bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Mechanical Response in a Thermal Barrier System Due to Martensitic Phase Transformation in the Bond Coat
Authors: Karlsson A. M.
Published: September 2003

Recent studies have shown that Pt-aluminide—a common bond coat material in thermal barrier coatings—undergoes martensitic transformations during thermal cycling. The transformations are associated with both large transformation strain and a strain hysteresis, leading to accumulation of a mismatch strain. Thermal barrier systems based on Pt-aluminide bond coats are susceptible to interfacial morphological instabilities. In this study, we investigate how the cyclic martensitic transformation influences the morphology. Two key results are: (i) the morphological instabilities are highly sensitive to the thermo-mechanical properties of the substrate due to the martensitic transformation; (ii) the hysteresis associated with cyclic martensitic transformation cannot drive the morphological instabilities; the strains associated with the formation of the thermally grown oxide do.
Assessment of the Fracture Behavior of an Asymmetrically Loaded Cantilever Composite Structure
Authors: Shan Baoxiang , Pelegri Assimina A.
Published: September 2003

The complex fracture behavior of a cross-ply composite cantilever beam with artificially embedded delamination is investigated analytically, numerically, and experimentally. The analysis of the cantilever beam is divided into two geometric configurations: the global bending of the undelaminated cantilever, and the local buckling of the delaminated part. A finite element model developed in ANSYS is used to concurrently analyze the effects of contact zone and delamination in the aforementioned asymmetrically loaded structure. The obtained experimental data are correlated and compared with the findings of the FEM simulations. All numerical, analytical, and experimental results illustrate that the fracture behavior of the laminate cantilever beam is dominated by mode II, mainly due to the effect of a large contact zone. The latter is determined by geometric and loading parameters. The dominance of mode II over mode I, leads to the initiation and propagation of an interfacial crack rather than an intralayer one. Furthermore, experimental evidence indicates that crack kinking during propagation depends on the architecture of the specimens.
Nanoindentation Measurements on Low-k Porous Silica Thin Films Spin Coated on Silicon Substrates
Authors: Huang Xiaoqin , Pelegri Assimina A.
Published: September 2003

MEMS (MicroElectroMechanical Systems) are composed of thin films and composite nanomaterials. Although the mechanical properties of their constituent materials play an important role in controlling their quality, reliability, and lifetime, they are often found to be different from their bulk counterparts. In this paper, low-k porous silica thin films spin coated on silicon substrates are studied. The roughness of spin-on coated porous silica films is analyzed with in-situ imaging and their mechanical properties are determined using nanoindentation. A Berkovich type nanoindenter, of a 142.3 deg total included angle, is used and continuous measurements of force and displacements are acquired. It is shown, that the measured results of hardness and Young’s modulus of these films depend on penetration depth. Furthermore, the film’s mechanical properties are influenced by the properties of the substrate, and the reproduction of the force versus displacement curves depends on the quality of the thin film. The hardness of the studied low-k spin coated silica thin film is measured as 0.35∼0.41 GPa and the Young’s modulus is determined as 2.74∼2.94 GPa.
Spatial Impact of a Slender Beam
Authors: Barbulescu Horatiu , Marghitu Dan B. , Vaidya Uday
Published: September 2003

In this paper, the dynamics of the spatial impact of a slender beam is analyzed. The equations of motion are calculated using Kane’s impact method. The generalized momentum and generalized impulse of the beam are considered to find the equations of motion of the beam. The frictional phenomenon at the contact point is analyzed. For the case of impact without slipping, it is used the assumption that the tangential component of the velocity of separation is null. In the case with slipping, the tangential impulse (at the plane of impact) is computed. The sliding direction after impact is calculated. A simulation of the impact of beam with a surface is developed and the velocity of separation, force of impact and kinetic energy of the beam after impact are studied for different incident angles of the beam. The incident angle is varied from 0 deg to 57 deg. The results are function of the incident angle of impact.
Surface Modification of Powder Metallurgy Components With a Direct Diode Laser
Authors: Barnes Stuart , Nash Michael J. , Kwok Y. K.
Published: September 2003

A 1200 W diode laser was used to modify the surface properties of a fully-sintered ferrous PM material. Two modifications were investigated; transformation hardening of selected areas and sealing of surface porosity by re-melting. The diode laser was used because the beam footprint is large (5×0.5 mm) and the wavelength short (0.94 μm). Processed samples were examined using metallographic and hardness testing techniques. Results indicated that hardness comparable to induction hardening could be achieved and re-melting could be controlled to seal porosity. Further work now needs to be undertaken to convert this demonstrated potential into a commercial reality.
Effect of Laser Pre-Treatment on the Machining Performance of Aluminum/SiC MMC
Authors: Barnes Stuart , Morgan Richard , Skeen Andrew
Published: September 2003

Although the abrasive reinforcement in MMCs primarily controls their machining behavior, the properties of the matrix also exert an influence. A 1200 W diode laser was used, due to the large footprint (5×0.3 mm) and the short wavelength (0.94 μm) to pre-treat a 2618 (18% SiC) alloy. The laser heating and self-quenching of the material modified the matrix properties. Machining performance was then assessed by measuring tool wear and edge condition, cutting forces, surface finish, and sub-surface damage. Results indicated that pre-treatment gave less wear, lower forces, and less sub-surface damage although abrasion remained the primary wear mechanism.
Effects of Temperature and Moisture on the High Strain Rate Compression Response of Graphite/Epoxy Composites
Authors: Hosur M. V. , Waliul Islam S. M. , Vaidya U. K. , Dutta P. K. , Jeelani S.
Published: September 2003

