bluuebunny/crossref_metadata_2025 huggingface dataset:
Lithological, structural, and geochemical characteristics of the Mesoarchean Târtoq greenstone belt, southern West Greenland, and the Chugach – Prince William accretionary complex, southern Alaska: evidence for uniformitarian plate-tectonic processes
Authors: Polat Ali , Kokfelt Thomas , Burke Kevin C. , Kusky Timothy M. , Bradley Dwight C. , Dziggel Annika , Kolb Jochen
Published: May 2016

The Mesoarchean Târtoq greenstone belt, southern West Greenland, consists of tectonically imbricated slices of metamorphosed basalt, gabbro, peridotite, and sedimentary rocks and is intruded by felsic rocks (now mylonites) with well-preserved duplex structures, representing a relict accretionary prism. The Târtoq greenstone belt is a remnant of a supra-subduction zone ophiolite that originated as back-arc basin oceanic crust. Following the initiation of intra-oceanic subduction, the back-arc oceanic crust accreted to the overriding plate, forming an accretionary prism. The felsic mylonites are compositionally akin to Archean tonalite–trondhjemite–granodiorite suites. Field observations, along with geochemical and zircon U–Pb age data, indicate that the protoliths of the felsic mylonites were derived from partial melting of back-arc basalts in the accretionary prism and emplaced along thrust faults between 3012 ± 4 and 2993 ± 6 Ma. It is proposed that the partial melting of the basalts likely occurred in response to ridge subduction. The Upper Cretaceous turbiditic greywackes of the Chugach – Prince William accretionary complex in southern Alaska are intruded by Paleogene felsic dykes. These felsic dykes appear to have been derived from partial melting of subducted and (or) accreted oceanic crust during slab window magmatism. Archean granitoid–greenstone terrains share many geological characteristics of Phanerozoic subduction–accretion complexes such as the Alaskan and Altaid subduction–accretion complexes, consistent with the operation of uniformitarian geological processes in the Archean. The Archean Earth might have been dominated by numerous smaller plates and greater ridge length than today that would have resulted in more frequent ridge-accretionary prism interactions and larger volumes of tonalite–trondhjemite–granodiorite generation in subduction–accretion complexes.
Factors that affect detection of threats from food competitors within a group
Authors: Beauchamp Guy
Published: May 2016

Early detection is crucial to avoid threats from predators and competitors. Factors that affect threat detection have rarely been investigated in the context of food competition. I examined the ability to detect threats of displacement from feeding areas by competitors in flocks of staging Semipalmated Sandpipers (Calidris pusilla (L., 1766)). I predicted that targeted birds would be more likely to detect competitors attacking from the side or from the front rather than from behind because a blind area behind the head interferes with detection. Preening or sleeping birds in feeding areas might be less likely to detect attacks if such activities interfere with vigilance. If targeted birds maintain vigilance against attackers, attacks launched from farther away should be detected more frequently since more time is available for detection. As predicted, attacks were detected less often when launched from behind and more often when launched from farther away. The longest attacks were detected less often perhaps because birds relaxed their vigilance when neighbours were farther away. The ability to detect threats did not vary with targeted bird activity. Several factors influence the ability to detect threats from food competitors providing us with a novel context in which to investigate threat detection.
Use of microsatellite markers for the assessment of bambara groundnut breeding system and varietal purity before genome sequencing
Authors: Ho Wai Kuan , Muchugi Alice , Muthemba Samuel , Kariba Robert , Mavenkeni Busiso Olga , Hendre Prasad , Song Bo , Van Deynze Allen , Massawe Festo , Mayes Sean
Published: May 2016

Maximizing the research output from a limited investment is often the major challenge for minor and underutilized crops. However, such crops may be tolerant to biotic and abiotic stresses and are adapted to local, marginal, and low-input environments. Their development through breeding will provide an important resource for future agricultural system resilience and diversification in the context of changing climates and the need to achieve food security. The African Orphan Crops Consortium recognizes the values of genomic resources in facilitating the improvement of such crops. Prior to beginning genome sequencing there is a need for an assessment of line varietal purity and to estimate any residual heterozygosity. Here we present an example from bambara groundnut (Vigna subterranea (L.) Verdc.), an underutilized drought tolerant African legume. Two released varieties from Zimbabwe, identified as potential genotypes for whole genome sequencing (WGS), were genotyped with 20 species-specific SSR markers. The results indicate that the cultivars are actually a mix of related inbred genotypes, and the analysis allowed a strategy of single plant selection to be used to generate non-heterogeneous DNA for WGS. The markers also confirmed very low levels of heterozygosity within individual plants. The application of a pre-screen using co-dominant microsatellite markers is expected to substantially improve the genome assembly, compared to a cultivar bulking approach that could have been adopted.
Periodically driven adiabatic bipolarons
Authors: Kornilovitch Pavel
Published: May 2016

Small lattice bipolarons driven by external harmonic fields are considered in the adiabatic approximation. Resonant excitation of ions modulates the trapping potential and promotes hole transfer between neighboring atomic layers. It leads to a dramatic decrease of the apparent bipolaron mass compared to the undriven case. This effect offers an explanation for dynamic stabilization of superconductivity at high temperatures recently observed in layered cuprates.
The ionized electron return phenomenon of Rydberg atom in crossed-fields
Authors: Dong Chengwei , Wang Peijie , Du Mengli , Uzer Turgay , Lan Yueheng
Published: May 2016

