bluuebunny/crossref_metadata_2025 huggingface dataset:
TEMAZ/O3 atomic layer deposition process with doubled growth rate and optimized interface properties in metal–insulator–metal capacitors
Authors: Weinreich Wenke , Tauchnitz Tina , Polakowski Patrick , Drescher Maximilian , Riedel Stefan , Sundqvist Jonas , Seidel Konrad , Shirazi Mahdi , Elliott Simon D. , Ohsiek Susanne , Erben Elke , Trui Bernhard
Published: November 2012

ZrO2 is of very high interest for various applications in semiconductor industry especially as high-k dielectric in metal–insulator–metal (MIM) capacitor devices. Further improvement of deposition processes, of material properties, and of integration schemes is essential in order to meet the strict requirements of future devices. In this paper, the authors describe a solution to solve one of the key challenges by reducing the process time of the bottle neck high-k atomic layer deposition (ALD). The authors extensively optimized the most common ALD process used for the ZrO2 deposition (TEMAZ/O3) resulting now in a doubled growth rate compared to the published growth rates of maximum 1 Å/cycle. Chemical reactions explaining the origin of the high growth rate are proposed by theoretical process modelling. At the same time, the outstanding electrical properties of ZrO2 thin films could be preserved. Finally, the integration of the ZrO2 process in MIM capacitor devices with TiN electrodes was evaluated. Thereby, the known effect of TiN bottom electrode oxidation by the O3 process was analyzed and significantly reduced by different integration approaches including wet chemical treatments and ALD process variations. The resulting MIM capacitors show low leakage current and high polarity symmetry.
Can surface cracks and unipolar arcs explain breakdown and gradient limits?
Authors: Insepov Zeke , Norem Jim
Published: November 2012

The authors argue that the physics of unipolar arcs and surface cracks can help understand rf breakdown and vacuum arc data. They outline a model of the basic mechanisms involved in breakdown and explore how the physics of unipolar arcs and cracks can simplify the picture of breakdown and gradient limits in accelerators, tokamaks as well as laser ablation, micrometeorites, and other applications. Cracks are commonly seen in SEM images of arc damage and they are produced as the liquid metal cools. They can produce the required field enhancements to explain field emission data and can produce mechanical failure of the surface that would trigger breakdown events. Unipolar arcs can produce currents sufficient to short out rf structures, and can cause the sort of damage seen in SEM images. They should be unstable, and possibly self-quenching, as seen in optical fluctuations and surface damage. The authors describe some details and consider the predictions of this simple model.
Bipolar resistive switching in an amorphous zinc tin oxide memristive device
Authors: Rajachidambaram Jaana S. , Murali Santosh , Conley John F. , Golledge Stephen L. , Herman Gregory S.
Published: November 2012

The integration of amorphous zinc tin oxide (ZTO) into crossbar memristor device structures has been investigated where asymmetric devices were fabricated with Al (top) and Pt (bottom) electrodes. The authors found that these devices had reproducible bipolar resistive switching with high switching ratios >104 and long retention times of >104 s. Electrical characterization of the devices suggests that both filamentary and interfacial mechanisms are important for device switching. The authors have used secondary ion mass spectrometry to characterize the devices and found that significant interfacial reactions occur at the Al/ZTO interface.
Considerations for further scaling of metal–insulator–metal DRAM capacitors
Authors: Kaczer B. , Clima S. , Tomida K. , Govoreanu B. , Popovici M. , Kim M.-S. , Swerts J. , Belmonte A. , Wang W.-C. , Afanas'ev V. V. , Verhulst A. S. , Pourtois G. , Groeseneken G. , Jurczak M.
Published: November 2012

Effective electron tunneling mass mtunnel is extracted from trap-assisted leakage in Sr-rich strontium titanate and rutile titanium oxide films in metal–insulator–metal (MIM) capacitors and compared with theoretical values obtained from first principles calculations of the imaginary band structure. Optimum orientations of films and stoichiometry impacting mtunnel are also discussed. Because future vertical DRAM integration schemes also stipulate maximum thickness of the MIM capacitor, mtunnel is shown to be a critical parameter influencing intrinsic leakage and potentially limiting further scaling.
Probing the properties of atomic layer deposited ZrO2 films on p-Germanium substrates
Authors: Kerasidou Ariadne P. , Botzakaki Martha A. , Xanthopoulos Nikolaos , Kennou Stella , Ladas Spyridon , Georga Stavroula N. , Krontiras Christoforos A.
Published: November 2012

Zirconium oxide (ZrO2) thin films of 5 and 25 nm thickness were deposited by atomic layer deposition at 250 °C on p-type Ge substrates. The stoichiometry, thickness, and valence band electronic structure of the ZrO2 films were investigated by x-ray and ultraviolet photoelectron spectroscopies. For the electrical characterization, metal-oxide-semiconductor (MOS) capacitive structures (Pt/ZrO2/p-Ge) have been fabricated. Capacitance–voltage and conductance–voltage (C–V, G–V) measurements performed by ac impedance spectroscopy in the temperature range from 153 to 313 K reveal a typical MOS behaviour with moderate frequency dispersion at the accumulation region attributed to leakage currents. For the determination of the leakage currents conduction mechanisms, current density–voltage (J–V) measurements were carried out in the whole temperature range.
Electrical characterization of atomic-layer-deposited hafnium oxide films from hafnium tetrakis(dimethylamide) and water/ozone: Effects of growth temperature, oxygen source, and postdeposition annealing
Authors: García Hector , Castán Helena , Dueñas Salvador , Bailón Luis , Campabadal Francesca , Beldarrain Oihane , Zabala Miguel , González Mireia Bargallo , Rafí Joan Marc
Published: November 2012