Experimental investigations were carried out on unidirectional Graphite/Epoxy laminate samples under dynamic compression loading using a modified Split Hopkinson Pressure Bar. High strain rate testing was carried out at room and elevated temperatures. 30 layered graphite/epoxy unidirectional laminates made using DA 4518U unidirectional prepregs system were fabricated. Tests were carried out on samples at room, 51.7°C, 121.1°C, and 190.6°C temperatures. Additional high strain rate tests were conducted on samples that were subjected to moist/freeze conditioning for 42 days. Failure modes were studied through scanning electron microscopy. Results of the study indicated plasticizing of matrix which was reflected through increased ductility of the samples as well as reduced slope of the stress-strain curves with the increase in temperature. Similar effect was evident in the samples that were subjected to moist/freeze conditioning.
Evaluation Method for Fatigue Strength of FRP/Metal Adhesive Joints Considering Mean Stress
Authors: Iwasa Masaaki , Hattori Toshio
Published: September 2003

The fatigue strength of two types of FRP/metal adhesive joints at low temperature, a double lap joint and an embedded joint, was evaluated analytically and experimentally. First, the stress singularity parameters of the delamination edges under mechanical and thermal loadings were analyzed by FEM for various delamination lengths. The delamination propagation rate of the double lap joint under mechanical cyclic loadings at room temperature was measured. Using the relationship between the measured propagation rates and the analyzed ranges of stress singularity intensity, we estimated the fatigue strength of the embedded joint, which coincided well with the measured one. Second, we developed an evaluation method that separates the effects of temperature on fatigue strength into two effects: thermal residual stress and low temperature. Third, the fatigue strengths of the double lap joints were measured for various mean stresses. Fatigue limit of adhesive joints was experimentally measured and compared with analytical intensity of stress singularity. A method for evaluating the fatigue strength of adhesive joints by taking mean stress into account was developed.
Statistical Analysis of Experimental Parameters in Continuous Indentation Tests Using Taguchi Method
Authors: Jeon Eun-chae , Park Joo-Seung , Kwon Dongil
Published: September 2003

The continuous indentation test, which applies an indentation load to a material and records the indentation depth, yields indentation tensile properties whose accuracy can vary depending on such experimental parameters as number of unloadings, unloading ratio, maximum depth ratio and indenter radius. The Taguchi method was used to quantify their effects and to determine their optimum values. Using signal-to-noise ratio calculated from the error in the indentation tensile properties, the criterions and the optimum values for the experimental parameters were presented. The indentation tensile properties evaluated with the optimum parameters were in better agreement with the tensile properties.
The Effect of Graded Strength on Damage Propagation in Continuously Nonhomogeneous Materials
Authors: Thamburaj Priya , Santare Michael H. , Gazonas George A.
Published: September 2003

A damage model developed by Johnson and Holmquist is implemented into a dynamic finite element code. This is then used to study the effect of grading of the phenomenological damage parameters on the propagation of damage through the material. The numerical results for two one-dimensional example problems with different boundary conditions are presented, wherein the effect of a gradient in the intact strength of the material on damage propagation is studied. The results show that introducing different strength gradients can alter the location of the site of maximum damage. This may have important implications in the design of impact resistant materials and structures.
Spatially Averaged Local Strains in Textile Composites Via the Binary Model Formulation
Authors: Yang Qingda , Cox Brian
Published: September 2003

A previously published computational model of textile composites known as the Binary Model is generalized to allow systematic study of the effects of mesh refinement. Calculations using different meshing orders show that predictions of local strains are mesh independent when the strains are averaged over gauge volumes whose dimensions are greater than or equal to approximately half the width dimensions of a single tow. Strains averaged over such gauges are favored for use in failure criteria for predicting various mechanisms of failure in a textile composite, including transverse cracking within tows, kink band failure in compression, tensile tow rupture, and shear failure. For the highest order representations (infinitely dense meshes), the generalized formulation of the Binary Model necessarily approaches conventional finite element meshing strategies for textile composites in its predictions. However, the work reported here implies that usefully accurate predictions of spatially averaged strains can be obtained even at the lowest level of mesh refinement. This preserves great simplicity in the model set-up and rapid computation for relatively large features of structural components. Calculations for some textile structures provide insight into the strength or relative absence of textile effects in local strains for different loading configurations.
Control of Damage in Composite Laminates by Ply-Stacking Designs: Characteristic Failure Signatures and Safety Criteria
Authors: Harik Vasyl Michael
Published: September 2003

