bluuebunny/crossref_metadata_2025 huggingface dataset:
The tomato cis–prenyltransferase gene family
Authors: Akhtar Tariq A. , Matsuba Yuki , Schauvinhold Ines , Yu Geng , Lees Hazel A. , Klein Samuel E. , Pichersky Eran
Published: November 2012

cis–prenyltransferases (CPTs) are predicted to be involved in the synthesis of long‐chain polyisoprenoids, all with five or more isoprene (C5) units. Recently, we identified a short‐chain CPT, neryl diphosphate synthase (NDPS1), in tomato (Solanum lycopersicum). Here, we searched the tomato genome and identified and characterized its entire CPT gene family, which comprises seven members (SlCPT1–7, with NDPS1 designated as SlCPT1). Six of the SlCPT genes encode proteins with N–terminal targeting sequences, which, when fused to GFP, mediated GFP transport to the plastids of Arabidopsis protoplasts. The SlCPT3–GFP fusion protein was localized to the cytosol. Enzymatic characterization of recombinant SlCPT proteins demonstrated that SlCPT6 produces Z,Z–FPP, and SlCPT2 catalyzes the formation of nerylneryl diphosphate while SlCPT4, SlCPT5 and SlCPT7 synthesize longer‐chain products (C25–C55). Although no in vitro activity was demonstrated for SlCPT3, its expression in the Saccharomyces cerevisiae dolichol biosynthesis mutant (rer2) complemented the temperature‐sensitive growth defect. Transcripts of SlCPT2, SlCPT4, SlCPT5 and SlCPT7 are present at low levels in multiple tissues, SlCPT6 is exclusively expressed in red fruit and roots, and SlCPT1, SlCPT3 and SlCPT7 are highly expressed in trichomes. RNAi‐mediated suppression of NDPS1 led to a large decrease in β–phellandrene (which is produced from neryl diphosphate), with greater reductions achieved with the general 35S promoter compared to the trichome‐specific MKS1 promoter. Phylogenetic analysis revealed CPT gene families in both eudicots and monocots, and showed that all the short‐chain CPT genes from tomato (SlCPT1, SlCPT2 and SlCPT6) are closely linked to terpene synthase gene clusters.
Backstepping Control Design for Vehicle Active Restraint Systems
Authors: Gu Edward Y.-L. , Das Manohar
Published: November 2012

Active control of vehicle restraint systems has been extensively investigated in past decades. Many promising results have shown that a seat-belt system can be controlled in real-time to minimize human driver/occupant's injuries by reducing the human chest acceleration after a frontal impact. This paper presents a new nonlinear model that groups the seat-belt restraint system and the human driver's nonlinear high-coupling dynamics together to form a cascaded system. By using a backstepping design procedure, a global control law is developed and aimed to actively and continuously adjust the seat-belt strain force so as to interact both the human's shoulder/chest and waist. Both the control theory development and 3D graphical simulation study show that the overall system stability is well achieved. Even if up to a freeway speed, such as at 65 mph, the accelerations of the three major human body joints: lumber, thorax, and neck after a frontal collision can still be reduced significantly.
Symbolic Dynamic Analysis of Transient Time Series for Fault Detection in Gas Turbine Engines
Authors: Sarkar Soumalya , Mukherjee Kushal , Sarkar Soumik , Ray Asok
Published: November 2012

This brief paper presents a symbolic dynamics-based method for detection of incipient faults in gas turbine engines. The underlying algorithms for fault detection and classification are built upon the recently reported work on symbolic dynamic filtering. In particular, Markov model-based analysis of quasi-stationary steady-state time series is extended to analysis of transient time series during takeoff. The algorithms have been validated by simulation on the NASA Commercial Modular Aero Propulsion System Simulation (C-MAPSS) transient test-case generator.
MnP nanoclusters embedded in GaP epitaxial films grown by organometallic vapor-phase epitaxy: A reciprocal space mapping and transmission electron microscopy study
Authors: Lambert-Milot Samuel , Gaudet Simon , Lacroix Christian , Ménard David , Masut Remo A. , Lavoie Christian , Desjardins Patrick
Published: November 2012

