bluuebunny/crossref_metadata_2025 huggingface dataset:
In Situ Chemical Oxidation of RDX‐Contaminated Groundwater with Permanganate at the Nebraska Ordnance Plant
Authors: Albano Jeffrey , Comfort Steve D. , Zlotnik Vitaly , Halihan Todd , Burbach Mark , Chokejaroenrat Chanat , Onanong Sathaporn , Clayton Wilson
Published: June 2010

Groundwater beneath the former Nebraska Ordnance Plant (NOP) is contaminated with the explosive hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine (RDX). The current pump and treat facility is preventing offsite migration but does not offer a short‐term solution. Our objective was to quantify the effectiveness of permanganate to degrade RDX in situ. This was accomplished by performing laboratory treatability experiments, aquifer characterization, and a pilot‐scale in situ chemical oxidation (ISCO) demonstration. Treatability experiments confirmed that permanganate could mineralize RDX in the presence of NOP aquifer solids. The pilot‐scale ISCO demonstration was performed using an extraction‐injection well configuration to create a curtain of permanganate between two injection wells. RDX destruction was then quantified as the RDX‐permanganate plume migrated downgradient through a monitoring well field. Electrical resistivity imaging (ERI) was used to identify the subsurface distribution of permanganate after injection. Results showed that RDX concentrations temporally decreased in wells closest to the injection wells by 70% to 80%. Observed degradation rates (0.12 and 0.087/d) were lower than those observed under laboratory batch conditions at 11.5 °C (0.20/d) and resulted from lower than projected permanganate concentrations. Both ERI and spatial electrical conductivity measurements verified that permanganate distribution was not uniform throughout the 6.1‐m (20 feet) well screens and that groundwater sampling captured both treated and nontreated groundwater during pumping. Although heterogeneous flow paths precluded a uniform permanganate distribution, pilot‐scale results provided proof‐of‐concept that permanganate can degrade RDX in situ and support permanganate as a possible remedial treatment for RDX‐contaminated groundwater.
Design of Potent IGF1‐R Inhibitors Related to Bis‐azaindoles
Authors: Nemecek Conception , Metz William A. , Wentzler Sylvie , Ding Fa‐Xiang , Venot Corinne , Souaille Catherine , Dagallier Anne , Maignan Sébastien , Guilloteau Jean‐Pierre , Bernard François , Henry Alain , Grapinet Sandrine , Lesuisse Dominique
Published: June 2010

From an azaindole lead, identified in high throughput screen, a series of potent bis‐azaindole inhibitors of IGF1‐R have been synthesized using rational drug design and SAR based on a in silico binding mode hypothesis. Although the resulting compounds produced the expected improved potency, the model was not validated by the co‐crystallization experiments with IGF1‐R.
Prevalence of adverse food reactions in 130 dogs in Italy with dermatological signs: a retrospective study
Authors: Proverbio D. , Perego R. , Spada E. , Ferro E.
Published: June 2010

Objectives: To determine the prevalence of adverse food reactions (AFRs) in dogs with dermatological signs presented to the referral dermatological clinic of the University of Milan.

Methods: The medical records of dogs with dermatological signs were reviewed. Prevalence of AFRs was calculated. Owner and clinician pruritus scores were compared. Breed, sex and age predisposition were statistically tested, as was the association between AFR and selected clinical features.

Results: The prevalence of AFRs in dogs with dermatological signs was 12% (16 of 130). AFR was diagnosed in 26% of dogs with allergic disease and 48% of those subjected to a dietary trial. There was a significant association between AFRs and early onset of clinical signs (<1 year) (OR=3·8; P=0·0221, 95% CI=1·27 to 11·16). There was a significant association between AFRs and both otitis externa (OR=5·9; P=0·0015, 95% CI=2 to 17·9) and perianal fistula (OR=26·1; P=0·0058, 95% CI=2·52 to 269·4), although all dogs with perianal fistulas were German shepherd dogs.

ClinicalSignificance: The prevalence of AFRs in the study population was higher than most reported values. Further studies are warranted to investigate the true prevalence of AFR and its possible association with perianal fistula and other potential markers.
Nutritionally Important Starch Fractions of Rice Cultivars Grown in Southern United States
Authors: Patindol James A. , Guraya Harmeet S. , Champagne Elaine T. , McClung Anna M.
Published: June 2010