Structural designs for composite laminated systems can be optimized for a fail-safe in-service performance by introducing the built-in cumulative-damage-indicators for the progressive degradation of material properties. This design methodology is based on the concepts of the characteristic failure signature (CFS), cumulative-damage states and a load-drop sequence that characterize the stress-strain response and progressive accumulation of damage. The cumulative damage mechanics is based on the three-dimensional laminate analysis that is used to predict nonlinear response of composites, accumulation of damage and failure behavior. An earlier-developed nonlinear analysis involves an incremental formulation that couples the three-dimensional laminate analysis with a progressive ply-failure methodology, which has been tested in the World-Wide Exercise on Composites Failure Theories. The failure signatures are shown to have unique “safety features” that depend on the ply stacking sequence and predominant loading. To refine the analysis of micromechanical damage a model for the macro-to-micro coupling is introduced. Various examples of failure envelopes, characteristic failure signatures, a safety criterion and the “safe” CFSs that lead to the desired controlled failures are discussed for symmetric balanced laminates.
The Effect of a Cationic Surfactant on Turbulent Flow Patterns
Authors: Hetsroni G. , Mosyak A. , Talmon Y. , Bernheim-Groswasser A. , Zakin J. L.
Published: September 2003

The thermal pattern on a heated wall was studied for the flow of water and drag-reducing surfactant solutions in a channel. The wall of the channel was made of a thin foil, which was heated by direct current. The temperature of the foil, which reflects the local flow velocities, was measured by an infrared technique with high spatial and temperature resolution. The microstructure of the surfactant solution was studied by direct imaging cryogenic temperature transmission electron microscopy (Cryo-TEM). The most prevalent structures observed are thread-like micelles, which have been suggested to cause the modification of the thermal patterns.
Inactivation of TNF Signaling by Rationally Designed Dominant-Negative TNF Variants
Authors: Steed Paul M. , Tansey Malú G. , Zalevsky Jonathan , Zhukovsky Eugene A. , Desjarlais John R. , Szymkowski David E. , Abbott Christina , Carmichael David , Chan Cheryl , Cherry Lisa , Cheung Peter , Chirino Arthur J. , Chung Hyo H. , Doberstein Stephen K. , Eivazi Araz , Filikov Anton V. , Gao Sarah X. , Hubert René S. , Hwang Marian , Hyun Linus , Kashi Sandhya , Kim Alice , Kim Esther , Kung James , Martinez Sabrina P. , Muchhal Umesh S. , Nguyen Duc-Hanh T. , O'Brien Christopher , O'Keefe Donald , Singer Karen , Vafa Omid , Vielmetter Jost , Yoder Sean C. , Dahiyat Bassil I.
Published: September 2003

Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.
The Role of Collinear Interaction in Dislocation-Induced Hardening
Authors: Madec R. , Devincre B. , Kubin L. , Hoc T. , Rodney D.
Published: September 2003

We connected dislocation-based atomic-scale and continuum models of plasticity in crystalline solids through numerical simulations of dislocation intersections in face-centered cubic crystals. The results contradict the traditional assumption that strain hardening is governed by the formation of sessile junctions between dislocations. The interaction between two dislocations with collinear Burgers vectors gliding in intersecting slip planes was found to be by far the strongest of all reactions. Its properties were investigated and discussed using a multiscale approach.
Reprogramming Control of an Allosteric Signaling Switch Through Modular Recombination
Authors: Dueber John E. , Yeh Brian J. , Chak Kayam , Lim Wendell A.
Published: September 2003

Many eukaryotic signaling proteins are composed of simple modular binding domains, yet they can display sophisticated behaviors such as allosteric gating and multi-input signal integration, properties essential for complex cellular circuits. To understand how such behavior can emerge from combinations of simple domains, we engineered variants of the actin regulatory protein N-WASP (neuronal Wiskott-Aldrich syndrome protein) in which the “output” domain of N-WASP was recombined with heterologous autoinhibitory “input” domains. Synthetic switch proteins were created with diverse gating behaviors in response to nonphysiological inputs. Thus, this type of modular framework can facilitate the evolution or engineering of cellular signaling circuits.
The Dog Genome: Survey Sequencing and Comparative Analysis
Authors: Kirkness Ewen F. , Bafna Vineet , Halpern Aaron L. , Levy Samuel , Remington Karin , Rusch Douglas B. , Delcher Arthur L. , Pop Mihai , Wang Wei , Fraser Claire M. , Venter J. Craig
Published: September 2003

A survey of the dog genome sequence (6.22 million sequence reads; 1.5× coverage) demonstrates the power of sample sequencing for comparative analysis of mammalian genomes and the generation of species-specific resources. More than 650 million base pairs (>25%) of dog sequence align uniquely to the human genome, including fragments of putative orthologs for 18,473 of 24,567 annotated human genes. Mutation rates, conserved synteny, repeat content, and phylogeny can be compared among human, mouse, and dog. A variety of polymorphic elements are identified that will be valuable for mapping the genetic basis of diseases and traits in the dog.
Particle Formation by Ion Nucleation in the Upper Troposphere and Lower Stratosphere
Authors: Lee S.-H. , Reeves J. M. , Wilson J. C. , Hunton D. E. , Viggiano A. A. , Miller T. M. , Ballenthin J. O. , Lait L. R.
Published: September 2003