The electrical properties of HfO2-based metal–insulator–semiconductor capacitors have been systematically investigated by means of I–V and C–V characteristics, admittance spectroscopy, deep level transient spectroscopy, conductance transient, and flat band voltage transient techniques. Attention is also given to the study of the temperature dependence of the leakage current. HfO2 films were grown on p-type silicon substrates by atomic layer deposition using hafnium tetrakis(dimethylamide) as hafnium precursor, and ozone or water as oxygen precursors. The growth temperature ranged from 150 to 350 °C. Low growth temperatures prevent decomposition and high growth rate, as well as high contamination levels. As a result, the leakage current is lower for lower deposition temperatures. Some of the deposited samples were submitted to a postdeposition annealing at 650 °C in N2 atmosphere, showing a decrease in the leakage current and an increase in the equivalent oxide thickness (EOT), whereas interfacial state density increases and defect density inside the dielectric bulk decreases. Regarding dielectric reliability, in our experimental conditions, HfO2 layers grown at 150 °C exhibit the largest EOT and breakdown voltage. The electrical behaviour is clearly linked with structural properties, and especially with the formation of an interfacial layer between the HfO2 layer and the silicon substrate, as well as with the presence of several impurities.
New approach toward transparent and conductive ZnO by atomic layer deposition: Hydrogen plasma doping
Authors: Thomas Matthew A. , Armstrong Johnathan C. , Cui Jingbiao
Published: November 2012

A hydrogen plasma doping process was combined with the traditional atomic layer deposition (ALD) technique in order to enhance the transparency and conductivity of ZnO films. The hydrogen plasma was included in situ during each ALD cycle and was found to be more effective at producing highly conductive ZnO when used before the H2O vapor pulse that is standard to thermal-ALD processes. Through the hydrogen plasma doping process, the resistivity and carrier concentration of the ALD ZnO films are improved to levels suitable for transparent conductive oxide applications. These favorable electrical properties, combined with improved transparency, make such H-doped ZnO films comparable to some of the best Al-doped ZnO materials achieved with ALD processes in the literature. At thicknesses well below 200 nm, the H-doped ALD ZnO films maintain optimal resistivities near 7 × 10−4 Ω cm along with average transmittance values of ∼92% from 400 to 1000 nm.
Effects of the gas ambient in thermal activation of Mg-doped p-GaN on Hall effect and photoluminescence
Authors: Lu Wei , Aplin David , Clawson Arthur R. , Yu Paul K. L.
Published: November 2012

The effects of thermal annealing in N2, O2, Ar or mixed gas ambient on the electrical and optical properties of metal-organic-chemical-vapor-deposition-grown Mg-doped p-type GaN were investigated by Hall effect and photoluminescence. A systematical study on optimizing annealing gas combination, time, and temperature for achieving high activation efficiency of Mg acceptors was conducted simultaneously. High hole concentration of 9.07 × 1017 cm−3 and low resistivity of 0.622 Ω-cm using the optimized annealing condition were achieved. In agreement with some previous studies, annealing in the mixed gas ambient of N2 and O2 provided significant improvements in activation efficiency of Mg acceptors compared with annealing in pure O2, N2, or Ar. The room- and low-temperature photoluminescence spectra measured from the samples annealed in N2-rich ambient showed significantly higher photoluminescence intensity at both 2.8- and 3.2-eV band transitions. Consistent with the study of others, the experimental results of this study indicated that when annealing in the mixed N2/O2 gas ambient O2 effectively helps activate Mg acceptors by releasing H from Mg-H complexes but also oxidizes GaN; it is likely that the presence of N2 is beneficial in reducing the formation of nitrogen vacancies.
Interface quality of Sc2O3 and Gd2O3 films based metal–insulator–silicon structures using Al, Pt, and Ti gates: Effect of buffer layers and scavenging electrodes
Authors: Gómez Alfonso , Castán Helena , García Héctor , Dueñas Salvador , Bailón Luis , Pampillón María Ángela , Feijoo Pedro Carlos , San Andrés Enrique
Published: November 2012

In this work, the electrical characterization of Gd2O3 and Sc2O3-based metal–insulator–silicon (MIS) structures has been performed using capacitance–voltage, deep level transient spectroscopy, conductance transients, flat-band voltage transients, and current–voltage techniques. High-k films were deposited by high pressure sputtering using Sc and Gd metallic films in a pure Ar plasma and, subsequently, in situ room temperature plasma oxidation in a mixed Ar/O2 atmosphere was performed. Three different metals were used as gate electrodes: aluminium, platinum, and titanium, in order to check electrical differences of the samples and to check the interface scavenging after high-k dielectric deposition. In particular, it was proved that Ti electrode is a well SiO2 interlayer scavenger for both materials. Additionally, the authors observed that the predominant conduction mechanism for these high-k based-MIS structures is Poole–Frenkel emission, as usually reported for high-k dielectrics.
Nonhomogeneous spatial distribution of filamentary leakage current paths in circular area Pt/HfO2/Pt capacitors
Authors: Miranda Enrique , Jiménez David , Suñé Jordi , O'Connor Eamon , Monaghan Scott , Povey Ian , Cherkaoui Karim , Hurley Paul Kennedy
Published: November 2012

