in Canada. The presence of NDM β-lactamases in a very successful and virulent
E. coli
sequence type is of concern.
Inhibitory Effect of a Triterpenoid Compound, with or without Alpha Interferon, on Hepatitis C Virus Infection
Authors: Watanabe Takako , Sakamoto Naoya , Nakagawa Mina , Kakinuma Sei , Itsui Yasuhiro , Nishimura-Sakurai Yuki , Ueyama Mayumi , Funaoka Yusuke , Kitazume Akiko , Nitta Sayuri , Kiyohashi Kei , Murakawa Miyako , Azuma Seishin , Tsuchiya Kiichiro , Oooka Shinya , Watanabe Mamoru
Published: March 2011

A lack of patient response to alpha interferon (α-IFN) plus ribavirin (RBV) treatment is a major problem in eliminating hepatitis C virus (HCV). We screened chemical libraries for compounds that enhanced cellular responses to α-IFN and identified a triterpenoid, toosendanin (TSN). Here, we studied the effects and mechanisms of action of TSN on HCV replication and its effect on α-IFN signaling. We treated HCV genotype 1b replicon-expressing cells and HCV-J6/JFH-infected cells with TSN, with or without α-IFN, and the level of HCV replication was quantified. To study the effects of TSN on α-IFN signaling, we detected components of the interferon-stimulated gene factor 3 (ISGF3), phosphorylated signal transducer and activator of transcription 1 (STAT1), and STAT2 by Western blotting analysis; expression levels of mRNA of interferon regulatory factor 9 using real-time reverse transcription-PCR (RT-PCR); and interferon-stimulated response element reporter activity and measured the expression levels of interferon-inducible genes for 2′,5′-oligoadenylate synthetase, MxA, protein kinase R, and p56 using real-time RT-PCR. TSN alone specifically inhibited expression of the HCV replicon (50% effective concentration = 20.6 nM, 50% cytotoxic concentration > 3 μM, selectivity index > 146). Pretreatment with TSN prior to α-IFN treatment was more effective in suppressing HCV replication than treatment with either drug alone. Although TSN alone did not activate the α-IFN pathway, it significantly enhanced the α-IFN-induced increase of phosphorylated STATs, interferon-stimulated response element activation, and interferon-stimulated gene expression. TSN significantly increased baseline expression of interferon regulatory factor 9, a component of interferon-stimulated gene factor 3. Antiviral effects of treatment with α-IFN can be enhanced by pretreatment with TSN. Its mechanisms of action could potentially be important to identify novel molecular targets to treat HCV infection.
Mutations in
gidB
Confer Low-Level Streptomycin Resistance in Mycobacterium tuberculosis
Authors: Wong Sharon Y. , Lee Jong Seok , Kwak Hyun Kyung , Via Laura E. , Boshoff Helena I. M. , Barry Clifton E.
Published: March 2011

The global threat posed by drug-resistant strains of
Mycobacterium tuberculosis
demands a greater understanding of the genetic basis and molecular mechanisms that govern how such strains develop resistance against various antituberculous drugs. In this report, we examine a new genetic basis for resistance to one of the oldest and most widely used second-line drugs employed in tuberculosis therapy, streptomycin (SM). This marker for SM resistance was first discovered on the basis of genomic data obtained from drug-resistant
M. tuberculosis
strains collected in Japan, wherein an association was observed between SM resistance and a mutation in
gidB
, a putative 16S rRNA methyltransferase. By evaluating an isogenic Δ
gidB
mutant strain constructed from strain H37Rv, we demonstrate the causal role of
gidB
in conferring a low-level SM-resistant phenotype in
M. tuberculosis
with a 16-fold increase in the MIC over the parent strain. Among clinical isolates, the modest increase in SM resistance conferred by a
gidB
mutation leads to an MIC distribution of
gidB
mutation-containing strains that spans the recommended SM breakpoint concentration currently used in drug susceptibility testing protocols. As such, some
gidB
mutation-containing isolates are found to be SM sensitive, while others are SM resistant. On the basis of a pharmacodynamic analysis and Monte Carlo simulation, those isolates that are found to be SM sensitive should still respond favorably to SM treatment, while nearly half of those found to be SM resistant will likely respond poorly. This report provides the first microbiological evidence for the contribution of
gidB
in streptomycin resistance and examines the clinical implications of mutations in the
gidB
gene.
Transitions to palliative care in acute hospitals in England: qualitative study: Table 1
Authors: Gott Merryn , Ingleton Christine , Bennett Michael I , Gardiner Clare
Published: March 2011

Objective

To explore how transitions to a palliative care approach are perceived to be managed in acute hospital settings in England.

Design

Qualitative study.

Setting

Secondary or primary care settings in two contrasting areas of England.

Participants

58 health professionals involved in the provision of palliative care in secondary or primary care.

Results

Participants identified that a structured transition to a palliative care approach of the type advocated in UK policy guidance is seldom evident in acute hospital settings. In particular they reported that prognosis is not routinely discussed with inpatients. Achieving consensus among the clinical team about transition to palliative care was seen as fundamental to the transition being effected; however, this was thought to be insufficiently achieved in practice. Secondary care professionals reported that discussions about adopting a palliative care approach to patient management were not often held with patients; primary care professionals confirmed that patients were often discharged from hospital with “false hope” of cure because this information had not been conveyed. Key barriers to ensuring a smooth transition to palliative care included the difficulty of “standing back” in an acute hospital situation, professional hierarchies that limited the ability of junior medical and nursing staff to input into decisions on care, and poor communication.

Conclusion

Significant barriers to implementing a policy of structured transitions to palliative care in acute hospitals were identified by health professionals in both primary and secondary care. These need to be addressed if current UK policy on management of palliative care in acute hospitals is to be established.
T'ai chi for the treatment of osteoarthritis: a systematic review and meta-analysis
Authors: Kang Jung Won , Lee Myeong Soo , Posadzki Paul , Ernst Edzard
Published: March 2011

Objectives

To summarise and critically evaluate the evidence from randomised clinical trials (RCTs) of t'ai chi as a treatment for patients with osteoarthritis (OA).

Design

Eleven databases were searched from their inception to July 2010. RCTs testing t'ai chi against any type of controls in human patients with OA localised in any joints that assessed any type of clinical outcome measures were considered. Two reviewers independently performed the selection of the studies, data abstraction and validations. The risk of bias was assessed using Cochrane criteria.

Results

Nine RCTs met the inclusion criteria, and most of them had significant methodological weaknesses. Six RCTs tested the effects of t'ai chi compared with that of an attention-control programme, a waiting list and routine care or self-help programmes in patients with OA in the knee. The meta-analysis suggested that t'ai chi has favourable effects on pain (n=256; standard mean difference (SMD), −0.79; 95% CI −1.19 to −0.39; p=0.0001; I2=55%), physical function (n=256; SMD, −0.86; 95% CI −1.20 to −0.52; p<0.00001; I2=38%) and joint stiffness (n=256; SMD, −0.53; 95% CI −0.99 to −0.08; p=0.02; I2=67%).

Conclusion

The results are encouraging and suggest that t'ai chi may be effective in controlling pain and improving physical function in patients with OA in the knee. However, owing to the small number of RCTs with a low risk of bias, the evidence that t'ai chi is effective in patients with OA is limited.