bluuebunny/crossref_metadata_2025 huggingface dataset:
Restoration Practices Have Positive Effects on Breeding Bird Species of Concern in the Chihuahuan Desert
Authors: Coffman John M. , Bestelmeyer Brandon T. , Kelly Jeffrey F. , Wright Timothy F. , Schooley Robert L.
Published: January 2014

Woody plant encroachment into grasslands is a global concern. Efforts to restore grasslands often assume that removal of woody plants benefits biodiversity but assumptions are rarely tested. In the Chihuahuan Desert of the Southwestern United States, we tested whether abundances of grassland specialist bird species would be greater in plant communities resulting from treatment with herbicides to remove encroaching shrubs compared with untreated shrub‐dominated areas that represented pre‐treatment conditions. In 2010, we surveyed breeding birds and vegetation at 16 treated–untreated pairs. In 2011, we expanded the survey effort to 21 treated–untreated pairs, seven unpaired treatment areas, and five reference grassland areas. Vegetation in treatment areas had higher perennial grass foliar and basal cover and lower shrub foliar cover compared with untreated areas. Several regionally declining grassland specialists exhibited higher occurrence and relative abundance in treated areas. A shrubland specialist, however, was associated with untreated areas and may be negatively impacted by shrub removal. Bird community composition differed between treated and untreated areas in both years. Our results indicate that shrub removal can have positive effects on grassland specialist bird species, but that a mosaic of treated and untreated areas might be most beneficial for regional biodiversity.
Experimental Testing and Full and Homogenized Numerical Models of the Low Velocity and Dynamic Deformation of the Trapezoidal Aluminium Corrugated Core Sandwich
Authors: Kιlιçaslan C. , Odacι İ. K. , Taşdemirci A. , Güden M.
Published: January 2014

The simulations of the low velocity and dynamic deformation of a multi‐layer 1050‐H14 Al trapezoidal zig‐zag corrugated core sandwich were investigated using the homogenized models (solid models) of a single core layer (without face sheets). In the first part of the study, the LS‐DYNA MAT‐26 material model parameters of a single core layer were developed through experimental and numerical compression tests on the single core layer. In the second part, the fidelities of the developed numerical models were checked by the split‐Hopkinson pressure bar direct impact, low velocity compression and indentation and projectile impact tests. The results indicated that the element size had a significant effect on the initial peak and post‐peak stresses of the homogenized models of the direct impact testing of the single‐layer corrugated sandwich. This was attributed to the lack of the inertial effects in the homogenized models, which resulted in reduced initial peak stresses as compared with the full model and experiment. However, the homogenized models based on the experimental stress–strain curve of the single core layer predicted the low velocity compression and indentation and projectile impact tests of the multi‐layer corrugated sandwich with an acceptable accuracy and reduced the computational time of the models significantly.
Quantum Random Walks and Decision Making
Authors: Shankar Karthik H.
Published: January 2014

How realistic is it to adopt a quantum random walk model to account for decisions involving two choices? Here, we discuss the neural plausibility and the effect of initial state and boundary thresholds on such a model and contrast it with various features of the classical random walk model of decision making.
Alternative Probability Theories for Cognitive Psychology
Authors: Narens Louis
Published: January 2014

Various proposals for generalizing event spaces for probability functions have been put forth in the mathematical, scientific, and philosophic literatures. In cognitive psychology such generalizations are used for explaining puzzling results in decision theory and for modeling the influence of context effects. This commentary discusses proposals for generalizing probability theory to event spaces that are not necessarily boolean algebras. Two prominent examples are quantum probability theory, which is based on the set of closed subspaces of a Hilbert space, and topological probability theory, which is based on the set of open sets of a topology. Both have been applied to a variety of cognitive situations. This commentary focuses on how event space properties can influence probability concepts and impact cognitive modeling.
Learning Representations of Animated Motion Sequences—A Neural Model
Authors: Layher Georg , Giese Martin A. , Neumann Heiko
Published: January 2014

The detection and categorization of animate motions is a crucial task underlying social interaction and perceptual decision making. Neural representations of perceived animate objects are partially located in the primate cortical region STS, which is a region that receives convergent input from intermediate‐level form and motion representations. Populations of STS cells exist which are selectively responsive to specific animated motion sequences, such as walkers. It is still unclear how and to what extent form and motion information contribute to the generation of such representations and what kind of mechanisms are involved in the learning processes. The article develops a cortical model architecture for the unsupervised learning of animated motion sequence representations. We demonstrate how the model automatically selects significant motion patterns as well as meaningful static form prototypes characterized by a high degree of articulation. Such key poses are selectively reinforced during learning through a cross talk between the motion and form processing streams. Furthermore, we show how sequence‐selective representations are learned in STS by fusing static form and motion input from the segregated bottom‐up driving input streams. Cells in STS, in turn, feed their activities recurrently to their input sites along top‐down signal pathways. We show how such learned feedback connections enable predictions about future input as anticipation generated by sequence‐selective STS cells. Network simulations demonstrate the computational capacity of the proposed model by reproducing several experimental findings from neurosciences and by accounting for recent behavioral data.
Modeling the Emergence of Lexicons in Homesign Systems
Authors: Richie Russell , Yang Charles , Coppola Marie
Published: January 2014