Filamentary leakage current paths can occur in circular area Pt/HfO2/Pt capacitors as the result of severe electrical stress. The spatial distribution of these paths is investigated using 2D statistical methods. The filamentary paths are associated with important thermal effects occurring inside the HfO2 layer and manifest externally as a random spot pattern on the top Pt electrode. It is shown in this paper that for the devices with the largest areas significant departures from homogeneity are detected close to the peripheries of the structures. These deviations are observed as a lower density of spots than expected for a homogeneous Poisson process. Although the ultimate reason for this anomaly is still under investigation, our results demonstrate that the complete spatial randomness frequently assumed in oxide reliability analysis should not be taken for granted.
Relation between plaque type, plaque thickness, blood shear stress, and plaque stress in coronary arteries assessed by X‐ray Angiography and Intravascular Ultrasound
Authors: Balocco Simone , Gatta Carlo , Alberti Marina , Carrillo Xavier , Rigla Juan , Radeva Petia
Published: November 2012

Purpose:

Atheromatic plaque progression is affected, among others phenomena, by biomechanical, biochemical, and physiological factors. In this paper, the authors introduce a novel framework able to provide both morphological (vessel radius, plaque thickness, and type) and biomechanical (wall shear stress and Von Mises stress) indices of coronary arteries.

Methods:

First, the approach reconstructs the three‐dimensional morphology of the vessel from intravascular ultrasound (IVUS) and Angiographic sequences, requiring minimal user interaction. Then, a computational pipeline allows to automatically assess fluid‐dynamic and mechanical indices. Ten coronary arteries are analyzed illustrating the capabilities of the tool and confirming previous technical and clinical observations.

Results:

The relations between the arterial indices obtained by IVUS measurement and simulations have been quantitatively analyzed along the whole surface of the artery, extending the analysis of the coronary arteries shown in previous state of the art studies. Additionally, for the first time in the literature, the framework allows the computation of the membrane stresses using a simplified mechanical model of the arterial wall.

Conclusions:

Circumferentially (within a given frame), statistical analysis shows an inverse relation between the wall shear stress and the plaque thickness. At the global level (comparing a frame within the entire vessel), it is observed that heavy plaque accumulations are in general calcified and are located in the areas of the vessel having high wall shear stress. Finally, in their experiments the inverse proportionality between fluid and structural stresses is observed.
Verification of TG‐61 dose for synchrotron‐produced monochromatic x‐ray beams using fluence‐normalized MCNP5 calculations
Authors: Brown Thomas A. D. , Hogstrom Kenneth R. , Alvarez Diane , Matthews Kenneth L. , Ham Kyungmin
Published: November 2012

Purpose:

Ion chamber dosimetry is being used to calibrate dose for cell irradiations designed to investigate photoactivated Auger electron therapy at the Louisiana State University Center for Advanced Microstructures and Devices (CAMD) synchrotron facility. This study performed a dosimetry intercomparison for synchrotron‐produced monochromatic x‐ray beams at 25 and 35 keV. Ion chamber depth‐dose measurements in a polymethylmethacrylate (PMMA) phantom were compared with the product of MCNP5 Monte Carlo calculations of dose per fluence and measured incident fluence.

Methods:

Monochromatic beams of 25 and 35 keV were generated on the tomography beamline at CAMD. A cylindrical, air‐equivalent ion chamber was used to measure the ionization created in a 10 × 10 × 10‐cm3 PMMA phantom for depths from 0.6 to 7.7 cm. The American Association of Physicists in Medicine TG‐61 protocol was applied to convert measured ionization into dose. Photon fluence was determined using a NaI detector to make scattering measurements of the beam from a thin polyethylene target at angles 30°–60°. Differential Compton and Rayleigh scattering cross sections obtained from xraylib, an ANSI C library for x‐ray‐matter interactions, were applied to derive the incident fluence. MCNP5 simulations of the irradiation geometry provided the dose deposition per photon fluence as a function of depth in the phantom.

Results:

At 25 keV the fluence‐normalized MCNP5 dose overestimated the ion‐chamber measured dose by an average of 7.2 ± 3.0%–2.1 ± 3.0% for PMMA depths from 0.6 to 7.7 cm, respectively. At 35 keV the fluence‐normalized MCNP5 dose underestimated the ion‐chamber measured dose by an average of 1.0 ± 3.4%–2.5 ± 3.4%, respectively.

Conclusions:

These results showed that TG‐61 ion chamber dosimetry, used to calibrate dose output for cell irradiations, agreed with fluence‐normalized MCNP5 calculations to within approximately 7% and 3% at 25 and 35 keV, respectively.
Small field segments surrounded by large areas only shielded by a multileaf collimator: Comparison of experiments and dose calculation
Authors: Kron T. , Clivio A. , Vanetti E. , Nicolini G. , Cramb J. , Lonski P. , Cozzi L. , Fogliata A.
Published: November 2012

Purpose:

Complex radiotherapy fields delivered using a tertiary multileaf collimator (MLC) often feature small open segments surrounded by large areas of the beam only shielded by the MLC. The aim of this study was to test the ability of two modern dose calculation algorithms to accurately calculate the dose in these fields which would be common, for example, in volumetric modulated arc treatment (VMAT) and study the impact of variations in dosimetric leaf gap (DLG), focal spot size, and MLC transmission in the beam models.

Methods:

Nine test fields with small fields (0.6–3 cm side length) surrounded by large MLC shielded areas (secondary collimator 12 × 12 cm2) were created using a 6 MV beam from a Varian Clinac iX linear accelerator with 120 leaf MLC. Measurements of output factors and profiles were performed using a diamond detector (PTW) and compared to two dose calculations algorithms anisotropic analytical algorithm [(AAA) and Acuros XB] implemented on a commercial radiotherapy treatment planning system (Varian Eclipse 10).