Abstract:  Dietary starches can be classified into 3 major fractions according to in vitro digestibility as rapidly digestible (RDS), slowly digestible (SDS), and resistant starch (RS). Literature indicates that SDS and/or RS have significant implications on human health, particularly glucose metabolism, diabetes management, colon cancer prevention, mental performance, and satiety. In this study, the nutritionally important starch fractions (RDS, SDS, and RS) in cooked rice were assayed in vitro, making use of 16 cultivars grown in 5 southern U.S. rice growing locations (Arkansas, Louisiana, Mississippi, Missouri, and Texas). RDS, SDS, and RS were 52.4% to 69.4%, 10.3% to 26.6%, and 1.2% to 9.0%, respectively, of cooked rice dry weight. Cultivar, location, and cultivar‐by‐location interaction contributed to the variations in RDS, SDS, and RS contents. Means pooled across locations indicated that SDS was higher for the Louisiana samples than those from Texas, whereas RS was higher for the Texas samples than those from Arkansas, Louisiana, and Mississippi. Some cultivars were identified to possess high levels of RS (for example, Bowman and Rondo) or SDS (for example, Dixiebelle and Tesanai‐2) and were also stable across growing locations. Apparent amylose content correlated positively with RS (n = 80, r = 0.54, P ≤ 0.001), negatively with RDS (n = 80, r =−0.29, P ≤ 0.05), and insignificantly with SDS (n = 80, r = 0.21, P > 0.05). RS and SDS were not collinear (n = 80, r =−0.18, P > 0.05); it does not follow that a cultivar high in RS will also be high in SDS, and vice versa. The observed differences in RDS, SDS, and RS among the samples are indicative of wide genetic diversity in rice.
Transient cavitation in high-quality-factor resonators at high static pressures
Authors: Gaitan D. Felipe , Tessien Ross A. , Hiller Robert A. , Gutierrez Joel , Scott Corey , Tardif Henry , Callahan Brant , Matula Thomas J. , Crum Lawrence A. , Holt R. Glynn , Church Charles C. , Raymond Jason L.
Published: June 2010

It is well known that cavitation collapse can generate intense concentrations of mechanical energy, sufficient to erode even the hardest metals and to generate light emissions visible to the naked eye [sonoluminescence (SL)]. Considerable attention has been devoted to the phenomenon of “single bubble sonoluminescence” (SBSL) in which a single stable cavitation bubble radiates light flashes each and every acoustic cycle. Most of these studies involve acoustic resonators in which the ambient pressure is near 0.1 MPa (1 bar), and with acoustic driving pressures on the order of 0.1 MPa. This study describes a high-quality factor, spherical resonator capable of achieving acoustic cavitation at ambient pressures in excess of 30 MPa (300 bars). This system generates bursts of violent inertial cavitation events lasting only a few milliseconds (hundreds of acoustic cycles), in contrast with the repetitive cavitation events (lasting several minutes) observed in SBSL; accordingly, these events are described as “inertial transient cavitation.” Cavitation observed in this high pressure resonator is characterized by flashes of light with intensities up to 1000 times brighter than SBSL flashes, as well as spherical shock waves with amplitudes exceeding 30 MPa at the resonator wall. Both SL and shock amplitudes increase with static pressure.
A deterministic (non-stochastic) low frequency method for geoacoustic inversion
Authors: Tolstoy A.
Published: June 2010

It is well known that multiple frequency sources are necessary for accurate geoacoustic inversion. This paper presents an inversion method which uses the low frequency (LF) spectrum only to estimate bottom properties even in the presence of expected errors in source location, phone depths, and ocean sound-speed profiles. Matched field processing (MFP) along a vertical array is used. The LF method first conducts an exhaustive search of the (five) parameter search space (sediment thickness, sound-speed at the top of the sediment layer, the sediment layer sound-speed gradient, the half-space sound-speed, and water depth) at 25 Hz and continues by retaining only the high MFP value parameter combinations. Next, frequency is slowly increased while again retaining only the high value combinations. At each stage of the process, only those parameter combinations which give high MFP values at all previous LF predictions are considered (an ever shrinking set). It is important to note that a complete search of each relevant parameter space seems to be necessary not only at multiple (sequential) frequencies but also at multiple ranges in order to eliminate sidelobes, i.e., false solutions. Even so, there are no mathematical guarantees that one final, unique “solution” will be found.
Monaural temporal integration and temporally selective listening in children and adults
Authors: He Shuman , Buss Emily , Hall Joseph W.
Published: June 2010

This study used two paradigms to investigate the development of temporal integration and temporally selective listening. Experiment 1 measured detection as a function of duration for a pure tone at 1625 or 6500 Hz. At both frequencies thresholds of children younger than 7 years old were higher than those for older children and adults. The pattern of temporal integration was similar across groups for the 6500-Hz signal, but younger children showed relatively more temporal integration for the 1625-Hz signal due to high thresholds for the briefest 1625-Hz signal. Experiment 2 measured detection thresholds for one or for three brief tone pips presented in a noise masker. In one set of conditions, the noise masker consisted of 100-ms steady bursts interleaved with 10-ms temporal gaps. In other conditions, the level of the central 50 ms of the 100-ms masking noise bursts was adjusted by either +6 or −6 dB. Children showed higher thresholds but similar temporal integration compared with adults. Overall, these data suggest that children are less efficient than adults in weighting the output of the monaural temporal window at 1625 but not 6500 Hz. Children are efficient in combining energy from brief temporal epochs that are separated by noise.
Updating signal typing in voice: Addition of type 4 signals
Authors: Sprecher Alicia , Olszewski Aleksandra , Jiang Jack J. , Zhang Yu
Published: June 2010