It is largely acknowledged that natural languages emerge not just from human brains but also from rich communities of interacting human brains (Senghas, 2005). Yet the precise role of such communities and such interaction in the emergence of core properties of language has largely gone uninvestigated in naturally emerging systems, leaving the few existing computational investigations of this issue at an artificial setting. Here, we take a step toward investigating the precise role of community structure in the emergence of linguistic conventions with both naturalistic empirical data and computational modeling. We first show conventionalization of lexicons in two different classes of naturally emerging signed systems: (a) protolinguistic “homesigns” invented by linguistically isolated Deaf individuals, and (b) a natural sign language emerging in a recently formed rich Deaf community. We find that the latter conventionalized faster than the former. Second, we model conventionalization as a population of interacting individuals who adjust their probability of sign use in response to other individuals' actual sign use, following an independently motivated model of language learning (Yang, 2002, 2004). Simulations suggest that a richer social network, like that of natural (signed) languages, conventionalizes faster than a sparser social network, like that of homesign systems. We discuss our behavioral and computational results in light of other work on language emergence, and other work of behavior on complex networks.
Maximizing Students' Retention via Spaced Review: Practical Guidance From Computational Models of Memory
Authors: Khajah Mohammad M. , Lindsey Robert V. , Mozer Michael C.
Published: January 2014

During each school semester, students face an onslaught of material to be learned. Students work hard to achieve initial mastery of the material, but when they move on, the newly learned facts, concepts, and skills degrade in memory. Although both students and educators appreciate that review can help stabilize learning, time constraints result in a trade‐off between acquiring new knowledge and preserving old knowledge. To use time efficiently, when should review take place? Experimental studies have shown benefits to long‐term retention with spaced study, but little practical advice is available to students and educators about the optimal spacing of study. The dearth of advice is due to the challenge of conducting experimental studies of learning in educational settings, especially where material is introduced in blocks over the time frame of a semester. In this study, we turn to two established models of memory—ACT‐R andMCM—to conduct simulation studies exploring the impact of study schedule on long‐term retention. Based on the premise of a fixed time each week to review, converging evidence from the two models suggests that an optimal review schedule obtains significant benefits over haphazard (suboptimal) review schedules. Furthermore, we identify two scheduling heuristics that obtain near optimal review performance: (a) review the material fromμ‐weeks back, and (b) review material whose predicted memory strength is closest to a particular threshold. The former has implications for classroom instruction and the latter for the design of digital tutors.
Toward a Physical Theory of Quantum Cognition
Authors: Takahashi Taiki
Published: January 2014

Recently, mathematical models based on quantum formalism have been developed in cognitive science. The target articles in this special issue of Topics in Cognitive Science clearly illustrate how quantum theoretical formalism can account for various aspects of human judgment and decision making in a quantitatively and mathematically rigorous manner. In this commentary, we show how future studies in quantum cognition and decision making should be developed to establish theoretical foundations based on physical theory, by introducing Taketani's three‐stage theory of the development of science. Also, implications for neuroeconomics (another rapidly evolving approach to human judgment and decision making) are discussed.
Effect of Micro-Injection Molding Processing Conditions on the Replication and Consistency of a Dense Network of High Aspect Ratio Microstructures
Authors: Rodgers John W. , Casey Meghan E. , Jedlicka Sabrina S. , Coulter John P.
Published: January 2014

When molding macroscale polymer parts with a high density of microfeatures (>1 × 106/cm2), a concern that presents itself is the ability to achieve uniform replication across the entire domain. In the given study, micro-injection molding was used to manufacture microfeatured polymer substrates containing over 10 × 106 microfeatures per cm2. Polystyrene (PS) plates containing microtopography were molded using different processing parameters to study the effect of flow rate and mold temperature on replication quality and uniformity. Flow rate was found to significantly affect replication at mold temperatures above the glass transition temperature (Tg) of PS while having no significant effect on filling at mold temperatures below Tg. Moreover, replication was dependent on distance from the main cavity entrance, with increased flow rate facilitating higher replication differentials and higher replication near the gate. Simulation of the molding process was used to corroborate experimental trials. A deeper understanding of polymer fluid behavior associated with micro-injection molding is vital to reliably manufacture parts containing consistent microtopography (Note: Values are expressed in average ± standard error).
A Review of Floating Platform Concepts for Offshore Wind Energy Generation
Authors: Thiagarajan K. P. , Dagher H. J.
Published: January 2014

Literature relating to offshore wind energy generation is produced at a significant rate as research efforts are diverted to the emerging area of future clean energy. This paper presents an overview of recent research in the specific area of floating offshore structure design for wind energy. Earlier literature has broadly grouped these platforms into three categories based on their source of stability: (1) ballast stabilized (low center of gravity), e.g., spar, (2) mooring stabilized, e.g., tension leg platform, and (3) buoyancy or water-plane stabilized, e.g., semisubmersible. These concepts were modifications of similar structures used in the offshore oil and gas industry. Recent papers have presented further improvements to these designs, including active ballasting and control systems. These are examined for stability and global performance behavior and ease of operability and maintenance. The paper also attempts to examine efforts to bring such concepts to fruition. This paper sets the stage for other papers in the Special Session on University of Maine/DeepCWind Consortium within the Offshore Renewable Energy Symposium at OMAE 2012, which are archived in the special section of the Journal of Offshore Mechanics and Arctic Engineering.
Steady State Engine Test Demonstration of Performance Improvement With an Advanced Turbocharger
Authors: Sun Harold , Hanna Dave , Hu Liangjun , Curtis Eric , Yi James , Tjong Jimi
Published: January 2014