Results:

Both calculation algorithms predicted output factors within 1% for field sizes larger than 1 × 1 cm2. For smaller fields AAA tended to underestimate the dose. Profiles were predicted well for all fields except for problems of Acuros XB to model the secondary penumbra between MLC shielded fields and the secondary collimator. A focal spot size of 1 mm or less, DLG 1.4 mm and MLC transmission of 1.4% provided a generally good model for our experimental setup.

Conclusions:

AAA and Acuros XB were found to predict the dose under small MLC defined field segments well. While DLG and focal spot affect mostly the penumbra, the choice of correct MLC transmission will be essential to model treatments such as VMAT accurately.
Imaging of cardiac perfusion of free‐breathing small animals using dynamic phase‐correlated micro‐CT
Authors: Sawall Stefan , Kuntz Jan , Socher Michaela , Knaup Michael , Hess Andreas , Bartling Sönke , Kachelrieß Marc
Published: November 2012

Purpose:

Mouse models of cardiac diseases have proven to be a valuable tool in preclinical research. The high cardiac and respiratory rates of free breathing mice prohibit conventionalin vivo cardiac perfusion studies using computed tomography even if gating methods are applied. This makes a sacrification of the animals unavoidable and only allows for the application of ex vivo methods.

Methods:

To overcome this issue the authors propose a low dose scan protocol and an associated reconstruction algorithm that allows forin vivo imaging of cardiac perfusion and associated processes that are retrospectively synchronized to the respiratory and cardiac motion of the animal. The scan protocol consists of repetitive injections of contrast media within several consecutive scans while the ECG, respiratory motion, and timestamp of contrast injection are recorded and synchronized to the acquired projections. The iterative reconstruction algorithm employs a six‐dimensional edge‐preserving filter to provide low‐noise, motion artifact‐free images of the animal examined using the authors’ low dose scan protocol.

Results:

The reconstructions obtained show that the complete temporal bolus evolution can be visualized and quantified in any desired combination of cardiac and respiratory phase including reperfusion phases. The proposed reconstruction method thereby keeps the administered radiation dose at a minimum and thus reduces metabolic inference to the animal allowing for longitudinal studies.

Conclusions:

The authors’ low dose scan protocol and phase‐correlated dynamic reconstruction algorithm allow for an easy and effective way to visualize phase‐correlated perfusion processes in routine laboratory studies using free‐breathing mice.
Dynamically accumulated dose and 4D accumulated dose for moving tumors
Authors: Li Heng , Li Yupeng , Zhang Xiaodong , Li Xiaoqiang , Liu Wei , Gillin Michael T. , Zhu X. Ronald
Published: November 2012

Purpose:

The purpose of this work was to investigate the relationship between dynamically accumulated dose (dynamic dose) and 4D accumulated dose (4D dose) for irradiation of moving tumors, and to quantify the dose uncertainty induced by tumor motion.

Methods:

The authors established that regardless of treatment modality and delivery properties, the dynamic dose will converge to the 4D dose, instead of the 3D static dose, after multiple deliveries. The bounds of dynamic dose, or the maximum estimation error using 4D or static dose, were established for the 4D and static doses, respectively. Numerical simulations were performed (1) to prove the principle that for each phase, after multiple deliveries, the average number of deliveries for any given time converges to the total number of fractions (K) over the number of phases (N); (2) to investigate the dose difference between the 4D and dynamic doses as a function of the number of deliveries for deliveries of a “pulsed beam”; and (3) to investigate the dose difference between 4D dose and dynamic doses as a function of delivery time for deliveries of a “continuous beam.” A Poisson model was developed to estimate the mean dose error as a function of number of deliveries or delivered time for both pulsed beam and continuous beam.

Results:

The numerical simulations confirmed that the number of deliveries for each phase converges toK/N, assuming a random starting phase. Simulations for the pulsed beam and continuous beam also suggested that the dose error is a strong function of the number of deliveries and/or total deliver time and could be a function of the breathing cycle, depending on the mode of delivery. The Poisson model agrees well with the simulation.

Conclusions:

Dynamically accumulated dose will converge to the 4D accumulated dose after multiple deliveries, regardless of treatment modality. Bounds of the dynamic dose could be determined using quantities derived from 4D doses, and the mean dose difference between the dynamic dose and 4D dose as a function of number of deliveries and/or total deliver time was also established.
A GPU tool for efficient, accurate, and realistic simulation of cone beam CT projections
Authors: Jia Xun , Yan Hao , Cerviño Laura , Folkerts Michael , Jiang Steve B.
Published: November 2012

Purpose:

Simulation of x‐ray projection images plays an important role in cone beam CT (CBCT) related research projects, such as the design of reconstruction algorithms or scanners. A projection image contains primary signal, scatter signal, and noise. It is computationally demanding to perform accurate and realistic computations for all of these components. In this work, the authors develop a package on graphics processing unit (GPU), called gDRR, for the accurate and efficient computations of x‐ray projection images in CBCT under clinically realistic conditions.

Methods:

The primary signal is computed by a trilinear ray‐tracing algorithm. A Monte Carlo (MC) simulation is then performed, yielding the primary signal and the scatter signal, both with noise. A denoising process specifically designed for Poisson noise removal is applied to obtain a smooth scatter signal. The noise component is then obtained by combining the difference between the MC primary and the ray‐tracing primary signals, and the difference between the MC simulated scatter and the denoised scatter signals. Finally, a calibration step converts the calculated noise signal into a realistic one by scaling its amplitude according to a specified mAs level. The computations of gDRR include a number of realistic features, e.g., a bowtie filter, a polyenergetic spectrum, and detector response. The implementation is fine‐tuned for a GPU platform to yield high computational efficiency.