Full three dimensional x-ray diffraction reciprocal space maps combined with transmission electron microscopy measurements provide a systematic determination of the texture of GaP epilayers containing embedded MnP nanoclusters grown on GaP(001) by organometallic vapor phase epitaxy. This approach reveals that the texture of the MnP clusters depends on the growth surface morphology and bonding configuration and on the lattice mismatch at the cluster/matrix interfaces during growth. It demonstrates that the orthorhombic MnP nanoclusters are oriented along specific GaP crystallographic directions, forming six well defined families, whose population is influenced by the growth temperature and the film thickness. The clusters principally grow on GaP(001) and GaP{111} facets with a small fraction of clusters nucleating on higher-index GaP{hhl} facets. Most epitaxial alignments share a similar component: the MnP(001) plane (c-axis plane) is parallel to the GaP{110} plane family. Axiotaxial ordering between the MnP clusters and the GaP matrix is also observed. Furthermore, with this systematic approach, all phases present in these heterogeneous films can be identified. In particular, traces of hexagonal Mn2P precipitates have been observed while their formation can be avoided by lowering the growth temperature. Comparing the structural results presented here with magnetic measurement carried out on similar samples confirms that the effective magnetic properties of the heterogeneous layer can be tuned by controlling the texture of the ferromagnetic nanoclusters.
Evaluation of lithographic performance of extreme ultra violet mask using coherent scattering microscope
Authors: Doh Jonggul , Uk Lee Jae , Ahn Jinho , Kim Seong-sue
Published: November 2012

The authors report the application of a coherent scattering microscope (CSM) equipped with a femtosecond laser based extreme ultra violet (EUV) source to analyze aerial images for an EUV lithography mask. The CSM employs an EUV beam with a 13.5 nm wavelength and an incident angle of 6° for the wafer scanner emulation. The CSM consists of a condenser optics that delivers the EUV beam to the mask and detector that measures the field spectrum diffracted by the mask pattern. Using a pair of spherical and plane EUV mirrors, coherent EUV light is relayed to the mask and the light diffracted by the mask pattern is measured by a 1 in. size charge-coupled device detector. The integration time of the EUV beam in the detector is controlled by a high speed shutter. This device experimentally records the coherent diffraction pattern from the EUV mask and reconstructs its aerial image using a phase retrieval algorithm. These features made it possible to investigate the projected image properties, such as depth-of-focus, exposure latitude, mask error enhancement factor, horizontal–vertical critical dimension (H–V CD) bias, normalized image log slope (NILS), and so on. The device also provides a mask CD from a rigorous coupled-wave analysis algorithm modeling based on the Maxwell equation through measured diffraction patterns. NILS according to half-pitch design node was measured by CSM and simulated using a Solid-EUV simulator. Illumination conditions of NA and sigma (σ) values are 0.25 and 0.8, respectively, which are the same as those of the EUV exposure tool. The NILS measured by CSM and that simulated using the Solid-EUV have good consistency.
Switchable electrowetting of droplets on dual-scale structured surfaces
Authors: Berry Shaun , Fedynyshyn Ted , Parameswaran Lalitha , Cabral Alberto
Published: November 2012

The authors report on the development of surfaces containing artificially fabricated structures of dual nanometer and micrometer surfaces that allow an aqueous droplet to be reversibly switched by electrowetting from a Cassie state with low adhesion to a Wenzel state with high adhesion. A variety of geometries were fabricated to study parameters that affect switchable wetting–dewetting. Nanometer parallel corrugations, posts, and holes were fabricated and combined with micrometer features consisting of parallel corrugations, streets, and checkerboard patterns of varying widths and pitches. It was observed that many combinations of the dual-textured surfaces produced superhydrophobic wetting states and aqueous droplets on these surfaces could be electrically controlled to switch from a Cassie state to a Wenzel state. Reversible switching between these wetting states occurred on specific combinations of surface geometries, namely surfaces that had parallel corrugations.
A Human Disease Model of Drug Toxicity–Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice
Authors: Huh Dongeun , Leslie Daniel C. , Matthews Benjamin D. , Fraser Jacob P. , Jurek Samuel , Hamilton Geraldine A. , Thorneloe Kevin S. , McAlexander Michael Allen , Ingber Donald E.
Published: November 2012