Heavy EGR required on diesel engines for future emission regulation compliance has posed a big challenge to conventional turbocharger technology for high efficiency and wide operation range. This study, as part of the U.S. Department of Energy sponsored research program, is focused on advanced turbocharger technologies that can improve turbocharger efficiency on customer driving cycles while extending the operation range significantly, compared to a production turbocharger. The production turbocharger for a medium-duty truck application was selected as a donor turbo. Design optimizations were focused on the compressor impeller and turbine wheel. On the compressor side, advanced impeller design with arbitrary surface can improve the efficiency and surge margin at the low end while extending the flow capacity, while a so-called active casing treatment can provide additional operation range extension without compromising compressor efficiency. On the turbine side, mixed flow turbine technology was revisited with renewed interest due to its performance characteristics, i.e., high efficiency at low-speed ratio, relative to the base conventional radial flow turbine, which is relevant to heavy EGR operation for future diesel applications. The engine dynamometer test shows that the advanced turbocharger technology enables over 3% BSFC improvement at part-load as well as full-load condition, in addition to an increase in rated power. The performance improvement demonstrated on an engine dynamometer seems to be more than what would typically be translated from the turbocharger flow bench data, indicating that mixed flow turbine may provide additional performance benefits under pulsed exhaust flow on an internal combustion engine and in the low-speed ratio areas that are typically not covered by steady state flow bench tests.
Realistic Trench Film Cooling With a Thermal Barrier Coating and Deposition
Authors: Kistenmacher David A. , Todd Davidson F. , Bogard David G.
Published: January 2014

Thermal barrier coatings (TBC) see extensive use in high-temperature gas turbines. However, little work has been done to experimentally characterize the combination of TBC and film cooling. The purpose of this study is to investigate the cooling performance of a thermally conducting turbine vane with a realistic film-cooling trench geometry embedded in TBC. Additionally, the effect of contaminant deposition on the realistic trench was studied. The trench is termed realistic because it takes into account probable manufacturing limitations. The vane model and TBC used for this study were designed to match the thermal behavior of an actual gas turbine vane with TBC by properly scaling their convective heat-transfer coefficients, thermal conductivities, and characteristic length scales. This study built upon previously published results with various film-cooling geometries consisting of round holes, craters, an ideal trench, and a novel trench. The previous study showed that large changes in blowing ratio resulted in negligible effects on cooling performance. Changes to film-cooling geometry also resulted in minor effects on cooling performance. This study found that the realistic trench and an idealized trench perform similarly. However, the width of the realistic trench left the vane wall more exposed to mainstream temperatures, especially at lower film-coolant flow rates. This study also found that the trench designs helped to mitigate deposition formation better than round holes; however, the realistic trench was more prone to deposition within the trench. The overall cooling effectiveness was similar for both trench designs and relatively unchanged from the predeposition performance, while the overall cooling effectiveness for round holes increased due to the additional thermal insulation offered by the unmitigated deposition.
InGaAs/GaAsSb based two-dimensional electron gases
Authors: Detz Hermann , Silvano de Sousa Jonathan , Leonhardt Horst , Klang Pavel , Zederbauer Tobias , Andrews Aaron Maxwell , Schrenk Werner , Smoliner Jürgen , Strasser Gottfried
Published: January 2014

The authors report on two-dimensional electron gases realized in the In0.53Ga0.47As/GaAs0.51Sb0.49 material system. For different doping levels, the sheet carrier densities were measured to be between 8.4. × 1010 and 8.3 × 1011 cm−2. A maximum electron mobility of 42 700 cm2/V s was observed at a temperature of 60 K. In addition to alloy scattering, remote ionized impurity scattering is a limiting factor for this material combination, as the GaAs0.51Sb0.49 barriers have the same low effective mass as the In0.53Ga0.47As channel and therefore allow the wavefunction to protrude into the barrier more than in other established material systems. Angle resolved Hall measurements revealed a strong influence of the crystallographic directions on the carrier mobility and two-dimensional electron population. An additional feature of these two-dimensional electron systems, originating from the fact that In0.53Ga0.47As and GaAs0.51Sb0.49 show a type-II band alignment and comparable bandgap energies, is spin splitting, due to the Rashba effect, with a Rashba-parameter of 0.42 eVÅ.
Dewetting of Au/Ni bilayer films on prepatterned substrates and the formation of arrays of supersaturated Au-Ni nanoparticles
Authors: Herz Andreas , Wang Dong , Schaaf Peter
Published: January 2014

Au/Ni bilayer thin films are studied with respect to their dewetting behavior on prepatterned SiO2/Si substrates (inverted pyramidal pits). Dewetting of Au-Ni solid-solutions is controlled by a rapid thermal treatment at temperatures above the miscibility gap followed by a fast cooling procedure. Upon annealing, it is observed that some Au-rich film material separates on the mesa in case of still coalescent (i.e., incomplete dewetting) nanoparticles. Moreover, arrays of supersaturated Au-Ni solid-solution nanoparticles are formed out of the bilayer film after templated dewetting. Faceting of the nanoparticles indicates textural effects. In order to prove that these findings are caused by the prepatterned substrate, a comparison with the bilayer dewetting on a flat SiO2/Si substrate is provided.
A Mechanosensory Pathway to the
Drosophila
Circadian Clock
Authors: Simoni Alekos , Wolfgang Werner , Topping Matthew P. , Kavlie Ryan G. , Stanewsky Ralf , Albert Joerg T.
Published: January 2014

Coordinating the Clock

In flies, the mechanosensory chordotonal organs help to coordinate the effects of temperature on circadian cycles.