Results:

For a typical CBCT projection with a polyenergetic spectrum, the calculation time for the primary signal using the ray‐tracing algorithms is 1.2–2.3 s, while the MC simulations take 28.1–95.3 s, depending on the voxel size. Computation time for all other steps is negligible. The ray‐tracing primary signal matches well with the primary part of the MC simulation result. The MC simulated scatter signal using gDRR is in agreement with EGSnrc results with a relative difference of 3.8%. A noise calibration process is conducted to calibrate gDRR against a real CBCT scanner. The calculated projections are accurate and realistic, such that beam‐hardening artifacts and scatter artifacts can be reproduced using the simulated projections. The noise amplitudes in the CBCT images reconstructed from the simulated projections also agree with those in the measured images at corresponding mAs levels.

Conclusions:

A GPU computational tool, gDRR, has been developed for the accurate and efficient simulations of x‐ray projections of CBCT with realistic configurations.
A patient alignment solution for lung SBRT setups based on a deformable registration technique
Authors: Lu Bo , Mittauer Kathryn , Li Jonathan , Samant Sanjiv , Dagan Roi , Okunieff Paul , Kahler Darren , Liu Chihray
Published: November 2012

Purpose:

In this work, the authors propose a novel registration strategy for translation‐only correction scenarios of lung stereotactic body radiation therapy setups, which can achieve optimal dose coverage for tumors as well as preserve the consistency of registrations with minimal human interference.

Methods:

The proposed solution (centroid‐to‐centroidor CTC solution) uses the average four‐dimensional CT (A4DCT) as the reference CT. The cone‐beam CT (CBCT) is deformed to acquire a new centroid for the internal target volume (ITV) on the CBCT. The registration is then accomplished by simply aligning the centroids of the ITVs between the A4DCT and the CBCT. Sixty‐seven cases using 64 patients (each case is associated with separate isocenters) have been investigated with the CTC method and compared with the conventional gray‐value (G) mode and bone (B) mode registration methods. Dosimetric effects among the tree methods were demonstrated by 18 selected cases. The uncertainty of the CTC method has also been studied.

Results:

The registration results demonstrate the superiority of the CTC method over the other two methods. The differences in the D99 and D95 ITV dose coverage between the CTC method and the original plan is small (within 5%) for all of the selected cases except for one for which the tumor presented significant growth during the period between the CT scan and the treatment. Meanwhile, the dose coverage differences between the original plan and the registration results using either the B or G method are significant, as tumor positions varied dramatically, relative to the rib cage, from their positions on the original CT. The largest differences between the D99 and D95 dose coverage of the ITV using the B or G method versus the original plan are as high as 50%. The D20 differences between any of the methods versus the original plan are all less than 2%.

Conclusions:

The CTC method can generate optimal dose coverage to tumors with much better consistency compared with either the G or B method, and it is especially useful when the tumor position varies greatly from its position on the original CT, relative to the rib cage.
The effect of breathing irregularities on quantitative accuracy of respiratory gated PET/CT
Authors: Teo Boon‐Keng , Saboury Babak , Munbodh Reshma , Scheuermann Joshua , Torigian Drew A. , Zaidi Habib , Alavi Abass
Published: November 2012

Purpose:

4D positron emission tomography and computed tomography (PET/CT) can be used to reduce motion artifacts by correlating the raw PET data with the respiratory cycle. The accuracy of each PET phase is dependent on the reproducibility and consistency of the breathing cycle during acquisition. The objective of this study is to evaluate the impact of breathing amplitude and phase irregularities on the quantitative accuracy of 4D PET standardized uptake value (SUV) measurements. In addition, the magnitude of quantitative errors due to respiratory motion and partial volume error are compared.

Methods:

Phantom studies were performed using spheres filled with18F ranging from 9 to 47 mm in diameter with background activity. Motion was simulated using patient breathing data. The authors compared the accuracy of SUVs derived from gated PET (4 bins and 8 bins, phase‐based) for ideal, average, and highly irregular breathing patterns.

Results:

Under ideal conditions, gated PET produced SUVs that were within (−5.4 ± 5.3)% of the static phantom measurements averaged across all sphere sizes. With breathing irregularities, the quantitative accuracy of gated PET decreased. Gated PET SUVs (best of 4 bins) were (−9.6 ± 13.0)% of the actual value for an average breather and decreased to (−17.1 ± 10.8)% for a highly irregular breather. Without gating, the differences in the SUV from actual value were (−28.5 ± 18.2)%, (−25.9 ± 14.4)%, and (−27.9 ± 18.2)% for the ideal, average, and highly irregular breather, respectively.