Rydberg atom is highly excited with one valence electron being in a high quantum state, which is very far away from the nucleus. The energy level is similar to that of the hydrogen atom. Introducing externally perpendicular electric and magnetic fields breaks the rotation symmetry and the traditional view is that the ionized electron crosses from the bound into the unbound region and will never return. However, we find that when the field is strong enough, the electron does not move off to infinity and there is a certain possibility of return. Three new periodic orbits are found by the variational method and the physical significance of the phenomenon is also discussed.
Generalized Darboux transformation and rogue wave solution of the coherently-coupled nonlinear Schrödinger system
Authors: Zhang Hai-Qiang , Yuan Sha-Sha , Wang Yue
Published: May 2016

In this paper, the generalized Darboux transformation for the coherently-coupled nonlinear Schrödinger (CCNLS) system is constructed in terms of determinant representations. Based on the Nth-iterated formula, the vector bright soliton solution and vector rogue wave solution are systematically derived under the nonvanishing background. The general first-order vector rogue wave solution can admit many different fundamental patterns including eye-shaped and four-petaled rogue waves. It is believed that there are many more abundant patterns for high order vector rogue waves in CCNLS system.
The second post-Newtonian light propagation and its astrometric measurement in the Solar System: Light time and frequency shift
Authors: Deng Xue-Mei
Published: May 2016

The light time equation and frequency shift are worked out in the framework of a second parametrized post-Newtonian (2PPN) formalism in the Solar System barycentric reference system (SSBRS) developed in a recently published paper. Effects of each body’s oblateness, spin and translational motion are taken into account for the light propagation. It is found that, at the second post-Newtonian (2PN) approximation, the light time and frequency shift depend on the parameter [Formula: see text] only.
IMPACTS OF ANNEAL TEMPERATURE ON THE STRUCTURAL, MAGNETIC AND OPTICAL PROPERTIES OF THE Fe:LaSrFeO4 COMPOSITE FILM
Authors: SHI J. , JIA Y. L. , LI X. H. , DAI X. H. , GUO J. X. , LOU J. Z. , ZHAO Q. X. , WANG J. , ZHANG X. Y. , LIU B. T.
Published: May 2016

We prepared the pulsed laser deposited Fe:LaSrFeO4 (LSFO) composite films on quartz substrates by decomposing the La[Formula: see text]Sr[Formula: see text]FeO3 target at room temperature in a high vacuum. Impacts of anneal temperature on the structural and physical properties have been investigated, and the systematic changes were found in structural, magnetic and optical absorption properties upon annealing. The LSFO (110) spacing decreases with the increase of annealing temperature, which can be attributed to the release of intrinsic strain; and there is an increase in spacing for the 750[Formula: see text]C annealed sample, which is ascribed to the oxygen loss in LSFO films.
HIGH-DIMENSIONAL PORTFOLIO OPTIMIZATION WITH TRANSACTION COSTS
Authors: BROADIE MARK , SHEN WEIWEI
Published: May 2016

This paper studies Merton’s portfolio optimization problem with proportional transaction costs in a discrete-time finite horizon. Facing short-sale and borrowing constraints, investors have access to a risk-free asset and multiple risky assets whose returns follow a multivariate geometric Brownian motion. Lower and upper bounds for optimal solutions up to the problem with 20 risky assets and 40 investment periods are computed. Three lower bounds are proposed: the value function optimization (VF), the hyper-sphere and the hyper-cube policy parameterizations (HS and HC). VF attacks the conundrums in traditional value function iteration for high-dimensional dynamic programs with continuous decision and state spaces. HS and HC respectively approximate the geometry of the trading policy in the high-dimensional state space by two surfaces. To evaluate lower bounds, two new upper bounds are provided via a duality method based on a new auxiliary problem (OMG and OMG2). Compared with existing methods across various suites of parameters, new methods lucidly show superiority. The three lower bound methods always achieve higher utilities, HS and HC cut run times by a factor of 100, and OMG and OMG2 mostly provide tighter upper bounds. In addition, how the no-trading region characterizing the optimal policy deforms when short-sale and borrowing constraints bind is investigated.
Optimal Strategies in Best-Choice Game with Incomplete Information — The Voice Show
Authors: Mazalov Vladimir V. , Ivashko Anna A. , Konovalchikova Elena N.
Published: May 2016

This paper studies a game-theoretic model of best choice with incomplete information. In this model, players observe a sequence of incoming objects each described by two random quality components. The first component is announced to players and the other one is hidden. Players choose an object based on known information about it. The winner is the player having a higher sum of the quality components than the opponents do. The optimal strategies of the players and their payoffs in the game are derived.
Competitive Traffic Assignment in a Green Transit Network
Authors: Krylatov Alexander Y. , Zakharov Victor V.
Published: May 2016

Currently, there is a lack of methodological tools, based on competitive behavioral models, available to support decision makers with regard to encouraging the use of green vehicles. This paper is devoted to the problem of competitive traffic flow assignment in a green transit network consisting of green and nongreen routes. The analysis of a competitive framework is performed, and an approach for defining Nash equilibrium assignment in a green subnetwork is developed. The conditions of an optimal green transit network are also defined explicitly for a network of parallel routes.
Monotonicity and concavity of integral functionals involving area measures of convex bodies
Authors: Colesanti Andrea , Hug Daniel , Saorín Gómez Eugenia
Published: May 2016