The addition of a fourth type of voice to Titze’s voice classification scheme is proposed. This fourth voice type is characterized by primarily stochastic noise behavior and is therefore unsuitable for both perturbation and correlation dimension analysis. Forty voice samples were classified into the proposed four types using narrowband spectrograms. Acoustic, perceptual, and correlation dimension analyses were completed for all voice samples. Perturbation measures tended to increase with voice type. Based on reliability cutoffs, the type 1 and type 2 voices were considered suitable for perturbation analysis. Measures of unreliability were higher for type 3 and 4 voices. Correlation dimension analyses increased significantly with signal type as indicated by a one-way analysis of variance. Notably, correlation dimension analysis could not quantify the type 4 voices. The proposed fourth voice type represents a subset of voices dominated by noise behavior. Current measures capable of evaluating type 4 voices provide only qualitative data (spectrograms, perceptual analysis, and an infinite correlation dimension). Type 4 voices are highly complex and the development of objective measures capable of analyzing these voices remains a topic of future investigation.
Ultrasonic wave propagation in stereo-lithographical bone replicas
Authors: Aygün Haydar , Attenborough Keith , Lauriks Walter , Langton Christian M.
Published: June 2010

Predictions of a modified anisotropic Biot–Allard theory are compared with measurements of pulses centered on 100 kHz and 1 MHz transmitted through water-saturated stereo-lithographical bone replicas. The replicas are 13 times larger than the original bone samples. Despite the expected effects of scattering, which is neglected in the theory, at 100 kHz the predicted and measured transmitted waveforms are similar. However, the magnitude of the leading negative edge of the waveform is overpredicted, and the trailing parts of the waveforms are not predicted well. At 1 MHz, although there are differences in amplitudes, the theory predicts that the transmitted waveform is almost a scaled version of that incident in conformity with the data.
On sound transmission loss across a Helmholtz resonator in a low Mach number flow duct
Authors: Tang S. K.
Published: June 2010

A simplified physical model, which described the generation of sound by a Helmholtz resonator upon flow excitation at its neck, was developed in the present investigation to study the drop in sound power transmission loss across such a resonator mounted on the wall of a duct conveying a low Mach number mean flow. Experiments were derived to validate the model. Mitigation methods derived according to the model were also tested experimentally. Results showed that the simplified model gave predictions which agreed with experimental observations. The proposed mitigation methods were also proved to be effective for building services application. It was also found that the sound intensity generated by the flow excited resonator scaled with approximately the ninth power of the flow velocity inside the duct.
Auditory and visual orienting responses in listeners with and without hearing-impairment
Authors: Brimijoin W. Owen , McShefferty David , Akeroyd Michael A.
Published: June 2010

Head movements are intimately involved in sound localization and may provide information that could aid an impaired auditory system. Using an infrared camera system, head position and orientation was measured for 17 normal-hearing and 14 hearing-impaired listeners seated at the center of a ring of loudspeakers. Listeners were asked to orient their heads as quickly as was comfortable toward a sequence of visual targets, or were blindfolded and asked to orient toward a sequence of loudspeakers playing a short sentence. To attempt to elicit natural orienting responses, listeners were not asked to reorient their heads to the 0° loudspeaker between trials. The results demonstrate that hearing-impairment is associated with several changes in orienting responses. Hearing-impaired listeners showed a larger difference in auditory versus visual fixation position and a substantial increase in initial and fixation latency for auditory targets. Peak velocity reached roughly 140°/s in both groups, corresponding to a rate of change of approximately 1 μs of interaural time difference per millisecond of time. Most notably, hearing-impairment was associated with a large change in the complexity of the movement, changing from smooth sigmoidal trajectories to ones characterized by abruptly changing velocities, directional reversals, and frequent fixation angle corrections.
Model calculations of the underwater noise of breaking waves and comparison with experiment
Authors: Deane Grant B. , Stokes M. Dale
Published: June 2010

A model for the underwater noise of whitecaps is presented and compared with the noise measured beneath plunging seawater laboratory waves. The noise from a few hundred hertz up to at least 80 kHz is assumed to be due to the pulses of sound radiated by bubbles formed within a breaking wave crest. The total noise level and its dependence on frequency are a function of bubble creation rate, bubble damping factor and an ‘acoustical skin depth’ associated with scattering and absorption by the bubble plume formed within the crest. Calculation of breaking wave noise is made using estimates of these factors, which are made independently of the noise itself. The results are in good agreement with wave noise measured in a laboratory flume when compensated for reverberation. A closed-form, analytical expression for the wave noise is presented, which shows a −11/6 power-law dependence of noise level on frequency, in good agreement with the −10/6 scaling law commonly observed in the open ocean.
Internal waves as a proposed mechanism for increasing ambient noise in an increasingly acidic ocean
Authors: Rouseff Daniel , Tang Dajun
Published: June 2010

The effect on the ambient noise level in shallow water of the ocean growing more acidic is modeled. Because most noise sources are near the surface, high-order acoustic modes are preferentially excited. Linear internal waves, however, can scatter the noise into the low-order, low-loss modes most affected by the changes in acidity. The model uses transport theory to couple the modes and assumes an isotropic distribution for the noise sources. For a scenario typical of the East China Sea, the noise at 3 kHz is predicted to increase by 30%, about one decibel, as the pH decreases from 8.0 to 7.4.
Measurement of thickness or plate velocity using ambient vibrations
Authors: Ing Ros K. , Etaix Nicolas , Leblanc Alexandre , Fink Mathias
Published: June 2010

Assuming the Green’s function is linear with respect to the boundary conditions, it is demonstrated that flexural waves detected by a point receiver and a circular array of point receivers centered on the previous receiver are proportional regardless location of the source and geometry of the plate. Therefore determination of plate velocity or thickness is done from the measurement of ambient vibrations without using any emitter. Experimental results obtained with a plate of non regular geometry excited with a single transducer or a remote loudspeaker are shown to verify the theoretical approach.
The northern Cascadia subduction zone at Vancouver Island: seismic structure and tectonic history
Authors: Hyndman R. D. , Yorath C. J. , Clowes R. M. , Davis E. E.
Published: June 2010