Conclusions:

Breathing irregularities reduce the quantitative accuracy of gated PET/CT. Current gated PET techniques may underestimate the actual lesion SUV due to phase assignment errors. Evaluation of respiratory trace is necessary to assess accuracy of data binning and its effect on 4D PET SUVs.
Regulation of Phosphatidylinositol-5-Phosphate Signaling by Pin1 Determines Sensitivity to Oxidative Stress
Authors: Keune Willem-Jan , Jones David R. , Bultsma Yvette , Sommer Lilly , Zhou Xiao Zhen , Lu Kun Ping , Divecha Nullin
Published: November 2012

Increasing the abundance of the phospholipid PtdIns5P protects cells from oxidative stress.
Ceramide Keeps Mast Cells in Check
Authors: Foley John F.
Published: November 2012

A receptor that binds to extracellular ceramide inhibits mast cell activation and allergic responses in vivo.
Neisseria gonorrhoeae Strain with High-Level Resistance to Spectinomycin Due to a Novel Resistance Mechanism (Mutated Ribosomal Protein S5) Verified in Norway
Authors: Unemo Magnus , Golparian Daniel , Skogen Vegard , Olsen Anne Olaug , Moi Harald , Syversen Gaute , Hjelmevoll Stig Ove
Published: November 2012

Gonorrhea may become untreatable, and new treatment options are essential. Verified resistance to spectinomycin is exceedingly rare. However, we describe a high-level spectinomycin-resistant (MIC, >1,024 μg/ml)
Neisseria gonorrhoeae
strain from Norway with a novel resistance mechanism. The resistance determinant was a deletion of codon 27 (valine) and a K28E alteration in the ribosomal protein 5S. The traditional spectinomycin resistance gene (16S rRNA) was wild type. Despite this exceedingly rare finding, spectinomycin available for treatment of ceftriaxone-resistant urogenital gonorrhea would be very valuable.
Raltegravir Pharmacokinetics in Treatment-Naive Patients Is Not Influenced by Race: Results from the Raltegravir Early Therapy in African-Americans Living with HIV (REAL) Study
Authors: Wohl David A. , Dumond Julie B. , Blevins Suzanne , Pittard Donna , Ragan David , Wang Ruili , Massengale Kelley , Walsh Kendall , Floris-Moore Michelle , Eron Joseph J. , Richardson Amy , Hudgens Michael G. , Kashuba Angela D. M.
Published: November 2012

Racial differences in antiretroviral treatment responses remain incompletely explained and may be a consequence of differential pharmacokinetics (PK) associated with race. Raltegravir, an inhibitor of HIV-1 integrase, is commonly used in the treatment of HIV-infected patients, many of whom are African-American. However, there are few data regarding the PK of raltegravir in African-Americans. HIV-infected men and women, self-described as African-American and naive to antiretroviral therapy were treated with raltegravir (RAL) at 400 mg twice a day, plus a fixed dose of tenofovir-emtricitabine (TDF/FTC) at 300 mg/200 mg once daily. Intensive PK sampling was conducted over 24 h at week 4. Drug concentrations at two trough values of 12 and 24 h after dosing (
C
12
and
C
24
), area under the concentration-curve values (AUC), maximum drug concentration (
C
max
), and the time at which this concentration occurred (
T
max
) in plasma were estimated with noncompartmental pharmacokinetic methods and compared to data from a subset of white subjects randomized to the RAL twice a day (plus TDF/FTC) arm of the QDMRK study, a phase III study of the safety and efficacy of once daily versus twice daily RAL in treatment naive patients. A total of 38 African-American participants were enrolled (90% male) into the REAL cohort with the following median baseline characteristics: age of 36 years, body mass index (BMI) of 23 kg/m
2
, and a CD4 cell count of 339/ml. Plasma HIV RNA levels were below 200 copies/ml in 95% of participants at week 4. The characteristics of the 16 white QDMRK study participants were similar, although fewer (69%) were male, the median age was higher (45 years), and BMI was lower (19 kg/m
2
). There was considerable interindividual variability in RAL concentrations in both cohorts. Median
C
12
in REAL was 91 ng/ml (range, 10 to 1,386) and in QDMRK participants was 128 ng/ml (range, 15 to 1,074). The
C
max
median concentration was 1,042 ng/ml (range, 196 to 10,092) for REAL and 1,360 ng/ml (range, 218 to 9,701) for QDMRK. There were no significant differences in any RAL PK parameter between these cohorts of African-American and white individuals. Based on plasma PK, and with similar adherence rates, the performance of RAL among HIV-infected African-Americans should be no different than that of infected patients who are white.
Preclinical Characterization of GS-9669, a Thumb Site II Inhibitor of the Hepatitis C Virus NS5B Polymerase
Authors: Fenaux Martijn , Eng Stacey , Leavitt Stephanie A. , Lee Yu-Jen , Mabery Eric M. , Tian Yang , Byun Daniel , Canales Eda , Clarke Michael O. , Doerffler Edward , Lazerwith Scott E. , Lew Willard , Liu Qi , Mertzman Michael , Morganelli Philip , Xu Lianhong , Ye Hong , Zhang Jennifer , Matles Mike , Murray Bernard P. , Mwangi Judy , Zhang Jingyu , Hashash Ahmad , Krawczyk Steve H. , Bidgood Alison M. , Appleby Todd C. , Watkins William J.
Published: November 2012

GS-9669 is a highly optimized thumb site II nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, with a binding affinity of 1.35 nM for the genotype (GT) 1b protein. It is a selective inhibitor of HCV RNA replication, with a mean 50% effective concentration (EC
50
) of ≤11 nM in genotype 1 and 5 replicon assays, but lacks useful activity against genotypes 2 to 4. The M423T mutation is readily generated clinically upon monotherapy with the thumb site II inhibitors filibuvir and lomibuvir, and it is notable that GS-9669 exhibited only a 3-fold loss in potency against this variant in the genotype 1b replicon. Rather than M423T, resistance predominantly tracks to residues R422K and L419M and residue I482L in GT 1b and 1a replicons, respectively. GS-9669 exhibited at least additive activity in combination with agents encompassing four other direct modes of action (NS3 protease, NS5A, NS5B via an alternative allosteric binding site, and NS5B nucleotide) as well as with alpha interferon or ribavirin in replicon assays. It exhibited high metabolic stability in
in vitro
human liver microsomal assays, which, in combination with its pharmacokinetic profiles in rat, dog, and two monkey species, is predictive of good human pharmacokinetics. GS-9669 is well suited for combination with other orally active, direct-acting antiviral agents in the treatment of genotype 1 chronic HCV infection. (This study has been registered at ClinicalTrials.gov under registration number NCT01431898.)
Pegylated Interferon Fractal Pharmacokinetics: Individualized Dosing for Hepatitis C Virus Infection
Authors: Jain Mamta K. , Pasipanodya Jotam G. , Alder Lara , Lee William M. , Gumbo Tawanda
Published: November 2012