For a broad class of integral functionals defined on the space of [Formula: see text]-dimensional convex bodies, we establish necessary and sufficient conditions for monotonicity, and necessary conditions for the validity of a Brunn–Minkowski type inequality. In particular, we prove that a Brunn–Minkowski type inequality implies monotonicity, and that a general Brunn–Minkowski type inequality is equivalent to the functional being a mixed volume.
Gradient estimates for Neumann boundary value problem of Monge–Ampère type equations
Authors: Jiang Feida , Xiang Ni , Xu Jinju
Published: May 2016

This paper concerns the gradient estimates for Neumann problem of a certain Monge–Ampère type equation with a lower order symmetric matrix function in the determinant. Under a one-sided quadratic structure condition on the matrix function, we present two alternative full discussions of the global gradient bound for the elliptic solutions.
New Method for Solving a General Multiple Criteria Decision-Making Problem Under Risk in Fuzzy Environment
Authors: Thillaigovindan N. , Shanthi S. Anita , Naidu J. Vadivel
Published: May 2016

This paper considers a multiple criteria decision-making (MCDM) problem under risk in fuzzy environment in its general form. There are m alternatives which need to be ranked on the basis of a set of n criteria. The alternatives and the criteria are evaluated based on a set of l characteristics. The entire data is presented in the form of interval valued intuitionistic fuzzy soft set of root type. In addition each criterion is assigned a subjective criterion weight based on expert’s evaluation and each characteristic is assigned a probability weight on the basis of decision maker’s knowlege and understanding of the importance of the characteristic. This problem may be called as a MCDM problem under risk in fuzzy environment in its general form. A method for ranking the alternatives using the new score functions, prospect theory and method of determining the optimum criteria weights is explained. An algorithm is developed for this purpose and its working illustrated with a suitable example.
Effect of Submergence Condition and Overtopping Depth on Gully Scour Dimensions: Observations from the 2011 Great East Japan Tsunami
Authors: Afreen Sazia , Yagisawa Junji , Tanaka Norio
Published: May 2016

When a tsunami reaches a shore, it propagates along river channels with tremendous energy and overtops river levees. It causes severe damage to the levee structures through scouring along levee slope. In the present study, gully scours created along the levee slopes of two rivers (Omotogawa and Sakarigawa Rivers) in Iwate Prefecture and three rivers (Nanakitagawa, New Kitakamigawa, and Abukumagawa Rivers) in Miyagi Prefecture were investigated after the 2011 Great East Japan tsunami. The energy head during levee overtopping for each location was calculated from post-tsunami surveys. The relationship between the energy head and gully scour dimensions (length, width, and depth) was analyzed. The analyses clarified that gully scour dimensions were greatly dominated by two important phenomena: (i) overflow type (free overflow or submerged overflow), and (ii) soil texture at the scoured region. The present study results can be utilized to obtain the overtopping flow height for post-tsunami analysis.
Standard deviation of recurrence times for piecewise linear transformations
Authors: Ismael Mimoon , Nillsen Rodney , Williams Graham
Published: May 2016

This paper is concerned with dynamical systems of the form [Formula: see text], where [Formula: see text] is a bounded interval and [Formula: see text] comes from a class of measure-preserving, piecewise linear transformations on [Formula: see text]. If [Formula: see text] is a Borel set and [Formula: see text], the Poincaré recurrence time of [Formula: see text] relative to [Formula: see text] is defined to be the minimum of [Formula: see text], if the minimum exists, and [Formula: see text] otherwise. The mean of the recurrence time is finite and is given by Kac’s recurrence formula. In general, the standard deviation of the recurrence times need not be finite but, for the systems considered here, a bound for the standard deviation is derived.
Diophantine quadruples and near-Diophantine quintuples from P3,K sequences
Authors: Ramasamy A. M. S.
Published: May 2016

The question of a non-[Formula: see text]-type [Formula: see text] sequence wherein the fourth term shares the property [Formula: see text] with the first term has not been investigated so far. The present paper seeks to fill up the gap in this unexplored area. Let [Formula: see text] denote the set of all natural numbers and [Formula: see text] the sequence of Fibonacci numbers. Choose two integers [Formula: see text] and [Formula: see text] with [Formula: see text] such that their product increased by [Formula: see text] is a square [Formula: see text]. Certain properties of the sequence [Formula: see text] defined by the relation [Formula: see text] are established in this paper and polynomial expressions for Diophantine quadruples from the [Formula: see text] sequence [Formula: see text] are derived. The concept of a near-Diophantine quintuple is introduced and it is proved that there exist an infinite number of near-Diophantine quintuples.
An all-on-chip method for testing neutrophil chemotaxis induced by fMLP and COPD patient’s sputum
Authors: Wu Jiandong , Hillier Craig , Komenda Paul , de Faria Ricardo Lobato , Santos Susy , Levin David , Zhang Michael , Lin Francis
Published: May 2016