Unexpectedly high concentrations of ultrafine particles were observed over a wide range of latitudes in the upper troposphere and lower stratosphere. Particle number concentrations and size distributions simulated by a numerical model of ion-induced nucleation, constrained by measured thermodynamic data and observed atmospheric key species, were consistent with the observations. These findings indicate that, at typical upper troposphere and lower stratosphere conditions, particles are formed by this nucleation process and grow to measurable sizes with sufficient sun exposure and low preexisting aerosol surface area. Ion-induced nucleation is thus a globally important source of aerosol particles, potentially affecting cloud formation and radiative transfer.
Epidermal Viral Immunity Induced by CD8α
+
Dendritic Cells But Not by Langerhans Cells
Authors: Allan Rhys S. , Smith Chris M. , Belz Gabrielle T. , van Lint Allison L. , Wakim Linda M. , Heath William R. , Carbone Francis R.
Published: September 2003

The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this, we show here that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8α
+
dendritic cell subset. Thus, the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response.
A Bacterial Cell-Cycle Regulatory Network Operating in Time and Space
Authors: McAdams Harley H. , Shapiro Lucy
Published: September 2003

Transcriptional regulatory circuits provide only a fraction of the signaling pathways and regulatory mechanisms that control the bacterial cell cycle. The CtrA regulatory network, important in control of the
Caulobacter
cell cycle, illustrates the critical role of nontranscriptional pathways and temporally and spatially localized regulatory proteins. The system architecture of
Caulobacter
cell-cycle control involves top-down control of modular functions by a small number of master regulatory proteins with cross-module signaling coordinating the overall process. Modeling the cell cycle probably requires a top-down modeling approach and a hybrid control system modeling paradigm to treat its combined discrete and continuous characteristics.
An Age-Induced Switch to a Hyper-Recombinational State
Authors: McMurray Michael A. , Gottschling Daniel E.
Published: September 2003

There is a strong correlation between age and cancer, but the mechanism by which this phenomenon occurs is unclear. We chose
Saccharomyces cerevisiae
to examine one of the hallmarks of cancer—genomic instability— as a function of cellular age. As diploid yeast mother cells aged, an ∼100-fold increase in loss of heterozygosity (LOH) occurred. Extending life-span altered neither the onset nor the frequency of age-induced LOH; the switch to hyper-LOH appears to be on its own clock. In young cells, LOH occurs by reciprocal recombination, whereas LOH in old cells was nonreciprocal, occurring predominantly in the old mother's progeny. Thus, nuclear genomes may be inherently unstable with age.
Intensive Pre-Incan Metallurgy Recorded by Lake Sediments from the Bolivian Andes
Authors: Abbott Mark B. , Wolfe Alexander P.
Published: September 2003

The history of pre-Columbian metallurgy in South America is incomplete because looting of metal artifacts has been pervasive. Here, we reconstruct a millennium of metallurgical activity in southern Bolivia using the stratigraphy of metals associated with smelting (Pb, Sb, Bi, Ag, Sn) from lake sediments deposited near the major silver deposit of Cerro Rico de Potosí. Pronounced metal enrichment events coincide with the terminal stages of Tiwanaku culture (1000 to 1200 A.D.) and Inca through early Colonial times (1400 to 1650 A.D.). The earliest of these events suggests that Cerro Rico ores were actively smelted at a large scale in the Late Intermediate Period, providing evidence for a major pre-Incan silver industry.
Salmonella
SipA Polymerizes Actin by Stapling Filaments with Nonglobular Protein Arms
Authors: Lilic Mirjana , Galkin Vitold E. , Orlova Albina , VanLoock Margaret S. , Egelman Edward H. , Stebbins C. Erec
Published: September 2003

Like many bacterial pathogens,
Salmonella
spp. use a type III secretion system to inject virulence proteins into host cells. The
Salmonella
invasion protein A (SipA) binds host actin, enhances its polymerization near adherent extracellular bacteria, and contributes to cytoskeletal rearrangements that internalize the pathogen. By combining x-ray crystallography of SipA with electron microscopy and image analysis of SipA-actin filaments, we show that SipA functions as a “molecular staple,” in which a globular domain and two nonglobular “arms” mechanically stabilize the filament by tethering actin subunits in opposing strands. Deletion analysis of the tethering arms provides strong support for this model.
Cyclic Variation and Solar Forcing of Holocene Climate in the Alaskan Subarctic
Authors: Hu Feng Sheng , Kaufman Darrell , Yoneji Sumiko , Nelson David , Shemesh Aldo , Huang Yongsong , Tian Jian , Bond Gerard , Clegg Benjamin , Brown Thomas
Published: September 2003

High-resolution analyses of lake sediment from southwestern Alaska reveal cyclic variations in climate and ecosystems during the Holocene. These variations occurred with periodicities similar to those of solar activity and appear to be coherent with time series of the cosmogenic nuclides
14
C and
10
Be as well as North Atlantic drift ice. Our results imply that small variations in solar irradiance induced pronounced cyclic changes in northern high-latitude environments. They also provide evidence that centennial-scale shifts in the Holocene climate were similar between the subpolar regions of the North Atlantic and North Pacific, possibly because of Sun-ocean-climate linkages.
R2D2, a Bridge Between the Initiation and Effector Steps of the
Drosophila
RNAi Pathway
Authors: Liu Qinghua , Rand Tim A. , Kalidas Savitha , Du Fenghe , Kim Hyun-Eui , Smith Dean P. , Wang Xiaodong
Published: September 2003