Despite recent advances in hepatitis C virus (HCV) therapeutics, the combination of pegylated interferon and ribavirin (PEGIFN/RBV) remains the cornerstone of treatment. Optimization and individualization of PEGIFN dosing could improve outcomes. Week one PEGIFN serum concentrations in 42 HCV genotype 1-infected patients treated with conventional PEGIFN/RBV were analyzed using multicompartmental pharmacokinetic models. For each patient, pharmacokinetic parameter estimates, weight, age, interleukin-28B (IL-28B) single-nucleotide polymorphism, CD4 count, baseline HCV RNA, gender, race, and HIV status were examined using classification and regression tree analysis to identify factors predictive of sustained viral response (SVR). Survival analysis was performed to compare the time to undetectable viral load in patients with and without the highest scoring predictor. PEGIFN concentrations varied at least 87-fold. Pharmacokinetics were best described by a two-compartment model with an 8.4-h absorption lag. Patient weight correlated with PEGIFN systemic clearance based on fractal geometry relationships. SVR was achieved in 36% of patients; a PEGIFN cumulative 1-week area under the curve (AUC) of ≤0.79 mg · h/liter scored highest in predicting poor response, followed by a weight of ≥93.7 kg. Patients with a PEGIFN AUC of >0.79 mg · h/liter achieved undetectable viral load more rapidly than those with a lower AUC (hazard ratio, 1.63; 95% confidence interval, 1.21 to 2.04). PEGIFN exhibits wide pharmacokinetic variability, mainly driven by patient weight, so that the standard dose may not reach levels needed to achieve SVR. Optimizing dose to patient weight and PEGIFN AUC in the first week offers a solution to improve SVR and to potentially shorten duration of therapy.
Recruitment and Rearrangement of Three Different Genetic Determinants into a Conjugative Plasmid Increase Copper Resistance in Pseudomonas syringae
Authors: Gutiérrez-Barranquero José A. , de Vicente Antonio , Carrión Víctor J. , Sundin George W. , Cazorla Francisco M.
Published: November 2012

We describe the genetic organization of a copper-resistant plasmid containing
copG
and
cusCBA
genes in the plant pathogen
Pseudomonas syringae
. Chromosomal variants of
czcCBA
and a plasmid variant of
cusCBA
were present in different
P. syringae
pathovar strains. Transformation of the copper-sensitive
Pseudomonas syringae
pv. syringae FF5 strain with
copG
or
cusCBA
conferred copper resistance, and quantitative real-time PCR (qRT-PCR) experiments confirmed their induction by copper.
Combinatorial Design of a Highly Efficient Xylose-Utilizing Pathway in Saccharomyces cerevisiae for the Production of Cellulosic Biofuels
Authors: Kim Byoungjin , Du Jing , Eriksen Dawn T. , Zhao Huimin
Published: November 2012

Balancing the flux of a heterologous metabolic pathway by tuning the expression and properties of the pathway enzymes is difficult, but it is critical to realizing the full potential of microbial biotechnology. One prominent example is the metabolic engineering of a
Saccharomyces cerevisiae
strain harboring a heterologous xylose-utilizing pathway for cellulosic-biofuel production, which remains a challenge even after decades of research. Here, we developed a combinatorial pathway-engineering approach to rapidly create a highly efficient xylose-utilizing pathway for ethanol production by exploring various combinations of enzyme homologues with different properties. A library of more than 8,000 xylose utilization pathways was generated using DNA assembler, followed by multitiered screening, which led to the identification of a number of strain-specific combinations of the enzymes for efficient conversion of xylose to ethanol. The balancing of metabolic flux through the xylose utilization pathway was demonstrated by a complete reversal of the major product from xylitol to ethanol with a similar yield and total by-product formation as low as 0.06 g/g xylose without compromising cell growth. The results also suggested that an optimal enzyme combination depends on not only the genotype/phenotype of the host strain, but also the sugar composition of the fermentation medium. This combinatorial approach should be applicable to any heterologous pathway and will be instrumental in the optimization of industrial production of value-added products.
Examination of the Genome-Wide Transcriptional Response of Escherichia coli O157:H7 to Cinnamaldehyde Exposure
Authors: Visvalingam Jeyachchandran , Hernandez-Doria Juan David , Holley Richard A.
Published: November 2012