Neutrophil migration and chemotaxis are fundamentally important biological processes and have direct relevance to various health problems. Microfluidic devices provide useful experimental tools for the quantitative analysis of neutrophil chemotaxis in controlled microenvironments. However, such experiments often require specialized research facilities and lengthy cell preparation from a large amount of blood. In this paper, we report a new, yet simple, all-on-chip method for the magnetic isolation of untouched neutrophils directly from small volumes of blood, followed by chemotaxis testing on the same microfluidic device. Furthermore, we incorporated a cell-docking structure to the microfluidic device for better control of the cells’ initial positions before the chemotaxis test and for improved data analysis. The whole experiment can be performed in less than 25 minutes. We successfully validated this method by testing neutrophil chemotaxis to both purified chemoattractant (i.e. fMLP) and clinical samples (sputum from patients with Chronic Obstructive Pulmonary Disease, COPD). Thus, the “all-on-chip” method can be a useful tool for research and clinical applications that require rapid and accurate chemotaxis testing of untouched neutrophils.
The Complexity of Learning Tree Patterns from Example Graphs
Authors: Cohen Sara , Weiss Yaacov Y.
Published: May 2016

This article investigates the problem of learning tree patterns that return nodes with a given set of labels, from example graphs provided by the user. Example graphs are annotated by the user as being either
positive
or
negative
. The goal is then to determine whether there exists a tree pattern returning tuples of nodes with the given labels in each of the positive examples, but in none of the negative examples, and furthermore, to find one such pattern if it exists. These are called the
satisfiability
and
learning
problems, respectively.

This article thoroughly investigates the satisfiability and learning problems in a variety of settings. In particular, we consider example sets that (1) may contain only positive examples, or both positive and negative examples, (2) may contain directed or undirected graphs, and (3) may have multiple occurrences of labels or be uniquely labeled (to some degree). In addition, we consider tree patterns of different types that can allow, or prohibit, wildcard labeled nodes and descendant edges. We also consider two different semantics for mapping tree patterns to graphs. The complexity of satisfiability is determined for the different combinations of settings. For cases in which satisfiability is polynomial, it is also shown that learning is polynomial. (This is nontrivial as satisfying patterns may be exponential in size.) Finally, the
minimal learning
problem, that is, that of finding a minimal-sized satisfying pattern, is studied for cases in which satisfiability is polynomial.
Neuromorphic Processors with Memristive Synapses
Authors: Wang Qian , Kim Yongtae , Li Peng
Published: May 2016

Due to their nonvolatile nature, excellent scalability, and high density, memristive nanodevices provide a promising solution for low-cost on-chip storage. Integrating memristor-based synaptic crossbars into digital neuromorphic processors (DNPs) may facilitate efficient realization of brain-inspired computing. This article investigates architectural design exploration of DNPs with memristive synapses by proposing two synapse readout schemes. The key design tradeoffs involving different analog-to-digital conversions and memory accessing styles are thoroughly investigated. A novel storage strategy optimized for feedforward neural networks is proposed in this work, which greatly reduces the energy and area cost of the memristor array and its peripherals.
Synchronization of Queries and Views Upon Schema Evolutions
Authors: Caruccio Loredana , Polese Giuseppe , Tortora Genoveffa
Published: May 2016

One of the problems arising upon the evolution of a database schema is that some queries and views defined on the previous schema version might no longer work properly. Thus, evolving a database schema entails the redefinition of queries and views to adapt them to the new schema. Although this problem has been mainly raised in the context of traditional information systems, solutions to it are also advocated in other database-related areas, such as Data Integration, Web Data Integration, and Data Warehouses. The problem is a critical one, since industrial organizations often need to adapt their databases and data warehouses to frequent changes in the real world. In this article, we provide a survey of existing approaches and tools to the problem of adapting queries and views upon a database schema evolution; we also propose a classification framework to enable a uniform comparison method among many heterogeneous approaches and tools.
Exploiting Sequential and Temporal Localities to Improve Performance of NAND Flash-Based SSDs
Authors: Lee Sungjin , Shin Dongkun , Kim Youngjin , Kim Jihong
Published: May 2016

NAND flash-based Solid-State Drives (SSDs) are becoming a viable alternative as a secondary storage solution for many computing systems. Since the physical characteristics of NAND flash memory are different from conventional Hard-Disk Drives (HDDs), flash-based SSDs usually employ an intermediate software layer, called a Flash Translation Layer (FTL). The FTL runs several firmware algorithms for logical-to-physical mapping, I/O interleaving, garbage collection, wear-leveling, and so on. These FTL algorithms not only have a great effect on storage performance and lifetime, but also determine hardware cost and data integrity. In general, a hybrid FTL scheme has been widely used in mobile devices because it exhibits high performance and high data integrity at a low hardware cost. Recently, a demand-based FTL based on page-level mapping has been rapidly adopted in high-performance SSDs. The demand-based FTL more effectively exploits the device-level parallelism than the hybrid FTL and requires a small amount of memory by keeping only popular mapping entries in DRAM. Because of this caching mechanism, however, the demand-based FTL is not robust enough for power failures and requires extra reads to fetch missing mapping entries from NAND flash. In this article, we propose a new flash translation layer called LAST++. The proposed LAST++ scheme is based on the hybrid FTL, thus it has the inherent benefits of the hybrid FTL, including low resource requirements, strong robustness for power failures, and high read performance. By effectively exploiting the locality of I/O references, LAST++ increases device-level parallelism and reduces garbage collection overheads. This leads to a great improvement of I/O performance and makes it possible to overcome the limitations of the hybrid FTL. Our experimental results show that LAST++ outperforms the demand-based FTL by 27% for writes and 7% for reads, on average, while offering higher robustness against sudden power failures. LAST++ also improves write performance by 39%, on average, over the existing hybrid FTL.
Almost first-class language embedding: taming staged embedded DSLs
Authors: Scherr Maximilian , Chiba Shigeru
Published: May 2016