Simoni
et al.

(p.
525
) provide a mechanism by which mechanosensory input is processed to help to synchronize the biological clock in
Drosophila melanogaster
. The chordotonal organs, which have similarities to the mammalian ear, were also required for sensation of a vibration stimulus and its effects on the endogenous brain clock. The chordotonal organs, present in the joints of the limbs, provide neuronal signals that allow the animal to sense its position or posture—and thus might mediate feedback of a range of behaviors onto the endogenous biological clock.
Resurrecting Surviving Neandertal Lineages from Modern Human Genomes
Authors: Vernot Benjamin , Akey Joshua M.
Published: January 2014

Neandertal Shadows in Us

Non-African modern humans carry a remnant of Neandertal DNA from interbreeding events that have been postulated to have occurred as humans migrated out of Africa. While the total amount of Neandertal sequence is estimated to be less than 3% of the modern genome, the specific retained sequences vary among individuals. Analyzing the genomes of more than 600 Europeans and East Asians,
Vernot and Akey
(p.
1017
, published online 29 January) identified Neandertal sequences within modern humans that taken together span approximately 20% of the Neandertal genome. Some Neandertal-derived sequences appear to be under positive selection in humans, including several genes associated with skin phenotypes.
Sound Isolation and Giant Linear Nonreciprocity in a Compact Acoustic Circulator
Authors: Fleury Romain , Sounas Dimitrios L. , Sieck Caleb F. , Haberman Michael R. , Alù Andrea
Published: January 2014

Acoustically Isolated

The control of sound transmission is desirable in a number of circumstances from noise suppression to imaging technologies.

Fleury
et al.

(p.
516
; see the cover; see the Perspective by

Cummer

) studied a subwavelength acoustic meta-atom consisting of a resonant ring cavity biased by an internally circulating fluid. The direction of rotational flow of the fluid (air) changed the resonant properties of the ring cavity, allowing the propagation of sound waves within the cavity to be controlled. With several ports connected to the cavity, sound could be directed to a certain port while isolating transmission in another.
Savanna Vegetation-Fire-Climate Relationships Differ Among Continents
Authors: Lehmann Caroline E. R. , Anderson T. Michael , Sankaran Mahesh , Higgins Steven I. , Archibald Sally , Hoffmann William A. , Hanan Niall P. , Williams Richard J. , Fensham Roderick J. , Felfili Jeanine , Hutley Lindsay B. , Ratnam Jayashree , San Jose Jose , Montes Ruben , Franklin Don , Russell-Smith Jeremy , Ryan Casey M. , Durigan Giselda , Hiernaux Pierre , Haidar Ricardo , Bowman David M. J. S. , Bond William J.
Published: January 2014

Surveying Savannas

Savannas are structurally similar across the three major continents where they occur, leading to the assumption that the factors controlling vegetation structure and function are broadly similar, too.

Lehmann
et al.

(p.
548
) report the results of an extensive analysis of ground-based tree abundance in savannas, sampled at more than 2000 sites in Africa, Australia, and South America. All savannas, independent of region, shared a common functional property in the way that moisture and fire regulated tree abundance. However, despite qualitative similarity in the moisture–fire–tree-biomass relationships among continents, key quantitative differences exist among the three regions, presumably as a result of unique evolutionary histories and climatic domains.
Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders
Authors: Novarino Gaia , Fenstermaker Ali G. , Zaki Maha S. , Hofree Matan , Silhavy Jennifer L. , Heiberg Andrew D. , Abdellateef Mostafa , Rosti Basak , Scott Eric , Mansour Lobna , Masri Amira , Kayserili Hulya , Al-Aama Jumana Y. , Abdel-Salam Ghada M. H. , Karminejad Ariana , Kara Majdi , Kara Bulent , Bozorgmehri Bita , Ben-Omran Tawfeg , Mojahedi Faezeh , Mahmoud Iman Gamal El Din , Bouslam Naima , Bouhouche Ahmed , Benomar Ali , Hanein Sylvain , Raymond Laure , Forlani Sylvie , Mascaro Massimo , Selim Laila , Shehata Nabil , Al-Allawi Nasir , Bindu P.S. , Azam Matloob , Gunel Murat , Caglayan Ahmet , Bilguvar Kaya , Tolun Aslihan , Issa Mahmoud Y. , Schroth Jana , Spencer Emily G. , Rosti Rasim O. , Akizu Naiara , Vaux Keith K. , Johansen Anide , Koh Alice A. , Megahed Hisham , Durr Alexandra , Brice Alexis , Stevanin Giovanni , Gabriel Stacy B. , Ideker Trey , Gleeson Joseph G.
Published: January 2014

Neurodegenerative Genetics

The underlying genetics of neurodegenerative disorders tend not to be well understood.

Novarino
et al.