The RNA interference (RNAi) pathway is initiated by processing long double-stranded RNA into small interfering RNA (siRNA). The siRNA-generating enzyme was purified from
Drosophila
S2cells and consists of two stoichiometric subunits: Dicer-2(DCR-2) and a previously unknown protein that we named R2D2. R2D2 is homologous to the
Caenorhabditis elegans
RNAi protein RDE-4. Association with R2D2 does not affect the enzymatic activity of DCR-2. Rather, the DCR-2/R2D2 complex, but not DCR-2 alone, binds to siRNA and enhances sequence-specific messenger RNA degradation mediated by the RNA-initiated silencing complex (RISC). These results indicate that R2D2 bridges the initiation and effector steps of the
Drosophila
RNAi pathway by facilitating siRNA passage from Dicer to RISC.
Nanoparticle-Based Bio-Bar Codes for the Ultrasensitive Detection of Proteins
Authors: Nam Jwa-Min , Thaxton C. Shad , Mirkin Chad A.
Published: September 2003

An ultrasensitive method for detecting protein analytes has been developed. The system relies on magnetic microparticle probes with antibodies that specifically bind a target of interest [prostate-specific antigen (PSA) in this case] and nanoparticle probes that are encoded with DNA that is unique to the protein target of interest and antibodies that can sandwich the target captured by the microparticle probes. Magnetic separation of the complexed probes and target followed by dehybridization of the oligonucleotides on the nanoparticle probe surface allows the determination of the presence of the target protein by identifying the oligonucleotide sequence released from the nanoparticle probe. Because the nanoparticle probe carries with it a large number of oligonucleotides per protein binding event, there is substantial amplification and PSA can be detected at 30 attomolar concentration. Alternatively, a polymerase chain reaction on the oligonucleotide bar codes can boost the sensitivity to 3 attomolar. Comparable clinically accepted conventional assays for detecting the same target have sensitivity limits of ∼3 picomdar, six orders of magnitude less sensitive than what is observed with this method.
Social Insect Networks
Authors: Fewell Jennifer H.
Published: September 2003

Social insect colonies have many of the properties of adaptive networks. The simple rules governing how local interactions among individuals translate into group behaviors are found across social groups, giving social insects the potential to have a profound impact on our understanding of the interplay between network dynamics and social evolution.
Biological Networks: The Tinkerer as an Engineer
Authors: Alon U.
Published: September 2003

This viewpoint comments on recent advances in understanding the design principles of biological networks. It highlights the surprising discovery of “good-engineering” principles in biochemical circuitry that evolved by random tinkering.
Molecular Networks: The Top-Down View
Authors: Bray Dennis
Published: September 2003

Network theory can give a useful overview of how a biological system works. But to make testable predictions, we need the details.
DNA-Templated Self-Assembly of Protein Arrays and Highly Conductive Nanowires
Authors: Yan Hao , Park Sung Ha , Finkelstein Gleb , Reif John H. , LaBean Thomas H.
Published: September 2003

A DNA nanostructure consisting of four four-arm junctions oriented with a square aspect ratio was designed and constructed. Programmable self-assembly of 4 × 4 tiles resulted in two distinct lattice morphologies: uniform-width nanoribbons and two-dimensional nanogrids, which both display periodic square cavities. Periodic protein arrays were achieved by templated self-assembly of streptavidin onto the DNA nanogrids containing biotinylated oligonucleotides. On the basis of a two-step metallization procedure, the 4 × 4 nanoribbons acted as an excellent scaffold for the production of highly conductive, uniform-width, silver nanowires.
Communication in Neuronal Networks
Authors: Laughlin Simon B. , Sejnowski Terrence J.
Published: September 2003

Brains perform with remarkable efficiency, are capable of prodigious computation, and are marvels of communication. We are beginning to understand some of the geometric, biophysical, and energy constraints that have governed the evolution of cortical networks. To operate efficiently within these constraints, nature has optimized the structure and function of cortical networks with design principles similar to those used in electronic networks. The brain also exploits the adaptability of biological systems to reconfigure in response to changing needs.
An Era's End and the Start of a New One?
Authors: Hopwood David A.
Published: September 2003

Antibiotics
Actions, Origins, Resistance. by Christopher Walsh. ASM Press, Washington, DC, 2003. 345 pp. $99.95. ISBN 1-55581-254-6.

Focusing on antibiotics that have been used to counter infectious disease of humans, Walsh provides an up-to-date analysis of how these small molecules interfere with crucial processes in bacteria.
Nota Bene: Cruising Mars with the Crater Guy
Authors: Rowan Linda
Published: September 2003

A Traveler's Guide to Mars
The Mysterious Landscapes of the Red Planet. by William K. Hartmann. Workman, New York, 2003. 480 pp. Paper, $18.95, C$29.95. ISBN 0-7611-2606-6.