Embedded domain-specific languages (EDSLs), inheriting a general-purpose language's features as well as look-and-feel, have traditionally been second-class or rather non-citizens in terms of host-language design. This makes sense when one regards them to be on the same level as traditional, non-EDSL library interfaces. However, this equivalence only applies to the simplest of EDSLs. In this paper we illustrate why this is detrimental when moving on to EDSLs that employ staging, i.e. program reification, by example of various issues that affect authors and users alike. We believe that if EDSLs are to be considered a reliable, language-like interface abstraction, they require exceptional attention and design scrutiny. Instead of unenforceable conventions, we advocate the acceptance of EDSLs as proper, i.e. almost first-class, citizens while retaining most advantages of pure embeddings. As a small step towards this goal, we present a pragmatic framework prototype for Java. It is based on annotations that explicate and document membership to explicit EDSL entities. In a nutshell, our framework identifies (annotated) method calls and field accesses as EDSL terms and dynamically constructs an abstract-syntax representation, which is eventually passed to a semantics-defining back end implemented by the EDSL author.
Migrating large object-oriented Applications into component-based ones: instantiation and inheritance transformation
Authors: Alshara Zakarea , Seriai Abdelhak-Djamel , Tibermacine Chouki , Bouziane Hinde Lilia , Dony Christophe , Shatnawi Anas
Published: May 2016

Large object-oriented applications have complex and numerous dependencies, and usually do not have explicit software architectures. Therefore they are hard to maintain, and parts of them are difficult to reuse. Component-based development paradigm emerged for improving these aspects and for supporting effective maintainability and reuse. It provides better understandability through a high-level architecture view of the application. Thereby migrating object-oriented applications to component-based ones will contribute to improve these characteristics (maintainability and reuse). In this paper, we propose an approach to automatically transform object-oriented applications to component-based ones. More particularly, the input of the approach is the result provided by software architecture recovery: a component-based architecture description. Then, our approach transforms the object-oriented source code in order to produce deployable components. We focus in this paper on the transformation of source code related to instantiation and inheritance dependencies between classes that are in different components. We experimented the proposed solution in the transformation of a collection of Java applications into the OSGi framework. The experimental results are discussed in this paper.
Recent Progress in Vaccine Development against Leishmania Species Infections
Authors: Papadopoulou Barbara , Olivier Martin , Ouellette Marc
Published: May 2016

The understanding of the immunobiology of infections caused by the
protozoan parasite leishmania is now extensive and has pinpointed
the importance of T cell‐mediated immunity. Several vaccination
strategies using either killed parasites, subunit vaccines, DNA
vaccines or live attenuated strains have been used successfully
with and without adjuvants to induce cellular immunity and protect
against leishmania infections. The most recent progress in
leishmania vaccine development is described.
Circadian Rhythms in Infectious Diseases: Do They Matter?
Authors: Beauchamp Denis , Labrecque Gaston
Published: May 2016

The present paper reviews the importance of the time of day in medicine, with a special emphasis on infectious diseases
and antibiotics. Data were obtained from scientific journals following a literature search and from studies carried out in
the authors’ laboratory. Data indicating that the signs and symptoms of disease do not appear at random over a 24 h
period are now available. For example. asthma occurs usually at night, while myocardial infarction or anginal attacks
occur in the early morning hours. Very little data are available on infectious diseases, and most studies were carried out
on the pharmacokinetics and toxicity of antibiotics. These data suggest that antimicrobial agents are eliminated more
rapidly when injected during the activity period of animals or humans. It is also noteworthy that aminoglycosides and
amphotericin B induced less toxicity during the activity period of laboratory animals or patients, and highest toxicity
occurred during the sleeping period. This is particularly evident with data on aminoglycosides. Temporal variations were
also observed in the effectiveness of aminoglycosides, but these data were found only in animal models of infectious
diseases. Temporal variations in the pharmacokinetics, toxicity and effectiveness of a ntibiotics may lead to a more
rational use of medications in patients.
Rapid Diagnosis of Bacterial Infections Using Technologies Based on Nucleic Acid Detection
Authors: Picard François J , Bergeron Michel G
Published: May 2016

Bacterial identification and antibiotic susceptibility testing methods used in clinical microbiology laboratories generally
require at least two days. This long delay often forces physicians to treat patients presumptively with broad‐spectrum
antibiotics. Novel diagnostic tests based on the detection of nucleic acids (DNA or RNA) offer a great potential for the
rapid (approximately 1 h) diagnosis of bacterial infections. The present article reviews various aspects of the development
and validation of nucleic acid‐based assays suitable for the detection and identification of bacteria as well as for
the detection of associated antibiotic resistance genes. The potential of these assays for routine use in clinical microbiology
laboratories is also discussed.
Recent Developments in Viral Load Measurements in Human Herpesviruses
Authors: Boivin Guy
Published: May 2016