(p.
506
; see the Perspective by

Singleton

) investigated the underlying genetics of hereditary spastic paraplegia (HSP), a human neurodegenerative disease, by sequencing the exomes of individuals with recessive neurological disorders. Loss-of-function gene mutations in both novel genes and genes previously implicated for this condition were identified, and several were functionally validated.
Methane on the Rise—Again
Authors: Nisbet Euan G. , Dlugokencky Edward J. , Bousquet Philippe
Published: January 2014

Atmospheric concentrations of the greenhouse gas methane are rising, but the reasons remain incompletely understood.
Timing Mechanism Dependent on Cell Division Is Invoked by Polycomb Eviction in Plant Stem Cells
Authors: Sun Bo , Looi Liang-Sheng , Guo Siyi , He Zemiao , Gan Eng-Seng , Huang Jiangbo , Xu Yifeng , Wee Wan-Yi , Ito Toshiro
Published: January 2014

A Matter of Timing

Plants flower only when their developmental programs give the go-ahead; otherwise floral genes remain repressed.

Sun
et al.

(
10.1126/science.1248559
; see the Perspective by

Zhang

) analyzed the regulatory program that controls expression of the transcription factor KNUCKLES (KNU), which is required in the control of floral genes. KNU expression was silenced by the presence of Polycomb group (PcG) proteins. The floral homeotic protein AGAMOUS competed for control of KNU and activated its expression, but with a 2-day lag time. Thus, eviction of PcG by activating DNA binding proteins can insert a lag time before a switch in gene expression takes place.
Chemical Warfare in the Battle of the Sexes
Authors: Promislow Daniel E. L. , Kaeberlein Matt
Published: January 2014

Merely perceiving the opposite sex can shorten an animal's life span.

[Also see Reports by
Shi and Murphy
,

Maures
et al.

, and

Gendron
et al.

]
Editing of Targeted Genes Proved Possible in Monkeys
Authors: Pennisi Elizabeth
Published: January 2014

Using a recently developed genome-editing technique called CRISPR, a Chinese team has successfully altered two target genes in cynomolgus monkeys, paving the way for the development of monkey models that mimic human diseases.
Antioxidants Could Spur Tumors by Acting on Cancer Gene
Authors: Kaiser Jocelyn
Published: January 2014

Mouse study could help explain why smokers taking vitamins to prevent cancer had higher lung cancer rates.
Quantum Spy Games
Authors: Cho Adrian
Published: January 2014

Someday a quantum computer may unlock all our secrets—if it isn't first stymied by simpler technologies.
Miniaturized and High-Throughput Assays for Analysis of T-Cell Immunity Specific for Opportunistic Pathogens and HIV
Authors: Li Pira Giuseppina , Ivaldi Federico , Starc Nadia , Landi Fabiola , Locatelli Franco , Rutella Sergio , Tripodi Gino , Manca Fabrizio
Published: January 2014

Monitoring of antigen-specific T-cell responses is valuable in numerous conditions that include infectious diseases, vaccinations, and opportunistic infections associated with acquired or congenital immune defects. A variety of assays that make use of peripheral lymphocytes to test activation markers, T-cell receptor expression, or functional responses are currently available. The last group of assays calls for large numbers of functional lymphocytes. The number of cells increases with the number of antigens to be tested. Consequently, cells may be the limiting factor, particularly in lymphopenic subjects and in children, the groups that more often require immune monitoring. We have developed immunochemical assays that measure secreted cytokines in the same wells in which peripheral blood mononuclear cells (PBMC) are cultured. This procedure lent itself to miniaturization and automation. Lymphoproliferation and the enzyme-linked immunosorbent spot (ELISPOT) assay have been adapted to a miniaturized format. Here we provide examples of immune profiles and describe a comparison between miniaturized assays based on cytokine secretion or proliferation. We also demonstrate that these assays are convenient for use in testing antigen specificity in established T-cell lines, in addition to analysis of PBMC. In summary, the applicabilities of miniaturization to save cells and reagents and of automation to save time and increase accuracy were demonstrated in this study using different methodological approaches valuable in the clinical immunology laboratory.
Correlations between Peripheral Blood Coxiella burnetii DNA Load, Interleukin-6 Levels, and C-Reactive Protein Levels in Patients with Acute Q Fever
Authors: Kremers M. N. T. , Janssen R. , Wielders C. C. H. , Kampschreur L. M. , Schneeberger P. M. , Netten P. M. , de Klerk A. , Hodemaekers H. M. , Hermans M. H. A. , Notermans D. W. , Wever P. C.
Published: January 2014

From 2007 to 2010, the Netherlands experienced the largest reported Q fever outbreak, with >4,000 notified cases. We showed previously that C-reactive protein is the only traditional infection marker reflecting disease activity in acute Q fever. Interleukin-6 is the principal inducer of C-reactive protein. We questioned whether increased C-reactive protein levels in acute Q fever patients coincide with increased interleukin-6 levels and if these levels correlate with the
Coxiella burnetii
DNA load in serum. In addition, we studied their correlation with disease severity, expressed by hospital admission and the development of fatigue. Interleukin-6 and C-reactive protein levels were analyzed in sera from 102 patients diagnosed with seronegative PCR-positive acute Q fever. Significant but weak negative correlations were observed between bacterial DNA loads expressed as cycle threshold values and interleukin-6 and C-reactive protein levels, while a significant moderate-strong positive correlation was present between interleukin-6 and C-reactive protein levels. Furthermore, significantly higher interleukin-6 and C-reactive protein levels were observed in hospitalized acute Q fever patients in comparison to those in nonhospitalized patients, while bacterial DNA loads were the same in the two groups. No marker was prognostic for the development of fatigue. In conclusion, the correlation between interleukin-6 and C-reactive protein levels in acute Q fever patients points to an immune activation pathway in which interleukin-6 induces the production of C-reactive protein. Significant differences in interleukin-6 and C-reactive protein levels between hospitalized and nonhospitalized patients despite identical bacterial DNA loads suggest an important role for host factors in disease presentation. Higher interleukin-6 and C-reactive protein levels seem predictive of more severe disease.
Colonic Immunopathogenesis of Clostridium difficile Infections
Authors: Darkoh Charles , Turnwald Bradley P. , Koo Hoonmo L. , Garey Kevin W. , Jiang Zhi-Dong , Aitken Samuel L. , DuPont Herbert L.
Published: January 2014