The structure and Tertiary tectonic history of the northern Cascadia subduction zone have been delineated by a series of new multichannel seismic lines acquired across the continental shelf to the deep sea, combined with adjacent land multichannel seismic data and results from a wide range of other geophysical and geological studies. The top of the downgoing oceanic crust is imaged for a remarkable distance downdip from the deep ocean basin to a depth of 40 km beneath Vancouver Island. The reflection depths are in good agreement with seismic refraction models and Benioff–Wadati seismicity. Two broad reflective bands imaged as dipping gently landward at depths of about 15 and 30 km on the land lines merge to a single reflector band offshore. They may represent underplated oceanic material or, alternatively, they may not be structural but may be zones of contrasting physical properties, perhaps representing trapped fluid. Two narrow terranes, the Mesozoic marine sedimentary Pacific Rim Terrane and the Eocene marine volcanic Crescent Terrane, have been thrust beneath, and accreted to, the margin in the Eocene, about 42 Ma, near the start of the present phase of subduction. They provide a landward-dipping backstop to the large sediment wedge accreted since that time. The deformation front is characterized by mainly landward-dipping thrust faults that cut close to basement. This result and the mass balance of the incoming sediment compared with that present in the accreted wedge suggest that there is little subduction of sediment into the mantle. The Tofino Basin sediments, up to 4 km in thickness, have been deposited on the continental shelf over the accreted terranes and the developing accretionary wedge.
Ridge subduction: kinematics and implications for the nature of mantle upwelling
Authors: Farrar Edward , Dixon John M.
Published: June 2010

Ridge subduction follows the approach of an oceanic spreading centre towards a trench and subduction of the leading oceanic plate beneath the overriding plate. There are four possible kinematic scenarios: (1) welding of the trailing and overriding plates (e.g., Aluk–Antarctic Ridge beneath Antarctica); (2) slower subduction of the trailing plate (e.g., Nazca–Antarctic Ridge beneath Chile and Pacific–Izanagi Ridge beneath Japan); (3) transform motion between the trailing and overriding plates (e.g., San Andreas Transform); or (4) divergence between the overriding and trailing plates (e.g., Pacific – North America). In case 4, the divergence may be accommodated in two ways: the overriding plate may be stretched (e.g., Basin and Range Province extension, which has brought the continental margin into collinearity (and, therefore, transform motion) with the Pacific – North America relative motion); or divergence may occur at the continental margin and be manifest as a change in rate and direction of sea-floor spreading because the pair of spreading plates changes (e.g., from Pacific–Farallon to Pacific – North America), spawning a secondary spreading centre (i.e., Gorda – Juan de Fuca – Explorer ridge system) that migrates away from the overriding plate.Mantle upwelling associated with sea-floor spreading ridges is widely regarded as a passive consequence, rather than an active cause, of plate divergence. Geological and geophysical phenomena attendant to ridge–trench interaction suggest that regardless of the kinematic relations among the three plates, a thermal anomaly formerly associated with the ridge migrates beneath the overriding plate. The persistence of this thermal anomaly demonstrates that active mantle upwelling may continue for tens of millions of years after ridge subduction. Thus, regardless of whether the mantle upwelling was active or passive at its origin, it becomes active if the spreading continues for sufficient time and, thus, must contribute to the driving mechanism of plate tectonics.
A NEW INTERIOR PENALTY DISCONTINUOUS GALERKIN METHOD FOR THE REISSNER–MINDLIN MODEL
Authors: BÖSING PAULO R. , MADUREIRA ALEXANDRE L. , MOZOLEVSKI IGOR
Published: June 2010

We introduce an interior penalty discontinuous Galerkin finite element method for the Reissner–Mindlin plate model that, as the plate's half-thickness ϵ tends to zero, recovers a hp interior penalty discontinuous Galerkin finite element methods for biharmonic equation. Our method does not introduce shear as an extra unknown, and does not need reduced integration techniques. We develop the a priori error analysis of these methods and prove error bounds that are optimal in h and uniform in ϵ. Numerical tests, that confirm our predictions, are provided.
ON THE UNIVERSALITY OF BARYONS AND DARK MATTER DENSITY PROFILES
Authors: POPOLO ANTONINO DEL , YEŞILYURT IBRAHIM SAFFET
Published: June 2010

We study the redshift and mass dependence of the inner slopes of relaxed ΛCDM dark matter haloes with and without baryons. We find that in the density profiles composed just of dark matter, the mass and redshift dependence of the slope is very slight, while the inner logarithmic density slope of dark matter haloes with baryons has a significant dependence on the halo mass and redshift. Slopes of structures increase with increasing mass and redshift, and this trend reduces from galaxies to clusters. The results of the present paper argue against universality of density profiles composed of dark matter and baryons, and confirm claims of a systematic variation in profile shape with halo mass, for dark matter haloes.
INTERACTING HOLOGRAPHIC TACHYON MODEL OF DARK ENERGY
Authors: ROZAS-FERNÁNDEZ ALBERTO , BRIZUELA DAVID , CRUZ NORMAN
Published: June 2010