Cinnamaldehyde is a natural antimicrobial that has been found to be effective against many food-borne pathogens, including
Escherichia coli
O157:H7. Although its antimicrobial effects have been well investigated, limited information is available on its effects at the molecular level. Sublethal treatment at 200 mg/liter cinnamaldehyde inhibited growth of
E. coli
O157:H7 at 37°C and for ≤2 h caused cell elongation, but from 2 to 4 h growth resumed and cells reverted to normal length. To understand this transient behavior, genome-wide transcriptional analysis of
E. coli
O157:H7 was performed at 2 and 4 h of exposure to cinnamaldehyde in conjunction with reverse-phase high-performance liquid chromatography (RP-HPLC) analysis for cinnamaldehyde and other cinnamic compounds. Drastically different gene expression profiles were obtained at 2 and 4 h. RP-HPLC analysis showed that cinnamaldehyde was structurally stable for at least 2 h. At 2 h of exposure, cinnamaldehyde induced expression of many oxidative stress-related genes and repressed expression of DNA, protein, O-antigen, and fimbrial synthetic genes. At 4 h, many cinnamaldehyde-induced repressive effects on
E. coli
O157:H7 gene expression were reversed, and cells became more motile and grew at a slightly higher rate. Data indicated that by 4 h,
E. coli
O157:H7 was able to convert cinnamaldehyde into the less toxic cinnamic alcohol using dehydrogenase/reductase enzymes (YqhD and DkgA). This is the first study to characterize the ability of
E. coli
O157:H7 to convert cinnamaldehyde into cinnamic alcohol which, in turn, showed that the antimicrobial activity of cinnamaldehyde is mainly attributable to its carbonyl aldehyde group.
Wide Distribution and Genetic Diversity of “Candidatus Neoehrlichia mikurensis” in Rodents from China
Authors: Li Hao , Jiang Jiafu , Tang Fang , Sun Yi , Li Zengde , Zhang Weilong , Gong Zhengda , Liu Kun , Yang Hong , Liu Wei , Cao Wuchun
Published: November 2012

“
Candidatus
Neoehrlichia mikurensis” was detected by PCR in 4.0% (34/841) of the rodents tested in this study. The 34 rodents represented nine species from seven regions of China. Phylogenetic analyses based on the partial
groEL
and nearly entire 16S rRNA gene sequences of the agent revealed genetic diversity, which was correlated with its geographic origins.
Gene Identification and Substrate Regulation Provide Insights into Sulfur Accumulation during Bioleaching with the Psychrotolerant Acidophile Acidithiobacillus ferrivorans
Authors: Liljeqvist Maria , Rzhepishevska Olena I. , Dopson Mark
Published: November 2012

The psychrotolerant acidophile
Acidithiobacillus ferrivorans
has been identified from cold environments and has been shown to use ferrous iron and inorganic sulfur compounds as its energy sources. A bioinformatic evaluation presented in this study suggested that
Acidithiobacillus ferrivorans
utilized a ferrous iron oxidation pathway similar to that of the related species
Acidithiobacillus ferrooxidans
. However, the inorganic sulfur oxidation pathway was less clear, since the
Acidithiobacillus ferrivorans
genome contained genes from both
Acidithiobacillus ferrooxidans
and
Acidithiobacillus caldus
encoding enzymes whose assigned functions are redundant. Transcriptional analysis revealed that the
petA1
and
petB1
genes (implicated in ferrous iron oxidation) were downregulated upon growth on the inorganic sulfur compound tetrathionate but were on average 10.5-fold upregulated in the presence of ferrous iron. In contrast, expression of
cyoB1
(involved in inorganic sulfur compound oxidation) was decreased 6.6-fold upon growth on ferrous iron alone. Competition assays between ferrous iron and tetrathionate with
Acidithiobacillus ferrivorans
SS3 precultured on chalcopyrite mineral showed a preference for ferrous iron oxidation over tetrathionate oxidation. Also, pure and mixed cultures of psychrotolerant acidophiles were utilized for the bioleaching of metal sulfide minerals in stirred tank reactors at 5 and 25°C in order to investigate the fate of ferrous iron and inorganic sulfur compounds. Solid sulfur accumulated in bioleaching cultures growing on a chalcopyrite concentrate. Sulfur accumulation halted mineral solubilization, but sulfur was oxidized after metal release had ceased. The data indicated that ferrous iron was preferentially oxidized during growth on chalcopyrite, a finding with important implications for biomining in cold environments.
Detection of Putatively Thermophilic Anaerobic Methanotrophs in Diffuse Hydrothermal Vent Fluids
Authors: Merkel Alexander Y. , Huber Julie A. , Chernyh Nikolay A. , Bonch-Osmolovskaya Elizaveta A. , Lebedinsky Alexander V.
Published: November 2012

The anaerobic oxidation of methane (AOM) is carried out by a globally distributed group of uncultivated
Euryarchaeota
, the anaerobic methanotrophic arachaea (ANME). In this work, we used G+C analysis of 16S rRNA genes to identify a putatively thermophilic ANME group and applied newly designed primers to study its distribution in low-temperature diffuse vent fluids from deep-sea hydrothermal vents. We found that the G+C content of the 16S rRNA genes (
P
GC
) is significantly higher in the ANME-1GBa group than in other ANME groups. Based on the positive correlation between the
P
GC
and optimal growth temperatures (
T
opt
) of archaea, we hypothesize that the ANME-1GBa group is adapted to thrive at high temperatures. We designed specific 16S rRNA gene-targeted primers for the ANME-1 cluster to detect all phylogenetic groups within this cluster, including the deeply branching ANME-1GBa group. The primers were successfully tested both
in silico
and in experiments with sediment samples where ANME-1 phylotypes had previously been detected. The primers were further used to screen for the ANME-1 microorganisms in diffuse vent fluid samples from deep-sea hydrothermal vents in the Pacific Ocean, and sequences belonging to the ANME-1 cluster were detected in four individual vents. Phylotypes belonging to the ANME-1GBa group dominated in clone libraries from three of these vents. Our findings provide evidence of existence of a putatively extremely thermophilic group of methanotrophic archaea that occur in geographically and geologically distinct marine hydrothermal habitats.