Recent developments in molecular biology have allowed precise quantitative analysis of herpesvirus DNA in many biological
fluids. Th is paper reviews the clinical utility of performing quantitative polymerase chain reaction testing for herpesviruses.
In particular, the assessment of the cytomegalovirus (CMV) DNA load in blood with regard to the
development of CMV disease in immunocompromised patients is discussed in greater detail. Relevant information exists
to support measuring the CMV burden in the blood of AIDS and transplant patients for diagnostic and treatment monitoring
purposes, and, to a lesser extent, to envision the monitoring of the circulating Epstein‐Barr virus load for the prevention
of pose‐transplant lymphoproliferative disorders. On the ocher hand, there are controversial data on the clinical
utility of measuring the herpes simplex virus (HSV) load in cerebrospinal fluid of patients with HSV encephalitis and on
the relationship between the human herpesvirus 8 DNA load in diverse biological fluids and the presence of Kaposi′s sarcoma.
There is a paucity of information about the clinical impact of quantifying the other human herpesviruses
(varicella‐zoster virus, and human herpesviruses 6 and 7).
A Practical Approach to Excessive Daytime Sleepiness: A Focused Review
Authors: Murray Brian J.
Published: May 2016

Excessive daytime sleepiness (EDS) is a common problem that is important to recognize and address. Initial steps in management are generally straightforward and only the most advanced cases would require referral to a subspecialist. Of particular concern is that of driving safety. There is a broad differential diagnosis for conditions contributing to EDS but a few common conditions account for the majority of clinical presentations. Subjective self-reporting will often lead to identification of potential problems, but this is often unreliable. Traditional neurophysiologic tests can help in objectively quantifying symptoms but current tests are not always practical clinically and may have little validation in real world situations. There are many treatment options that should generally be able to sufficiently manage most patients presenting with hypersomnolence. This review provides a practical clinical approach to the problem based on current guidelines.
Activation Mechanism of LRRK2 and Its Cellular Functions in Parkinson’s Disease
Authors: Rosenbusch Katharina E. , Kortholt Arjan
Published: May 2016

Human LRRK2 (Leucine-Rich Repeat Kinase 2) has been associated with both familial and idiopathic Parkinson’s disease (PD). Although several LRRK2 mediated pathways and interaction partners have been identified, the cellular functions of LRRK2 and LRRK2 mediated progression of PD are still only partially understood. LRRK2 belongs to the group of Roco proteins which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), a kinase, and several protein-protein interaction domains. Roco proteins exhibit a complex activation mechanism involving intramolecular signaling, dimerization, and substrate/effector binding. Importantly, PD mutations in LRRK2 have been linked to a decreased GTPase and impaired kinase activity, thus providing putative therapeutic targets. To fully explore these potential targets it will be crucial to understand the function and identify the pathways responsible for LRRK2-linked PD. Here, we review the recent progress in elucidating the complex LRRK2 activation mechanism, describe the accumulating evidence that link LRRK2-mediated PD to mitochondrial dysfunction and aberrant autophagy, and discuss possible ways for therapeutically targeting LRRK2.
Fc-γ Receptor Polymorphisms, Cetuximab Therapy, and Survival in the NCIC CTG CO.17 Trial of Colorectal Cancer
Authors: Liu Geoffrey , Tu Dongsheng , Lewis Marcia , Cheng Dangxiao , Sullivan Leslie A. , Chen Zhuo , Morgen Eric , Simes John , Price Timothy J. , Tebbutt Niall C. , Shapiro Jeremy D. , Jeffery G. Mark , Mellor J. Daniel , Mikeska Thomas , Virk Shakeel , Shepherd Lois E. , Jonker Derek J. , O'Callaghan Christopher J. , Zalcberg John R. , Karapetis Christos S. , Dobrovic Alexander
Published: May 2016

Purpose: Two germline Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A;His(H)131Arg(R)] and rs396991 [FCGR3A;Phe(F)158Val(V)] produce altered proteins through amino acid substitutions; both are reported to be associated with cetuximab-related outcomes. We performed a validation of these polymorphisms in NCIC CTG CO.17, a randomized trial of cetuximab monotherapy in refractory, metastatic colorectal cancer expressing EGFR.

Experimental Design: DNA extracted from formalin-fixed paraffin-embedded tissue was genotyped. In addition to log-rank tests, Cox proportional hazard models assessed their relationships with overall (OS) and progression-free survival (PFS), adjusting for clinically important prognostic factors, along with a polymorphism–treatment arm interaction term.

Results: Somatic KRAS status was wild-type for exon 2 in 153 (52%) of 293 patients, from whom tumor DNA was available. For FCGR2A H/H, a genotype–treatment interaction for KRAS wild-type patients was observed for OS (P = 0.03). In KRAS wild-type patients carrying FCGR2A H/H, cetuximab (vs. no cetuximab) improved survival substantially, with adjusted HRs (aHR) of 0.36 (OS) and 0.19 (PFS) and absolute benefits of 5.5 months (OS; P = 0.003) and 3.7 months (PFS; P = 0.02). In contrast, patients carrying FCGR2A R alleles (H/R or R/R) had aHRs of only 0.78 (OS; 2.8-month benefit) and 0.53 (PFS; 1.6-month benefit). No relationships were found for rs396991 (FCGR3A).