Hartmann offers a profusely illustrated survey of features of the martian surface and discusses the processes that have led to them.
Pathogenicity of Different Baboon
Herpesvirus Papio 2
Isolates Is Characterized by either Extreme Neurovirulence or Complete Apathogenicity
Authors: Rogers Kristin M. , Ealey Katie A. , Ritchey Jerry W. , Black Darla H. , Eberle R.
Published: September 2003

In comparisons of the pathogenicity of simian alphaherpesviruses in mice, two isolates of the baboon virus HVP2 were nearly as lethal as monkey B virus, a biological safety level 4 agent (J. W. Ritchey, K. A. Ealey, M. Payton, and R. Eberle, J. Comp. Pathol.
127:
150-161, 2002). To confirm these results, mice were inoculated intramuscularly with 10
5
PFU of HVP2 isolates obtained from different baboon subspecies and primate centers. Some of the HVP2 isolates (6 of 13) caused paralysis and death in the mice, while 7 of 13 HVP2 isolates produced no clinical signs of disease. The apathogenic HVP2 isolates (HVP2
ap
) induced only low levels of serum antiviral immunoglobulin G relative to levels observed in sera from mice infected with the neurovirulent isolates of HVP2 (HVP2
nv
). Histological examination of tissues from mice inoculated with HVP2
nv
isolates showed extensive neural tissue destruction, while mice infected with HVP2
ap
isolates showed no lesions. Tissue samples collected at 48-h intervals postinfection suggested that HVP2
ap
isolates failed to replicate at the site of inoculation. There was no significant difference in the in vitro replication, plaque size, or cytopathic effect morphology of HVP2
ap
versus HVP2
nv
isolates. While HVP2 isolates replicated better in Vero monkey kidney cells than in murine L cells, plaquing efficiency of individual isolates did not correlate with the dichotomous pathogenic properties seen in mice. Phylogenetic analyses of both coding and intergenic regions (US4-6) of the HVP2 genome separated isolates into two distinct clades that correlated with the two in vivo virulence phenotypes. Taken together, these results demonstrate that two subtypes of HVP2 exist that are very closely related but differ dramatically in their ability to cause disease in a murine model.
AIDS Vaccination Studies Using an Ex Vivo Feline Immunodeficiency Virus Model: Protection from an Intraclade Challenge Administered Systemically or Mucosally by an Attenuated Vaccine
Authors: Pistello Mauro , Matteucci Donatella , Bonci Francesca , Isola Patrizia , Mazzetti Paola , Zaccaro Lucia , Merico Antonio , Del Mauro Daniela , Flynn Norman , Bendinelli Mauro
Published: September 2003

Feline immunodeficiency virus (FIV) infection of domestic cats represents a valuable system through which to investigate criteria for antilentiviral vaccines in a natural host species. Here, we examined whether vaccination with a strain of FIV attenuated as a result of prolonged growth in vitro could protect against a fully virulent, highly heterologous intraclade challenge. The results indicated that the vaccine virus produced a low-grade infection with no detectable pathological effects and afforded a long-lasting sterilizing immunity if the challenge was delivered intraperitoneally as cell-free virus but not against a cell-associated intravaginal challenge. In the latter case, however, the replication and pathological consequences of the challenge virus were markedly suppressed. Together with similar results obtained in rhesus monkey models, these findings should give impulse to the development of attenuated FIV vaccines to be tested in controlled studies in field cats. Field studies may provide answers to some of the existing safety concerns surrounding attenuated AIDS vaccines in humans.
Persistence and Dissemination of Simian Retrovirus Type 2 DNA in Relation to Viremia, Seroresponse, and Experimental Transmissibility in
Macaca fascicularis
Authors: Wilkinson Roseanne C. , Murrell Claire K. , Guy Rebecca , Davis Gail , Hall Joanna M. , North David C. , Rose Nicola J. , Almond Neil
Published: September 2003

Endemic simian retrovirus (SRV) infection can cause fatal simian AIDS in
Macaca fascicularis
, but many individuals survive with few clinical signs. To further clarify the parameters of SRV pathogenesis, we investigated the persistence of viral DNA forms in relation to active viremia, antibody response, and transmissibility of infection. In
M. fascicularis
from endemically SRV-2-infected colonies, viral DNA was present in both linear and unintegrated long terminal repeat circular forms in peripheral blood mononuclear cells of all viremic and many nonviremic animals. Long-term followup of three individuals with distinct infection patterns demonstrated persistence of linear and circular forms of viral DNA in peripheral blood mononuclear cells and tissues, irrespective of viremia or antibody status, but reactivation of latent infections was not observed. The role of viral DNA in transmission and early pathogenesis of SRV-2 was investigated by inoculation of SRV-2 DNA-positive blood into groups of naïve
M. fascicularis
from either a viremic or nonviremic donor and subsequent analysis of the virological and serological status of the recipients. Transmission of SRV and development of anti-SRV antibodies were only observed in recipients of blood from the viremic donor; transfer of SRV provirus and unintegrated circular DNA in blood from the nonviremic donor did not lead to infection of the recipients. These results indicate that a proportion of
M. fascicularis
are able to effectively control the replication and infectivity of SRV despite long-term persistence of viral DNA forms in infected lymphocytes.
Tyrosine Residues Direct the Ubiquitination and Degradation of the NY-1 Hantavirus G1 Cytoplasmic Tail
Authors: Geimonen Erika , Fernandez Imelyn , Gavrilovskaya Irina N. , Mackow Erich R.
Published: September 2003