An in vitro model of human pulmonary edema predicts drug toxicity and efficacy previously observed in humans.
Cryptococcus neoformans Requires the ESCRT Protein Vps23 for Iron Acquisition from Heme, for Capsule Formation, and for Virulence
Authors: Hu Guanggan , Caza Mélissa , Cadieux Brigitte , Chan Vivienne , Liu Victor , Kronstad James
Published: November 2012

Iron availability is a key regulator of virulence factor elaboration in
Cryptococcus neoformans
, the causative agent of fungal meningoencephalitis in HIV/AIDS patients. In addition, iron is an essential nutrient for pathogen proliferation in mammalian hosts but little is known about the mechanisms of iron sensing and uptake in fungal pathogens that attack humans. In this study, we mutagenized
C. neoformans
by
Agrobacterium
-mediated T-DNA insertion and screened for mutants with reduced growth on heme as the sole iron source. Among 34 mutants, we identified a subset with insertions in the gene for the ESCRT-I (
e
ndosomal
s
orting
c
omplex
r
equired for
t
ransport) protein Vps23 that resulted in a growth defect on heme, presumably due to a defect in uptake via endocytosis or misregulation of iron acquisition from heme. Remarkably,
vps23
mutants were also defective in the elaboration of the cell-associated capsular polysaccharide that is a major virulence factor, while overexpression of
Vps23
resulted in cells with a slightly enlarged capsule. These phenotypes were mirrored by a virulence defect in the
vps23
mutant in a mouse model of cryptococcosis and by hypervirulence of the overexpression strain. Overall, these results reveal an important role for trafficking via ESCRT functions in both heme uptake and capsule formation, and they further reinforce the connection between iron and virulence factor deployment in
C. neoformans
.
Mycobacterium tuberculosis Requires Phosphate-Responsive Gene Regulation To Resist Host Immunity
Authors: Tischler Anna D. , Leistikow Rachel L. , Kirksey Meghan A. , Voskuil Martin I. , McKinney John D.
Published: November 2012

Mycobacterium tuberculosis
persists in the tissues of mammalian hosts despite inducing a robust immune response dominated by the macrophage-activating cytokine gamma interferon (IFN-γ). We identified the
M. tuberculosis
phosphate-specific transport (Pst) system component PstA1 as a factor required to resist IFN-γ-dependent immunity. A Δ
pstA1
mutant was fully virulent in IFN-γ
−/−
mice but attenuated in wild-type (WT) mice and mice lacking specific IFN-γ-inducible immune mechanisms: nitric oxide synthase (NOS2), phagosome-associated p47 GTPase (Irgm1), or phagocyte oxidase (phox). These phenotypes suggest that Δ
pstA1
bacteria are sensitized to an IFN-γ-dependent immune mechanism(s) other than NOS2, Irgm1, or phox. In other species, the Pst system has a secondary role as a negative regulator of phosphate starvation-responsive gene expression through an interaction with a two-component signal transduction system. In
M. tuberculosis
, we found that Δ
pstA1
bacteria exhibited dysregulated gene expression during growth in phosphate-rich medium that was mediated by the two-component sensor kinase/response regulator system SenX3-RegX3. Remarkably, deletion of the
regX3
gene suppressed the replication and virulence defects of Δ
pstA1
bacteria in NOS2
−/−
mice, suggesting that
M. tuberculosis
requires the Pst system to negatively regulate activity of RegX3 in response to available phosphate
in vivo
. We therefore speculate that inorganic phosphate is readily available during replication in the lung and is an important signal controlling
M. tuberculosis
gene expression via the Pst-SenX3-RegX3 signal transduction system. Inability to sense this environmental signal, due to Pst deficiency, results in dysregulation of gene expression and sensitization of the bacteria to the host immune response.
Exploring the Parallel Development of Microbial Systems in Neonates with Cystic Fibrosis
Authors: Rogers Geraint B. , Bruce Kenneth D.
Published: November 2012