There are major gaps in our understanding of the immunopathogenesis of
Clostridium difficile
infections (CDIs). In this study, 36 different biomarkers were examined in the stools of CDI and non-CDI patients using the Proteome Profiler human cytokine array assay and quantitative enzyme-linked immunosorbent assay. Diarrheal stools from patients with CDI (CDI-positive diarrheal stools) showed higher relative amounts of the following inflammatory markers than the diarrheal stools from CDI-negative patients (CDI-negative diarrheal stools): C5a, CD40L, granulocyte colony-stimulating factor, I-309, interleukin-13 (IL-13), IL-16, IL-27, monocyte chemoattractant protein 1, tumor necrosis factor alpha, and IL-8. IL-8 and IL-23 were present in a larger number of CDI-positive diarrheal stools than CDI-negative diarrheal stools. Th1 and Th2 cytokines were not significantly different between the CDI-positive and CDI-negative diarrheal stools. Lactoferrin and calprotectin concentrations were also higher in the CDI-positive diarrheal stools. Our results demonstrate that CDI elicits a proinflammatory host response, and we report for the first time that IL-23 is a major marker in CDI-positive diarrheal stools. IL-23 may explain the lack of a robust immunological response exhibited by a proportion of CDI patients and may relate to recurrence; the IL-23 levels induced during CDI in these patients may be inadequate to sustain the cellular immunity conferred by this cytokine in promoting the induction and proliferation of effector memory T cells.
Potential Impact of a Microarray-Based Nucleic Acid Assay for Rapid Detection of Gram-Negative Bacteria and Resistance Markers in Positive Blood Cultures
Authors: Mancini Nicasio , Infurnari Laura , Ghidoli Nadia , Valzano Grazia , Clementi Nicola , Burioni Roberto , Clementi Massimo
Published: January 2014

We evaluated the Verigene Gram-negative blood culture (BC-GN) test, a microarray that detects Gram-negative bacteria and several resistance genes. A total of 102 positive blood cultures were tested, and the BC-GN test correctly identified 97.9% of the isolates within its panel. Resistance genes (CTX-M, KPC, VIM, and OXA genes) were detected in 29.8% of the isolates, with positive predictive values of 95.8% (95% confidence interval [CI], 87.7% to 98.9%) in
Enterobacteriaceae
and 100% (95% CI, 75.9% to 100%) in
Pseudomonas aeruginosa
and negative predictive values of 100% (95% CI, 93.9% to 100%) and 78.6% (95% CI, 51.0% to 93.6%), respectively.
De Novo
Meningitis Caused by Propionibacterium acnes in a Patient with Metastatic Melanoma
Authors: Burnham Jason P. , Thomas Benjamin S. , Trevino Sergio E. , McElvania TeKippe Erin , Burnham Carey-Ann D. , Kuhlmann F. Matthew
Published: January 2014

Propionibacterium acnes
is a known cause of postneurosurgical meningitis; however, it is rarely implicated in
de novo
meningitis. Herein we report a case of a 49-year-old male with
de novo
meningitis caused by
P. acnes
with metastatic melanoma as the only identified risk factor for his infection.
A Multiplex Real-Time PCR Assay for Identification of Pneumocystis jirovecii, Histoplasma capsulatum, and Cryptococcus neoformans/Cryptococcus gattii in Samples from AIDS Patients with Opportunistic Pneumonia
Authors: Gago Sara , Esteban Cristina , Valero Clara , Zaragoza Óscar , Puig de la Bellacasa Jorge , Buitrago María José
Published: January 2014

A molecular diagnostic technique based on real-time PCR was developed for the simultaneous detection of three of the most frequent causative agents of fungal opportunistic pneumonia in AIDS patients:
Pneumocystis jirovecii
,
Histoplasma capsulatum
, and
Cryptococcus neoformans
/
Cryptococcus gattii
. This technique was tested in cultured strains and in clinical samples from HIV-positive patients. The methodology used involved species-specific molecular beacon probes targeted to the internal transcribed spacer regions of the rDNA. An internal control was also included in each assay. The multiplex real-time PCR assay was tested in 24 clinical strains and 43 clinical samples from AIDS patients with proven fungal infection. The technique developed showed high reproducibility (
r
2
of >0.98) and specificity (100%). For
H. capsulatum
and
Cryptococcus
spp., the detection limits of the method were 20 and 2 fg of genomic DNA/20 μl reaction mixture, respectively, while for
P. jirovecii
the detection limit was 2.92 log
10
copies/20 μl reaction mixture. The sensitivity
in vitro
was 100% for clinical strains and 90.7% for clinical samples. The assay was positive for 92.5% of the patients. For one of the patients with proven histoplasmosis,
P. jirovecii
was also detected in a bronchoalveolar lavage sample. No PCR inhibition was detected. This multiplex real-time PCR technique is fast, sensitive, and specific and may have clinical applications.
Comparison of Two Assays for Molecular Determination of Rifampin Resistance in Clinical Samples from Patients with Buruli Ulcer Disease
Authors: Jansson Moritz , Beissner Marcus , Phillips Richard Odame , Badziklou Kossi , Piten Ebekalisai , Maman Issaka , Sarfo Fred Stephen , Huber Kristina Lydia , Rhomberg Agata , Symank Dominik , Wagner Magdalena , Wiedemann Franz , Nitschke Jörg , Banla Kere Abiba , Herbinger Karl-Heinz , Adjei Ohene , Löscher Thomas , Bretzel Gisela
Published: January 2014