Conclusions: In the CO.17 trial, cetuximab worked best for patients with KRAS wild-type colorectal cancers carrying FCGR2A H/H genotypes. Significantly lower benefits were observed in patients carrying germline FCGR2A R alleles. Clin Cancer Res; 22(10); 2435–44. ©2016 AACR.
Clinical Significance of TLR1 I602S Polymorphism for Patients with Metastatic Colorectal Cancer Treated with FOLFIRI plus Bevacizumab
Authors: Okazaki Satoshi , Loupakis Fotios , Stintzing Sebastian , Cao Shu , Zhang Wu , Yang Dongyun , Ning Yan , Sunakawa Yu , Stremitzer Stefan , Matsusaka Satoshi , Berger Martin D. , Parekh Anish , West Jordan D. , Miyamoto Yuji , Suenaga Mitsukuni , Schirripa Marta , Cremolini Chiara , Falcone Alfredo , Heinemann Volker , DePaolo R. William , Lenz Heinz-Josef
Published: May 2016

The purpose of this study was to evaluate the clinical significance of single-nucleotide polymorphisms in TLR1, TLR2, TLR6, and TAK1 in patients with metastatic colorectal cancer (mCRC). We genotyped 9 SNPs of TLR1, TLR2, TLR6, and TAK1 in mCRC patients treated with first-line FOLFIRI (combination therapy of irinotecan, 5-fluorouracil, and folinic acid) plus bevacizumab, using a discovery cohort (TRIBE trial, n = 228) and a validation cohort (FIRE-3 trial, n = 297), and analyzed for the association with response rate (RR), progression-free survival (PFS), and overall survival (OS). There was a significant association of TLR1 rs5743618 (T1805G) with the clinical outcome. In the TRIBE cohort, a homozygous wild-type genotype (T/T) associated with a significantly lower RR compared with variant T/G and G/G genotypes (43% vs. 62%, P = 0.025), and this observation was validated in the FIRE-3 cohort (46% vs. 65%, P = 0.021). In addition, those patients with the T/T genotype had significantly worse PFS (median, 8.2 vs. 10.5 months; HR, 1.57; 95% CI, 1.09–2.28, P = 0.014) and OS (median: 19.9 vs. 27.9 months; HR, 1.63; 95% CI, 1.14–2.35, P = 0.007), compared with those with other genotypes in the TRIBE cohort. These differences remained statistically significant in multivariate analysis. Our data suggest that TLR1 rs5743618 could serve as a predictor of clinical response to FOLFIRI plus bevacizumab in patients with mCRC. Mol Cancer Ther; 15(7); 1740–5. ©2016 AACR.
Hypertension and the Brain: A Risk Factor for More Than Heart Disease
Authors: Meissner Anja
Published: May 2016

Background: Cerebral small vessel disease (cSVD), a common risk factor for cognitive impairment, involves unspecific arteriopathy characterized by hypertrophy and endothelial dysfunction that alter cerebrovascular function and auto-regulation of cerebral blood flow (CBF). Microbleedings, subcortical lacunar infarctions and diffuse areas of white matter lesions resulting from vascular injury are associated with reduced cognitive function mostly characterized by difficulties in learning and retention, attention deficits, gait disorders or depression. In recent years, it has become evident that vascular risk factors contribute to the development of cSVD and associated vascular cognitive impairment (VCI). Among them, hypertension emerged as such a major modifiable risk factor since the brain presents an early target for organ damage due to changes in blood pressure (BP). Subsequently both high and, especially in the elderly, low BP have been linked to cognitive decline, which initiated controversial discussions about BP control as a potential therapeutic strategy to achieve optimal brain perfusion and thus, reduce the occurrence of cSVD and cognitive dysfunction. Yet, recent randomized controlled trials examined the impact of anti-hypertensive therapy on cognitive performance with conflicting results. Summary: In light of the current knowledge, it becomes apparent that there is an urgent need to understand the mechanisms underlying hypertension-induced cerebrovascular complications in order to identify effective therapeutic targets to prevent and most importantly also reverse cognitive decline mediated through hypertension. Key Message: This review summarizes the current knowledge of cSVD pathogenesis as well as possible links to hypertension-mediated cerebrovascular complications. By pointing out knowledge gaps, it aims to spur future studies in search of specific targets helping to prevent therapy failures and decelerate the rapidly progressing neuro-degeneration of patients suffering from cerebrovascular diseases emanating from hypertension.
Sclerostin and Bone Aging: A Mini-Review
Authors: Hay Eric , Bouaziz Wafa , Funck-Brentano Thomas , Cohen-Solal Martine
Published: May 2016

Sclerostin, mainly produced by osteocytes, is now considered a major regulator of bone formation. Identified from patients with a low bone mass, sclerostin inhibits the Wnt pathway by binding to LRP5/6 and subsequently increases bone formation. Sclerostin may also play a role in the mediation of systemic and local factors such as calcitriol, PTH, glucocorticoids and tumor necrosis factor-alpha. Circulating sclerostin levels increase with age and with the decline of kidney function. However, they are surprisingly higher in patients with a high bone mineral density, suggesting that sclerostin may be a relevant marker of the pool of mature osteocytes. The anti-anabolic properties lead to the development of anti-sclerostin biotherapies that are under current evaluation. The results of these clinical trials will open new promising opportunities for the treatment of osteoporosis and bone fragility fractures.
Metabolomics of Chronic Kidney Disease Progression: A Case-Control Analysis in the Chronic Renal Insufficiency Cohort Study
Authors: Rhee Eugene P. , Clish Clary B. , Wenger Julia , Roy Jason , Elmariah Sammy , Pierce Kerry A. , Bullock Kevin , Anderson Amanda H. , Gerszten Robert E. , Feldman Harold I.
Published: May 2016