Recent studies have greatly extended our understanding of the microbiota present in and on the human body. Here, advanced sequencing strategies have provided unprecedented analytical power. The important implications that the emerging data have for human health emphasize the need to intensify research in this area (D. A. Relman, Nature 486:194-195, 2012). It is already clear from these studies that the microbiotas characterized in different body locations of healthy individuals are both complex and diverse (The Human Microbiome Project Consortium, Nature 486:215-221). These studies also provide a point of contrast for investigations that aim to characterize the microbiota present in disease conditions. In this regard, Madan et al. (mBio 3(4):e00251-12, 2012) monitored the development over time of microbiota in the oropharynges and feces of neonates with cystic fibrosis and explored the potential for interactions between these complex microbial systems.
Human Disease Isolates of Serotype M4 and M22 Group A Streptococcus Lack Genes Required for Hyaluronic Acid Capsule Biosynthesis
Authors: Flores Anthony R. , Jewell Brittany E. , Fittipaldi Nahuel , Beres Stephen B. , Musser James M.
Published: November 2012

Group A streptococcus (GAS) causes human pharyngitis and invasive infections and frequently colonizes individuals asymptomatically. Many lines of evidence generated over decades have shown that the hyaluronic acid capsule is a major virulence factor contributing to these infections. While conducting a whole-genome analysis of the
in vivo
molecular genetic changes that occur in GAS during longitudinal human pharyngeal interaction, we discovered that serotypes M4 and M22 GAS strains lack the
hasABC
genes necessary for hyaluronic acid capsule biosynthesis. Using targeted PCR, we found that all 491 temporally and geographically diverse disease isolates of these two serotypes studied lack the
hasABC
genes. Consistent with the lack of capsule synthesis genes, none of the strains produced detectable hyaluronic acid. Despite the lack of a hyaluronic acid capsule, all strains tested multiplied extensively
ex vivo
in human blood. Thus, counter to the prevailing concept in GAS pathogenesis research, strains of these two serotypes do not require hyaluronic acid to colonize the upper respiratory tract or cause abundant mucosal or invasive human infections. We speculate that serotype M4 and M22 GAS have alternative, compensatory mechanisms that promote virulence.

IMPORTANCE
A century of study of the antiphagocytic hyaluronic acid capsule made by group A streptococcus has led to the concept that it is a major virulence factor contributing to human pharyngeal and invasive infections. However, the discovery that some strains that cause abundant human infections lack hyaluronic acid biosynthetic genes and fail to produce this capsule provides a new stimulus for research designed to understand the group A streptococcus factors contributing to pharyngeal infection and invasive disease episodes.
Soil drainage class, host tree species, and thinning influence host tree resistance to the spruce budworm
Authors: Fuentealba Alvaro , Bauce Éric
Published: November 2012