This study evaluates a novel assay for detecting rifampin resistance in clinical
Mycobacterium ulcerans
isolates. Although highly susceptible for PCR inhibitors in 50% of the samples tested, the assay was 100%
M. ulcerans
specific and yielded >98% analyzable sequences with a lower limit of detection of 100 to 200 copies of the target sequence.
Bacterial Lymphadenitis at a Major Referral Hospital in France from 2008 to 2012
Authors: Safont Marion , Angelakis Emmanouil , Richet Hervé , Lepidi Hubert , Fournier Pierre-Edouard , Drancourt Michel , Raoult Didier
Published: January 2014

Lymph node enlargement is a common medical problem, and in a large number of patients, the causes of lymphadenopathy remain undiagnosed. We report a thorough microbiological analysis of 1,688 lymph node biopsy specimens collected in our bartonellosis reference center. We studied lymph node biopsy samples from patients with suspected regional infectious lymph node enlargement from January 2008 to December 2012. To evaluate a useful strategy for the diagnosis of infectious lymphadenitis, specimens were cultured and subjected to molecular assays. Histologic analysis was done when possible. A total of 642 (38%) biopsy specimens were infected with a bacterial agent, and quantitative PCR (qPCR) was significantly better than 16S rRNA gene PCR (
rrs
) for the detection of
Bartonella henselae
(
P
= 0.05),
Mycobacterium tuberculosis
(
P
= 0.05), and
Mycobacterium avium
(
P
= 0.007). Molecular assays were significantly better than bacterial cultures for the diagnosis of
Francisella tularensis
(
P
= 0.017) but were less effective for detecting
M. tuberculosis
(
P
= 0.004) and
M. avium
(
P
= 0.001). Histologic analysis was done for 412 lymph nodes, and 20% of these were compatible with an infectious lymphadenitis, whereas a neoplasm was found in 29% of these lymph nodes.
M. tuberculosis
was detected significantly more in female than in male patients (
P
= 0.01), and patients with cat scratch disease (CSD) were younger than patients with
M. tuberculosis
,
Tropheryma whipplei
, and
F. tularensis
. Negative
rrs
PCR does not exclude the diagnosis of infectious lymphadenitis. Histologic analysis of lymph node biopsy specimens is critical, as a diagnosis of infectious lymphadenitis does not preclude other concurrent diseases.
Prevalence of Mupirocin Resistance in Staphylococcus pseudintermedius
Authors: Godbeer Stacey M. , Gold Randi M. , Lawhon Sara D.
Published: January 2014

In the United States, veterinary use of mupirocin is primarily limited to the treatment of canine pyoderma caused by methicillin-resistant
Staphylococcus pseudintermedius
(MRSP). In this study, only 1 of 581
S. pseudintermedius
isolates tested was resistant to mupirocin and carried the high-level mupirocin resistance gene,
ileS2
, on a plasmid.
Natural Single-Nucleotide Polymorphisms in the 3′ Region of the HIV-1
pol
Gene Modulate Viral Replication Ability
Authors: Nomaguchi Masako , Miyake Ariko , Doi Naoya , Fujiwara Sachi , Miyazaki Yasuyuki , Tsunetsugu-Yokota Yasuko , Yokoyama Masaru , Sato Hironori , Masuda Takao , Adachi Akio
Published: January 2014

We previously showed that prototype macaque-tropic human immunodeficiency virus type 1 (HIV-1) acquired nonsynonymous growth-enhancing mutations within a narrow genomic region during the adaptation process in macaque cells. These adaptive mutations were clustered in the 3′ region of the
pol
gene, encoding a small portion of the C-terminal domain of integrase (IN). Mutations in HIV-1 IN have been reported to have pleiotropic effects on both the early and late phases in viral replication.
cis
-acting functions in the IN-coding sequence for viral gene expression have also been reported. We here demonstrated that the adaptive mutations promoted viral growth by increasing virion production with no positive effects on the early replication phase. Synonymous codon alterations in one of the adaptive mutations influenced virion production levels, which suggested nucleotide-dependent regulation. Indeed, when the single-nucleotide natural polymorphisms observed in the 3′ regions of 196 HIV-1/simian immunodeficiency virus (SIVcpz)
pol
genes (nucleotides [nt] 4895 to 4929 for HIV-1 NL4-3) were introduced into macaque- and human-tropic HIV-1 clones, more than half exhibited altered replication potentials. Moreover, single-nucleotide mutations caused parallel increases or decreases in the expression levels of viral late proteins and viral replication potentials. We also showed that the overall expression profiles of viral mRNAs were markedly changed by single-nucleotide mutations. These results demonstrate that the 3′ region of the HIV-1
pol
gene (nt 4895 to 4929) can alter viral replication potential by modulating the expression pattern of viral mRNAs in a nucleotide-dependent manner.