The hantavirus G1 protein contains a long C-terminal cytoplasmic tail of 142 residues. Hantavirus pulmonary syndrome-associated hantaviruses contain conserved tyrosine residues near the C terminus of G1 which form an immunoreceptor tyrosine activation motif (ITAM) and interact with Src and Syk family kinases. During studies of the G1 ITAM we observed that fusion proteins containing the G1 cytoplasmic tail were poorly expressed. Expression of G1 cytoplasmic tail constructs were dramatically enhanced by treating cells with the proteasome inhibitor ALLN, suggesting that the protein is ubiquitinated and degraded via the 26S proteasome. By using a 6-His-tagged ubiquitin, we demonstrated that the G1 cytoplasmic tail is polyubiquitinated and degraded in the absence of proteasome inhibitors. Expression of only the ITAM-containing domain also directed protein ubiquitination and degradation in the absence of upstream residues. Deleting the C-terminal 51 residues of G1, including the ITAM, stabilized G1 and blocked polyubiquitination and degradation of the protein. Site-directed mutagenesis of both ITAM tyrosines (Y619 and Y632) to phenylalanine also blocked polyubiquitination of G1 proteins and dramatically enhanced G1 protein stability. In contrast, the presence of Y627, which is not part of the ITAM motif, had no effect on G1 stability. Mutagenesis of just Y619 enhanced G1 stability, inhibited G1 ubiquitination, and increased the half-life of G1 by threefold. Mutating only Y632 had less of an effect on G1 protein stability, although Y619 and Y632 synergistically contributed to G1 instability. These findings suggest that Y619, which is conserved in all hantaviruses, is the primary signal for directing G1 ubiquitination and degradation. Collectively these findings indicate that specific conserved tyrosines within the G1 cytoplasmic tail direct the polyubiquitination and degradation of expressed G1 proteins and provide a potential means for down-regulating hantavirus G1 surface glycoproteins and cellular proteins that interact with G1.
Cytopathic and Noncytopathic Interferon Responses in Cells Expressing Hepatitis C Virus Subgenomic Replicons
Authors: Guo Ju-Tao , Zhu Qing , Seeger Christoph
Published: September 2003

Hepatitis C virus (HCV) is the only known positive-stranded RNA virus that causes persistent lifelong infections in humans. Accumulation of HCV RNA can be inhibited with alpha interferon (IFN-α) in vivo and in culture cells. We used cell-based assay systems to investigate the mechanisms responsible for the cytokine-induced inhibition of HCV replication. The results showed that IFN-α could suppress the accumulation of viral RNA by a noncytopathic pathway and could also induce apoptosis of virally infected cells in a concentration- and cell line-dependent fashion. Whereas the noncytopathic IFN-α response depended on a functional Jak-STAT signal transduction pathway, it did not appear to require double-stranded RNA-dependent pathways. Moreover, we found that functional proteasomes were required for establishment of the IFN-α response against HCV. Based on the results described in this study we propose a model for the mechanism by which IFN-α therapy suppresses HCV replication in chronic infections by both cytopathic and noncytopathic means.
Oral Vaccination of Mice with Adenoviral Vectors Is Not Impaired by Preexisting Immunity to the Vaccine Carrier
Authors: Xiang Z. Q. , Gao G. P. , Reyes-Sandoval A. , Li Y. , Wilson J. M. , Ertl H. C. J.
Published: September 2003

E1 deletion adenoviral vectors of the human serotype 5 (AdHu5) and the chimpanzee serotype 68 (AdC68) expressing the rabies virus glycoprotein (rab.gp) were tested for induction of transgene product-specific antibodies upon intranasal or oral immunization of newborn mice. Both vectors induced antibodies to rabies virus that could be detected in serum and mucosal secretions. Serum rabies virus-neutralizing antibody titers sufficed to protect neonatally vaccinated mice against a subsequent challenge with rabies virus. The efficacy of the AdHu5rab.gp vector given orally to newborn mice born to AdHu5-immune dams was not impaired by maternally transferred antibodies to the vaccine carrier.
Coordinate Replication of Alfalfa Mosaic Virus RNAs 1 and 2 Involves
cis
- and
trans
-Acting Functions of the Encoded Helicase-Like and Polymerase-Like Domains
Authors: Vlot A. Corina , Laros Sebastiaan M. , Bol John F.
Published: September 2003

RNAs 1 and 2 of the tripartite genome of alfalfa mosaic virus encode the replicase proteins P1 and P2, respectively, whereas RNA 3 encodes the movement protein and coat protein. Transient expression of wild-type (wt) and mutant viral RNAs and proteins by agroinfiltration of plant leaves was used to study
cis
- and
trans
-acting functions of the helicase-like domain in P1 and the polymerase-like domain in P2. Three mutations in conserved motifs of the helicase-like domain of P1 affected one or more steps leading to synthesis of minus-strand RNAs 1, 2, and 3. In leaves containing transiently expressed P1 and P2, replication of wt but not mutant RNA 1 was observed. Apparently, the transiently expressed P1 could not complement the defect in replication of the RNA 1 mutant. Moreover, the transiently expressed wt replicase supported replication of RNA 2, but this replication was blocked in
trans
by coexpression of mutant RNA 1. However, expression of mutant RNA 1 did not interfere with the replication of RNA 3 by the wt replicase. Similarly, a mutation in the GDD motif encoded by RNA 2 could not be complemented in
trans
and affected the replication of RNA 1 by a wt replicase, while replication of RNA 3 remained unaffected. In competition assays, the transient wt replicase preferentially replicated RNA 3 over RNAs 1 and 2. The results indicate that one or more functions of P1 and P2 act in
cis
and point to the existence of a mechanism that coordinates the replication of RNAs 1 and 2.
Aichi Virus Leader Protein Is Involved in Viral RNA Replication and Encapsidation
Authors: Sasaki Jun , Nagashima Shigeo , Taniguchi Koki
Published: September 2003