Thinning has frequently been recommended for reducing damage caused by spruce budworm ( Choristoneura fumiferana (Clemens)). It is believed that this technique enhances the mechanisms of resistance of trees (antibiosis and tolerance) to this insect. However, various research projects that have focused upon effects of this silvicultural tool on host tree resistance have yielded equivocal results. A better understanding of the effects of this technique on host tree resistance and budworm performance can help us to reduce the impact of this insect while respecting the ecological integrity of the forests. We examined the effects of stand commercial thinning and drainage class on balsam fir ( Abies balsamea (L.) Mill.)), white spruce ( Picea glauca (Moench) Voss), and black spruce ( Picea mariana (Mill.) Britton, Sterns & Poggenb.) resistance to spruce budworm 3 years after thinning. We wanted to determine if this technique could be used as preventive tool against insect defoliators. Field-rearing experiments of spruce budworm were conducted, together with foliar chemical analyses, along a gradient of stand thinning intensity (0% (control), 25% (light), and 40% (heavy)) and drainage class (rapidly drained, class 2; mesic with seepage, class 3; subhygric, class 4; and hydric, class 5). Despite having favoured budworm performance (high pupal mass) and winter survival, heavy thinning increased balsam fir and white spruce tolerance (amount of current-year foliage remaining) to a level that resulted in overall increased host tree resistance to the insect. This response was caused by strong foliage production in reaction to the thinning treatment. Light thinning did not increase host tolerance, except in balsam fir and white spruce that were growing on hydric and subhygric sites, respectively, demonstrating the importance of this variable in determining host tree resistance. These results suggest that heavy thinning may be used as a preventive measure during the low-density phase of budworm populations, since this technique increased foliar production in balsam fir and white spruce, rendering them more resistant to attack by this insect.
Interaction between Diplodia pinea or Diplodia scrobiculata and fungal endophytes isolated from pine shoots
Authors: Santamaría Oscar , Smith Denise R. , Stanosz Glen R.
Published: November 2012

Four endophytes isolated from healthy shoots of adult red pine ( Pinus resinosa Aiton) or jack pine ( Pinus banksiana Lamb.) trees were tested as potential biocontrol agents of the conifer shoot blight and canker pathogens Diplodia pinea (Desmaz.) J. Kickx fil. and Diplodia scrobiculata J. de Wet, B. Slippers & M.J. Wingfield. The effect of the endophytes on the germination of Diplodia species conidia and on the symptom severity caused by these pathogens on P. banksiana seedlings under greenhouse conditions was evaluated. Aggressiveness of each organism also was determined by means of single inoculations on jack pine seedlings. The results indicated that the endophyte Trichoderma atroviride P. Karst. showed a clear antagonism to Diplodia species. The culture filtrate of this fungus was able to reduce spore germination of D. scrobiculata. Furthermore, it was able to inhibit the D. pinea invasion when both organisms were inoculated in the same seedling. The observed reduction in the symptom severity on jack pine seedlings might be due to parasitism and (or) production of inhibitory compounds. Therefore, T. atroviride might deserve further investigations for its use as biocontrol agent against D. pinea.
VACUUM FLUCTUATION FORCE ON A RIGID CASIMIR CAVITY IN DE SITTER AND SCHWARZSCHILD–DE SITTER SPACE–TIME
Authors: CHEN XIANG
Published: November 2012

We investigate the net force on a rigid Casimir cavity generated by vacuum fluctuations of electromagnetic field in three cases: de Sitter space–time, de Sitter space–time with weak gravitational field and Schwarzschild–de Sitter space–time. In de Sitter space–time the resulting net force follows the square inverse law but unfortunately it is too weak to be measurable due to the large universe radius. By introducing a weak gravitational field into the de Sitter space–time, we find that the net force can now be split into two parts, one is the gravitational force due to the induced effective mass between the two plates and the other one is generated by the metric structure of de Sitter space–time. In order to investigate the vacuum fluctuation force on the rigid cavity under strong gravitational field, we perform a similar analysis in Schwarzschild–de Sitter space–time and results are obtained in three different limits. The most interesting one is when the cavity gets closer to the horizon of a blackhole, square inverse law is recovered and the repulsive force due to negative energy/mass of the cavity now has an observable strength. More importantly the force changes from being repulsive to attractive when the cavity crosses the event horizon, so that the energy/mass of the cavity switches the sign, which suggests the unusual time direction inside the event horizon.
AN ITERATIVE CONVEX HULL APPROACH FOR IMAGE SEGMENTATION AND CONTOUR EXTRACTION
Authors: ZHAO JIAN , AN JIAN
Published: November 2012