We propose a holographic tachyon model of dark energy with interaction between the components of the dark sector. The correspondence between the tachyon field and the holographic dark energy densities allows the reconstruction of the potential and the dynamics of the tachyon scalar field in a flat Friedmann–Robertson–Walker universe. We show that this model can describe the observed accelerated expansion of our universe with a parameter space given by the most recent observational results.
COSMIC DYNAMICS IN CHAMELEON COSMOLOGY
Authors: FARAJOLLAHI H. , SALEHI A.
Published: June 2010

We study in this paper chameleon cosmology applied to Friedmann–Robertson–Walker space, which gives rise to the equation of state (EoS) parameter larger than -1 in the past and less than -1 today, satisfying current observations. We also study cosmological constraints on the model using the time evolution of the cosmological redshift of distant sources, which directly probes the expansion history of the universe. Due to the evolution of the universe's expansion rate, the model-independent cosmological redshift drift (CRD) test is expected to experience a small, systematic drift as a function of time. The model is supported by the observational data obtained from the test.
Virus Entry by Endocytosis
Authors: Mercer Jason , Schelhaas Mario , Helenius Ari
Published: June 2010

Although viruses are simple in structure and composition, their interactions with host cells are complex. Merely to gain entry, animal viruses make use of a repertoire of cellular processes that involve hundreds of cellular proteins. Although some viruses have the capacity to penetrate into the cytosol directly through the plasma membrane, most depend on endocytic uptake, vesicular transport through the cytoplasm, and delivery to endosomes and other intracellular organelles. The internalization may involve clathrin-mediated endocytosis (CME), macropinocytosis, caveolar/lipid raft-mediated endocytosis, or a variety of other still poorly characterized mechanisms. This review focuses on the cell biology of virus entry and the different strategies and endocytic mechanisms used by animal viruses.
Functions and Regulation of RNA Editing by ADAR Deaminases
Authors: Nishikura Kazuko
Published: June 2010

One type of RNA editing converts adenosines to inosines (A→I editing) in double-stranded RNA (dsRNA) substrates. A→I RNA editing is mediated by adenosine deaminase acting on RNA (ADAR) enzymes. A→I RNA editing of protein-coding sequences of a limited number of mammalian genes results in recoding and subsequent alterations of their functions. However, A→I RNA editing most frequently targets repetitive RNA sequences located within introns and 5′ and 3′ untranslated regions (UTRs). Although the biological significance of noncoding RNA editing remains largely unknown, several possibilities, including its role in the control of endogenous short interfering RNAs (esiRNAs), have been proposed. Furthermore, recent studies have revealed that the biogenesis and functions of certain microRNAs (miRNAs) are regulated by the editing of their precursors. Here, I review the recent findings that indicate new functions for A→I editing in the regulation of noncoding RNAs and for interactions between RNA editing and RNA interference mechanisms.
Nanomaterials Based on DNA
Authors: Seeman Nadrian C.
Published: June 2010

The combination of synthetic stable branched DNA and sticky-ended cohesion has led to the development of structural DNA nanotechnology over the past 30 years. The basis of this enterprise is that it is possible to construct novel DNA-based materials by combining these features in a self-assembly protocol. Thus, simple branched molecules lead directly to the construction of polyhedrons, whose edges consist of double helical DNA and whose vertices correspond to the branch points. Stiffer branched motifs can be used to produce self-assembled two-dimensional and three-dimensional periodic lattices of DNA (crystals). DNA has also been used to make a variety of nanomechanical devices, including molecules that change their shapes and molecules that can walk along a DNA sidewalk. Devices have been incorporated into two-dimensional DNA arrangements; sequence-dependent devices are driven by increases in nucleotide pairing at each step in their machine cycles.
Somatic Mitochondrial DNA Mutations in Mammalian Aging
Authors: Larsson Nils-Göran
Published: June 2010

Mitochondrial dysfunction is heavily implicated in the multifactorial aging process. Aging humans have increased levels of somatic mtDNA mutations that tend to undergo clonal expansion to cause mosaic respiratory chain deficiency in various tissues, such as heart, brain, skeletal muscle, and gut. Genetic mouse models have shown that somatic mtDNA mutations and cell type-specific respiratory chain dysfunction can cause a variety of phenotypes associated with aging and age-related disease. There is thus strong observational and experimental evidence to implicate somatic mtDNA mutations and mosaic respiratory chain dysfunction in the mammalian aging process. The hypothesis that somatic mtDNA mutations are generated by oxidative damage has not been conclusively proven. Emerging data instead suggest that the inherent error rate of mitochondrial DNA (mtDNA) polymerase γ (Pol γ) may be responsible for the majority of somatic mtDNA mutations. The roles for mtDNA damage and replication errors in aging need to be further experimentally addressed.
Structure and Dynamics of a Processive Brownian Motor: The Translating Ribosome
Authors: Frank Joachim , Gonzalez Ruben L.
Published: June 2010