IMPORTANCE
Viruses have the plasticity to adapt themselves under various constraints. HIV-1 can mutate and evolve in growth-restrictive cells by acquiring adaptive changes in its genome. We have previously identified some growth-enhancing mutations in a narrow region of the IN-coding sequence, in which a number of
cis
-acting elements are located. We now focus on the virological significance of this
pol
gene region and the mechanistic basis underlying its effects on viral replication. We have found several naturally occurring synonymous mutations within this region that alter viral replication potentials. The effects caused by these natural single-nucleotide polymorphisms are linked to the definite expression patterns of viral mRNAs. We show here that the nucleotide sequence of the
pol
gene (nucleotides 4895 to 4929 for HIV-1 NL4-3) plays an important role in HIV-1 replication by modulating viral gene expression.
Human Papillomavirus E7 Oncoprotein Increases Production of the Anti-Inflammatory Interleukin-18 Binding Protein in Keratinocytes
Authors: Richards Kathryn H. , Doble Rosella , Wasson Christopher W. , Haider Mohammed , Blair G. Eric , Wittmann Miriam , Macdonald Andrew
Published: January 2014

Human papillomavirus (HPV) can successfully evade the host immune response to establish a persistent infection. We show here that expression of the E7 oncoprotein in primary human keratinocytes results in increased production of interleukin-18 (IL-18) binding protein (IL-18BP). This anti-inflammatory cytokine binding protein is a natural antagonist of IL-18 and is necessary for skin homeostasis. We map increased IL-18BP production to the CR3 region of E7 and demonstrate that this ability is shared among E7 proteins from different HPV types. Furthermore, mutagenesis shows that increased IL-18BP production is mediated by a gamma-activated sequence (GAS) in the IL-18BP promoter. Importantly, the increased IL-18BP levels seen in E7-expressing keratinocytes are capable of diminishing IL-18-mediated CD4 lymphocyte activation. This study provides the first evidence for a virus protein that targets IL-18BP and further validates E7 as a key component of the HPV immune evasion armor.

IMPORTANCE
Infection with human papillomavirus is a leading cause of morbidity and mortality worldwide. This study demonstrates that the E7 protein increases production of the anti-inflammatory IL-18BP, a major regulator of epithelial homeostasis. A number of E7 proteins can increase IL-18BP production, and a region within the CR3 of E7 is necessary for mediating the increase. A consequence of increased IL-18BP production is a reduction in CD4-positive lymphocyte activation in response to IL-18 costimulation. These findings may shed light on the immune evasion abilities of HPV.
Recombinant Adeno-Associated Virus Utilizes Host Cell Nuclear Import Machinery To Enter the Nucleus
Authors: Nicolson Sarah C. , Samulski R. Jude
Published: January 2014

Recombinant adeno-associated viral (rAAV) vectors have garnered much promise in gene therapy applications. However, widespread clinical use has been limited by transduction efficiency. Previous studies suggested that the majority of rAAV accumulates in the perinuclear region of cells, presumably unable to traffic into the nucleus. rAAV nuclear translocation remains ill-defined; therefore, we performed microscopy, genetic, and biochemical analyses
in vitro
in order to understand this mechanism. Lectin blockade of the nuclear pore complex (NPC) resulted in inhibition of nuclear rAAV2. Visualization of fluorescently labeled particles revealed that rAAV2 localized to importin-β-dense regions of cells in late trafficking steps. Additionally, small interfering RNA (siRNA) knockdown of importin-β partially inhibited rAAV2 nuclear translocation and inhibited transduction by 50 to 70%. Furthermore, coimmunopreciptation (co-IP) analysis revealed that capsid proteins from rAAV2 could interact with importin-β and that this interaction was sensitive to the small GTPase Ran. More importantly, mutations to key basic regions in the rAAV2 capsid severely inhibited interactions with importin-β. We tested several other serotypes and found that the extent of importin-β interaction varied, suggesting that different serotypes may utilize alternative import proteins for nuclear translocation. Co-IP and siRNA analyses were used to investigate the role of other karyopherins, and the results suggested that rAAV2 may utilize multiple import proteins for nuclear entry. Taken together, our results suggest that rAAV2 interacts with importin-β alone or in complex with other karyopherins and enters the nucleus via the NPC. These results may lend insight into the design of novel AAV vectors that have an enhanced nuclear entry capability and transduction potential.

IMPORTANCE
Use of recombinant adeno-associated viral (rAAV) vectors for gene therapy applications is limited by relatively low transduction efficiency, in part due to cellular barriers that hinder successful subcellular trafficking to the nucleus, where uncoating and subsequent gene expression occur. Nuclear translocation of rAAV has been regarded as a limiting step for successful transduction but it remains ill-defined. We explored potential nuclear entry mechanisms for rAAV2 and found that rAAV2 can utilize the classical nuclear import pathway, involving the nuclear pore complex, the small GTPase Ran, and cellular karyopherins. These results could lend insight into the rational design of novel rAAV vectors that can more efficiently translocate to the nucleus, which may lead to more efficient transduction.