Background: Whereas several longitudinal metabolomics studies have been conducted in individuals with normal estimated glomerular filtration rate (eGFR) at baseline, disease progression among individuals with established chronic kidney disease (CKD) has not been rigorously examined. Methods: We performed a nested case-control study of rapid CKD progression in the Chronic Renal Insufficiency Cohort Study, profiling baseline plasma from 200 individuals each with eGFR slope <-3 ml/min/1.73 m2/year (cases) or between -1 and +1 ml/min/1.73 m2/year (controls), matched on baseline eGFR and proteinuria. To directly assess how the kidney modulates circulating metabolites, we profiled plasma from the aorta and renal vein of 25 hospital-based individuals. Results: At baseline, cases and controls had a mean eGFR of 41.7 ± 13.3 and 45.0 ± 14.5 ml/min/1.73 m2, respectively. Ten plasma metabolites were nominally associated with CKD progression in logistic regression models adjusted for age, sex, race/ethnicity, hypertension, systolic and diastolic blood pressure, diabetes, eGFR and proteinuria; no metabolite achieved the Bonferroni-adjusted significance threshold (p < 0.0003). In a cross-sectional analysis, all 6 of the metabolites that were higher in cases than controls were significantly associated with eGFR at baseline. By contrast, threonine, methionine and arginine were lower in cases than in controls and had no association with baseline eGFR. Furthermore, in the hospital-based cohort that underwent renal arteriovenous sampling, these 3 metabolites were net released from the kidney. Combining these metabolites into a panel of markers further strengthened their association with CKD progression. Conclusion: Our results motivate interest in arginine, methionine and threonine as potential indicators of renal metabolic function and markers of renal prognosis.
A randomised, double blind comparison of tecarfarin, a novel vitamin K antagonist, with warfarin
Authors: Whitlock Richard P. , Fordyce Christopher B. , Midei Mark G. , Ellis Dave , Garcia David , Weitz Jeffrey I. , Canafax Daniel M. , Albrecht Detlef , Milner Peter G.
Published: May 2016

Tecarfarin is a novel vitamin K antagonist that is metabolised by carboxyl estererase, thereby eliminating the variability associated with cytochrome-mediated metabolism. EmbraceAC was designed to compare the quality of anticoagulation with tecarfarin and warfarin as determined by time in therapeutic range (TTR). In this phase 2/3 randomised and blinded trial, 607 patients with indications for chronic anticoagulation were assigned to warfarin (n=304) or tecarfarin (n=303). Dosing of study drugs was managed by a centralised dose control centre, which had access to genotyping. The primary analysis tested superiority of tecarfarin over warfarin for TTR. Patients were recruited between May 12, 2008 and May 12, 2009. TTR with tecarfarin and warfarin were similar (72.3% and 71.5%, respectively; p=0.51). In those taking CYP2C9 interacting drugs, the TTR on tecarfarin (n=92) was similar to that on warfarin (n=87, 72.2% and 69.9%, respectively; p=0.15). In patients with mechanical heart valves, the TTR of tecarfarin (n=42) was similar to that of warfarin (n=42, 68.4% and 66.3%, respectively; p=0.51). The same was true for the TTR in patients with any CYP2C9 variant allele and on CYP2C9-interacting drugs (tecarfarin, n=24, 76.5% vs warfarin, n=31, 69.5%; p=0.09). There was no difference in thromboembolic or bleeding events. In conclusion, superiority of tecarfarin over warfarin for TTR was not demonstrated. The TTR with tecarfarin was similar to that with well-controlled warfarin and tecarfarin appeared to be safe and well tolerated with few major bleeding and no thrombotic events. Favourable trends in certain subpopulations make tecarfarin a promising oral anticoagulant that deserves further study.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Interleukin-33 stimulates GM-CSF and M-CSF production by human endothelial cells
Authors: Montanari Eliana , Stojkovic Stefan , Kaun Christoph , Lemberger Christof E. , de Martin Rainer , Rauscher Sabine , Gröger Marion , Maurer Gerald , Neumayer Christoph , Huk Ihor , Huber Kurt , Demyanets Svitlana , Wojta Johann
Published: May 2016

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in various inflammatory conditions targeting amongst other cells the endothelium. Besides regulating the maturation and functions of myeloid cells, granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) have been shown to play a role in such pathologies too. It was the aim of our study to investigate a possible influence of IL-33 on GM-CSF and M–CSF production by human endothelial cells. IL-33, but not IL-18 or IL-37, stimulated GM-CSF and M-CSF mRNA expression and protein production by human umbilical vein endothelial cells (HUVECs) and human coronary artery ECs (HCAECs) through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in an IL–1-independent way. This effect was inhibited by the soluble form of ST2 (sST2), which is known to act as a decoy receptor for IL-33. The 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor fluvastatin could also be shown to moderately reduce the IL-33-mediated effect on M-CSF, but not on GM-CSF expression. In addition, IL–33, IL-1β, GM-CSF and M-CSF were detected in endothelial cells of human carotid atherosclerotic plaques using immunofluorescence. Upregulation of GM-CSF and M–CSF production by human endothelial cells, an effect that appears to be mediated by NF–κB and to be independent of IL-1, may be an additional mechanism through which IL-33 contributes to inflammatory activation of the vessel wall.

Supplementary Material to this article is available online at www.thrombosis-online.com.