There is mounting evidence indicating that protein synthesis is driven and regulated by mechanisms that direct stochastic, large-scale conformational fluctuations of the translational apparatus. This mechanistic paradigm implies that a free-energy landscape governs the conformational states that are accessible to and sampled by the translating ribosome. This scenario presents interdependent opportunities and challenges for structural and dynamic studies of protein synthesis. Indeed, the synergism between cryogenic electron microscopic and X-ray crystallographic structural studies, on the one hand, and single-molecule fluorescence resonance energy transfer (smFRET) dynamic studies, on the other, is emerging as a powerful means for investigating the complex free-energy landscape of the translating ribosome and uncovering the mechanisms that direct the stochastic conformational fluctuations of the translational machinery. In this review, we highlight the principal insights obtained from cryogenic electron microscopic, X-ray crystallographic, and smFRET studies of the elongation stage of protein synthesis and outline the emerging themes, questions, and challenges that lie ahead in mechanistic studies of translation.
Bacterial Nitric Oxide Synthases
Authors: Crane Brian R. , Sudhamsu Jawahar , Patel Bhumit A.
Published: June 2010

Nitric oxide synthases (NOSs) are multidomain metalloproteins first identified in mammals as being responsible for the synthesis of the wide-spread signaling and protective agent nitric oxide (NO). Over the past 10 years, prokaryotic proteins that are homologous to animal NOSs have been identified and characterized, both in terms of enzymology and biological function. Despite some interesting differences in cofactor utilization and redox partners, the bacterial enzymes are in many ways similar to their mammalian NOS (mNOS) counterparts and, as such, have provided insight into the structural and catalytic properties of the NOS family. In particular, spectroscopic studies of thermostable bacterial NOSs have revealed key oxyheme intermediates involved in the oxidation of substrate L-arginine (Arg) to product NO. The biological functions of some bacterial NOSs have only more recently come to light. These studies disclose new roles for NO in biology, such as taking part in toxin biosynthesis, protection against oxidative stress, and regulation of recovery from radiation damage.
Botulinum Neurotoxin: A Marvel of Protein Design
Authors: Montal Mauricio
Published: June 2010

Botulinum neurotoxin (BoNT), the causative agent of botulism, is acknowledged to be the most poisonous protein known. BoNT proteases disable synaptic vesicle exocytosis by cleaving their cytosolic SNARE (soluble NSF attachment protein receptor) substrates. BoNT is a modular nanomachine: an N-terminal Zn2+-metalloprotease, which cleaves the SNAREs; a central helical protein-conducting channel, which chaperones the protease across endosomes; and a C-terminal receptor-binding module, consisting of two subdomains that determine target specificity by binding to a ganglioside and a protein receptor on the cell surface and triggering endocytosis. For BoNT, functional complexity emerges from its modular design and the tight interplay between its component modules—a partnership with consequences that surpass the simple sum of the individual component's action. BoNTs exploit this design at each step of the intoxication process, thereby achieving an exquisite toxicity. This review summarizes current knowledge on the structure of individual modules and presents mechanistic insights into how this protein machine evolved to this level of sophistication. Understanding the design principles underpinning the function of such a dynamic modular protein remains a challenging task.
Amphipols, Nanodiscs, and Fluorinated Surfactants: Three Nonconventional Approaches to Studying Membrane Proteins in Aqueous Solutions
Authors: Popot Jean-Luc
Published: June 2010

Membrane proteins (MPs) are usually handled in aqueous solutions as protein/detergent complexes. Detergents, however, tend to be inactivating. This situation has prompted the design of alternative surfactants that can be substituted for detergents once target proteins have been extracted from biological membranes and that keep them soluble in aqueous buffers while stabilizing them. The present review focuses on three such systems: Amphipols (APols) are amphipathic polymers that adsorb onto the hydrophobic transmembrane surface of MPs; nanodiscs (NDs) are small patches of lipid bilayer whose rim is stabilized by amphipathic proteins; fluorinated surfactants (FSs) resemble detergents but interfere less than detergents do with stabilizing protein/protein and protein/lipid interactions. The structure and properties of each of these three systems are described, as well as those of the complexes they form with MPs. Their respective usefulness, constraints, and prospects for functional and structural studies of MPs are discussed.
Biochemical Principles of Small RNA Pathways
Authors: Liu Qinghua , Paroo Zain
Published: June 2010

The discovery of RNA interference (RNAi) is among the most significant biomedical breakthroughs in recent history. Multiple classes of small RNA, including small-interfering RNA (siRNA), micro-RNA (miRNA), and piwi-interacting RNA (piRNA), play important roles in many fundamental biological and disease processes. Collective studies in multiple organisms, including plants, Drosophila, Caenorhabditis elegans, and mammals indicate that these pathways are highly conserved throughout evolution. Thus, scientists across disciplines have found novel pathways to unravel, new insights in probing pathology, and nascent technologies to develop. The field of RNAi also provides a clear framework for understanding fundamental principles of biochemistry. The current review highlights elegant, reason-based experimentation in discovering RNA-directed biological phenomena and the importance of robust assay development in translating these observations into mechanistic understanding. This biochemical template also provides a conceptual framework for overcoming emerging challenges in the field and for understanding an expanding small RNA world.
The Mechanism of Double-Strand DNA Break Repair by the Nonhomologous DNA End-Joining Pathway
Authors: Lieber Michael R.
Published: June 2010