Aichi virus
, a member of the family
Picornaviridae
, encodes a leader (L) protein of 170 amino acids (aa). The Aichi virus L protein exhibits no significant sequence homology to those of other picornaviruses. In this study, we investigated the function of the Aichi virus L protein in virus growth. In vitro translation and cleavage assays indicated that the L protein has no autocatalytic activity and is not involved in polyprotein cleavage. The L-VP0 junction was cleaved by 3C proteinase. Immunoblot analysis showed that the L protein is stably present in infected cells. Characterization of various L mutants derived from an infectious cDNA clone revealed that deletion of 93 aa of the center part (aa 43 to 135), 50 aa of the N-terminal part (aa 4 to 53), or 90 aa of the C-terminal part (aa 74 to 163) abolished viral RNA replication. A mutant (Δ114-163) in which 50 aa of the C-terminal part (aa 114 to 163) were deleted exhibited efficient RNA replication and translation abilities, but the virus yield was 4 log orders lower than that of the wild type. Sedimentation analysis of viral particles generated in mutant Δ114-163 RNA-transfected cells showed that the mutant has a severe defect in the formation of mature virions, but not in that of empty capsids. Thus, the data obtained in this study indicate that the Aichi virus L protein is involved in both viral RNA replication and encapsidation.
Mapping of Abutilon Mosaic Geminivirus Minichromosomes
Authors: Pilartz Marcel , Jeske Holger
Published: September 2003

The single-stranded circular DNA ofAbutilon mosaic geminivirionsis complemented to double-stranded DNA by host proteins after infecting cells. This double-stranded DNA serves as a template for replication as well as transcription and is assembled into host nucleosomes, yielding circular viral minichromosomes. Their chromatin structure was analyzed by use of isolated nuclei combining nuclease sensitivity assays with ligation-mediated PCR, evaluating nucleosomal ladders and topoisomer distributions in one- and two-dimensional gels by blot hybridization. Viral minichromosomes were found to exist in at least two defined structures covered with 11 or 12 nucleosomes, leaving open gaps accessible for interactions with other host factors. Nucleosome-free gaps were colocalized with promoter structures and the origin of replication in both components of genomic DNA (DNA A and DNA B). Nucleosomes were positioned over the entire viral DNA in at least two alternative phases with different periodicities. The distribution of topoisomers of monomeric viral circular double-stranded DNA confirmed the presence of variable chromatin structures revealing maximum frequencies of molecules with either 11, 12, or 13 superhelical turns (corresponding to respective numbers of nucleosomes) at maximal frequency at different stages during leaf development of infected plants. The role of variable chromatin structures for gene regulation of geminiviruses is discussed.
Effects of Human Metapneumovirus and Respiratory Syncytial Virus Antigen Insertion in Two 3′ Proximal Genome Positions of Bovine/Human Parainfluenza Virus Type 3 on Virus Replication and Immunogenicity
Authors: Tang Roderick S. , Schickli Jeanne H. , MacPhail Mia , Fernandes Fiona , Bicha Leenas , Spaete Joshua , Fouchier Ron A. M. , Osterhaus Albert D. M. E. , Spaete Richard , Haller Aurelia A.
Published: September 2003

A live attenuated bovine parainfluenza virus type 3 (PIV3), harboring the fusion (F) and hemagglutinin-neuraminidase (HN) genes of human PIV3, was used as a virus vector to express surface glycoproteins derived from two human pathogens, human metapneumovirus (hMPV) and respiratory syncytial virus (RSV). RSV and hMPV are both paramyxoviruses that cause respiratory disease in young children, the elderly, and immunocompromised individuals. RSV has been known for decades to cause acute lower respiratory tract infections in young children, which often result in hospitalization, while hMPV has only been recently identified as a novel human respiratory pathogen. In this study, the ability of bovine/human PIV3 to express three different foreign transmembrane surface glycoproteins and to induce a protective immune response was evaluated. The RNA-dependent RNA polymerase of paramyxoviruses binds to a single site at the 3′ end of the viral RNA genome to initiate transcription of viral genes. The genome position of the viral gene determines its level of gene expression. The promoter-proximal gene is transcribed with the highest frequency, and each downstream gene is transcribed less often due to attenuation of transcription at each gene junction. This feature of paramyxoviruses was exploited using the PIV3 vector by inserting the foreign viral genes at the 3′ terminus, at position 1 or 2, of the viral RNA genome. These locations were expected to yield high levels of foreign viral protein expression stimulating a protective immune response. The immunogenicity and protection results obtained with a hamster model showed that bovine/human PIV3 can be employed to generate bivalent PIV3/RSV or PIV3/hMPV vaccine candidates that will be further evaluated for safety and efficacy in primates.