Double-strand DNA breaks are common events in eukaryotic cells, and there are two major pathways for repairing them: homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). The various causes of double-strand breaks (DSBs) result in a diverse chemistry of DNA ends that must be repaired. Across NHEJ evolution, the enzymes of the NHEJ pathway exhibit a remarkable degree of structural tolerance in the range of DNA end substrate configurations upon which they can act. In vertebrate cells, the nuclease, DNA polymerases, and ligase of NHEJ are the most mechanistically flexible and multifunctional enzymes in each of their classes. Unlike repair pathways for more defined lesions, NHEJ repair enzymes act iteratively, act in any order, and can function independently of one another at each of the two DNA ends being joined. NHEJ is critical not only for the repair of pathologic DSBs as in chromosomal translocations, but also for the repair of physiologic DSBs created during variable (diversity) joining [V(D)J] recombination and class switch recombination (CSR). Therefore, patients lacking normal NHEJ are not only sensitive to ionizing radiation (IR), but also severely immunodeficient.
Adding New Chemistries to the Genetic Code
Authors: Liu Chang C. , Schultz Peter G.
Published: June 2010

The development of new orthogonal aminoacyl-tRNA synthetase/tRNA pairs has led to the addition of approximately 70 unnatural amino acids (UAAs) to the genetic codes of Escherichia coli, yeast, and mammalian cells. These UAAs represent a wide range of structures and functions not found in the canonical 20 amino acids and thus provide new opportunities to generate proteins with enhanced or novel properties and probes of protein structure and function.
Physical Mechanisms of Signal Integration by WASP Family Proteins
Authors: Padrick Shae B. , Rosen Michael K.
Published: June 2010

The proteins of the Wiskott-Aldrich syndrome protein (WASP) family are activators of the ubiquitous actin nucleation factor, the Arp2/3 complex. WASP family proteins contain a C-terminal VCA domain that binds and activates the Arp2/3 complex in response to numerous inputs, including Rho family GTPases, phosphoinositide lipids, SH3 domain–containing proteins, kinases, and phosphatases. In the archetypal members of the family, WASP and N-WASP, these signals are integrated through two levels of regulation, an allosteric autoinhibitory interaction, in which the VCA is sequestered from the Arp2/3 complex, and dimerization/oligomerization, in which multi-VCA complexes are better activators of the Arp2/3 complex than monomers. Here, we review the structural, biochemical, and biophysical details of these mechanisms and illustrate how they work together to control WASP activity in response to multiple inputs. These regulatory principles, derived from studies of WASP and N-WASP, are likely to apply broadly across the family.
Translocation of an Intrauterine Contraceptive Device: Incidental Finding in the Rectosigmoid Colon
Authors: Vilallonga R. , Rodriguez N. , Vilchez M. , Armengol M.
Published: June 2010

The presence of an intrauterine device (IUD) within the colon is rare. Complications have been reported with IUDs among which uterine perforation. Translocation of IUDs to the uterine cavity, to the bladder and also through the wall of the bowel, and sigmoid colon has been reported. We believe there may be a case that surgeons should know the result of despite being a priori gynaecological complication. This paper reports on a case of colon perforation by an IUD.
TLR2 and TLR4 in Ischemia Reperfusion Injury
Authors: Arslan F. , Keogh B. , McGuirk P. , Parker A. E.
Published: June 2010

Ischemia reperfusion (I/R) injury refers to the tissue damage which occurs when blood supply returns to tissue after a period of ischemia and is associated with trauma, stroke, myocardial infarction, and solid organ transplantation. Although the cause of this injury is multifactorial, increasing experimental evidence suggests an important role for the innate immune system in initiating the inflammatory cascade leading to detrimental/deleterious changes. The Toll-like Receptors (TLRs) play a central role in innate immunity recognising both pathogen- and damage-associated molecular patterns and have been implicated in a range of inflammatory and autoimmune diseases. In this paper, we summarise the current state of knowledge linking TLR2 and TLR4 to I/R injury, including recent studies which demonstrate that therapeutic inhibition of TLR2 has beneficial effects on I/R injury in a murine model of myocardial infarction.
Impact of Sleep and Its Disturbances on Hypothalamo-Pituitary-Adrenal Axis Activity
Authors: Balbo Marcella , Leproult Rachel , Van Cauter Eve
Published: June 2010

The daily rhythm of cortisol secretion is relatively stable and primarily under the influence of the circadian clock. Nevertheless, several other factors affect hypothalamo-pituitary-adrenal (HPA) axis activity. Sleep has modest but clearly detectable modulatory effects on HPA axis activity. Sleep onset exerts an inhibitory effect on cortisol secretion while awakenings and sleep offset are accompanied by cortisol stimulation. During waking, an association between cortisol secretory bursts and indices of central arousal has also been detected. Abrupt shifts of the sleep period induce a profound disruption in the daily cortisol rhythm, while sleep deprivation and/or reduced sleep quality seem to result in a modest but functionally important activation of the axis. HPA hyperactivity is clearly associated with metabolic, cognitive and psychiatric disorders and could be involved in the well-documented associations between sleep disturbances and the risk of obesity, diabetes and cognitive dysfunction. Several clinical syndromes, such as insomnia, depression, Cushing's syndrome, sleep disordered breathing (SDB) display HPA hyperactivity, disturbed sleep, psychiatric and metabolic impairments. Further research to delineate the functional links between sleep and HPA axis activity is needed to fully understand the pathophysiology of these syndromes and to develop adequate strategies of prevention and treatment.
HPV16 E2 Is an Immediate Early Marker of Viral Infection, Preceding E7 Expression in Precursor Structures of Cervical Carcinoma
Authors: Xue Yuezhen , Bellanger Sophie , Zhang Wenying , Lim Diana , Low Jeffrey , Lunny Declan , Thierry Françoise
Published: June 2010

The viral E2 gene product plays a crucial role in the human papillomavirus (HPV) vegetative cycle by regulating both transcription and replication of the viral genome. E2 is a transcriptional repressor of the E6 and E7 viral oncogenes for HPV types 16 and 18, which are involved in cervical cancers. Using new polyclonal antibodies against the HPV16 E2 protein, we showed that E2 is expressed at various precursor stages of cervical carcinoma by immunohistochemistry on paraffin-embedded clinical samples. E2 was found to be highly expressed in the nuclei and cytoplasm of cells forming the intermediate and upper layers of cervical intraepithelial neoplasia (CIN). We could show that the expressions of E2 and p16INK4a (surrogate marker for oncogenic E7 expression) were exclusive in most of the cases, thus implying that E2 is not expressed together with high levels of E7. Moreover, we found that E2 is expressed in a subset of columnar cells adjacent to the CIN. We could show that expression of E2 is topologically distinct from the proliferation markers p63 and Ki67, whereas it coincides with the expression of cytokeratin K13, a marker of squamous cell differentiation. Expression of E2 also topologically coincides with episomal amplification of viral genomes in the upper layers of CIN1. These in vivo data thus validate previous assumptions of the crucial role of E2 in the early steps of HPV infection and of its negative link with expression of the viral E6 and E7 oncogenes. Cancer Res; 70(13); 5316–25. ©2010 AACR.
Low Molecular Weight Cyclin E Overexpression Shortens Mitosis, Leading to Chromosome Missegregation and Centrosome Amplification
Authors: Bagheri-Yarmand Rozita , Biernacka Anna , Hunt Kelly K. , Keyomarsi Khandan
Published: June 2010

Overexpression of the low molecular weight isoforms (LMW-E) of cyclin E induces chromosome instability; however, the degree to which these tumor-specific forms cause genomic instability differs from that of full-length cyclin E (EL), and the underlying mechanism(s) has yet to be elucidated. Here, we show that EL and LMW-E overexpression impairs the G2-M transition differently and leads to different degrees of chromosome instability in a breast cancer model system. First, the most significant difference is that EL overexpression prolongs cell cycle arrest in prometaphase, whereas LMW-E overexpression reduces the length of mitosis and accelerates mitotic exit. Second, LMW-E–overexpressing cells are binucleated or multinucleated with amplified centrosomes, whereas EL-overexpressing cells have the normal complement of centrosomes. Third, LMW-E overexpression causes mitotic defects, chromosome missegregation during metaphase, and anaphase bridges during anaphase, most of which are not detected on EL induction. LMW-E induces additional mitotic defects in cooperation with p53 loss in both normal and tumor cells. Fourth, LMW-E–overexpressing cells fail to arrest in the presence of nocodazole. Collectively, the mitotic defects mediated by LMW-E induction led to failed cytokinesis and polyploidy, suggesting that LMW-E expression primes cells to accrue chromosomal instability by shortening the length of mitosis. Lastly, LMW-E expression in human breast cancer tissues correlates with centrosome amplification and higher nuclear grade. These results suggest that LMW-E overexpression leads to higher centrosome numbers in breast cancer, which is a prerequisite for genomic instability. Cancer Res; 70(12); 5074–84. ©2010 AACR.
Effects of Ionizing Radiation on Self-Renewal and Pluripotency of Human Embryonic Stem Cells
Authors: Wilson Kitchener D. , Sun Ning , Huang Mei , Zhang Wendy Y. , Lee Andrew S. , Li Zongjin , Wang Shan X. , Wu Joseph C.
Published: June 2010

Human embryonic stem cells (hESC) present a novel platform for in vitro investigation of the early embryonic cellular response to ionizing radiation. Thus far, no study has analyzed the genome-wide transcriptional response to ionizing radiation in hESCs, nor has any study assessed their ability to form teratomas, the definitive test of pluripotency. In this study, we use microarrays to analyze the global gene expression changes in hESCs after low-dose (0.4 Gy), medium-dose (2 Gy), and high-dose (4 Gy) irradiation. We identify genes and pathways at each radiation dose that are involved in cell death, p53 signaling, cell cycling, cancer, embryonic and organ development, and others. Using Gene Set Enrichment Analysis, we also show that the expression of a comprehensive set of core embryonic transcription factors is not altered by radiation at any dose. Transplantation of irradiated hESCs to immune-deficient mice results in teratoma formation from hESCs irradiated at all doses, definitive proof of pluripotency. Further, using a bioluminescence imaging technique, we have found that irradiation causes hESCs to initially die after transplantation, but the surviving cells quickly recover by 2 weeks to levels similar to control. To conclude, we show that similar to somatic cells, irradiated hESCs suffer significant death and apoptosis after irradiation. However, they continue to remain pluripotent and are able to form all three embryonic germ layers. Studies such as this will help define the limits for radiation exposure for pregnant women and also radiotracer reporter probes for tracking cellular regenerative therapies. Cancer Res; 70(13); 5539–48. ©2010 AACR.