The contours and segments of objects in digital images have many important applications. Contour extractions of gray images can be converted into contour extractions of binary images. This paper presents a novel contour-extraction algorithm for binary images and provides a deduction theory for this algorithm. First, we discuss the method used to construct convex hulls of regions of objects. The contour of an object evolves from a convex polygon until the exact boundary is obtained. Second, the projection methods from lines to objects are studied, in which, a polygon iteration method is presented using linear projection. The result of the iteration is the contour of the object region. Lastly, addressing the problem that direct projections probably cannot find correct projection points, an effective discrete ray-projection method is presented. Comparisons with other contour deformation algorithms show that the algorithm in the present paper is very robust with respect to the shapes of the object regions. Numerical tests show that time consumption is primarily concentrated on convex hull computation, and the implementation efficiency of the program can satisfy the requirement of interactive operations.
COMPUTATION OF QUANTUM ELECTRICAL CURRENTS THROUGH THE RAMO–SHOCKLEY–PELLEGRINI THEOREM WITH TRAJECTORIES
Authors: ALBAREDA G. , TRAVERSA F. L. , BENALI A. , ORIOLS X.
Published: November 2012

Motivated by a recent approach to solve quantum dynamics with full Coulomb correlations [X. Oriols, Phys. Rev. Lett.98 (2007) 066803], we present here an extension of the Ramo–Shockley–Pellegrini theorem for quantum systems to compute the total (conduction plus displacement) current in terms of quantum (Bohmian) trajectories. By way of test, we derive an extension of the Ramo-Shockley-Pellegrini theorem using standard quantum mechanics and we compare it to our former result. As expected, both formulations give identical results, however we emphasize the numerical viability of computing self-consistently the total current by means of quantum trajectories in front of the difficulties to do it in terms of standard quantum mechanics.
TELEPARALLEL LAGRANGE GEOMETRY AND A UNIFIED FIELD THEORY: LINEARIZATION OF THE FIELD EQUATIONS
Authors: WANAS M. I. , YOUSSEF NABIL L. , SID-AHMED A. M.
Published: November 2012

This paper is a natural continuation of our previous paper: "Teleparallel Lagrange geometry and a unified field theory, Class. Quantum Grav.27 (2010) 045005 (29 pp)". In this paper, we apply a linearization scheme on the field equations obtained in the above-mentioned paper. Three important results under the linearization assumption are accomplished. First, the vertical fundamental geometric objects of the EAP-space lose their dependence on the positional argument x. Secondly, our linearized theory in the Cartan-type case coincides with the GFT in the first-order of approximation. Finally, an approximate solution of the vertical field equations is obtained.
Window brokers
Authors: Arthur Richard , Olsen Dan R.
Published: November 2012

As users travel from place to place, they can encounter display servers, that is, machines which supply a collaborative content-sharing environment. Users need a way to control how content is arranged on these display spaces. The software for controlling these display spaces should be consistent from display server to display server. However, display servers could be controlled by institutions which may not allow for the control software to be installed. This article introduces the window broker protocol which allows users to carry familiar control techniques on portable personal devices and use the control technique on any display server without installing the control software on the display server. This article also discusses how the window broker protocol mitigates some security risks that arise from potentially malicious display servers.
“Without the clutter of unimportant words”
Authors: Chuang Jason , Manning Christopher D. , Heer Jeffrey
Published: November 2012

Keyphrases aid the exploration of text collections by communicating salient aspects of documents and are often used to create effective visualizations of text. While prior work in HCI and visualization has proposed a variety of ways of presenting keyphrases, less attention has been paid to selecting the best descriptive terms. In this article, we investigate the statistical and linguistic properties of keyphrases chosen by human judges and determine which features are most predictive of high-quality descriptive phrases. Based on 5,611 responses from 69 graduate students describing a corpus of dissertation abstracts, we analyze characteristics of human-generated keyphrases, including phrase length, commonness, position, and part of speech. Next, we systematically assess the contribution of each feature within statistical models of keyphrase quality. We then introduce a method for grouping similar terms and varying the specificity of displayed phrases so that applications can select phrases dynamically based on the available screen space and current context of interaction. Precision-recall measures find that our technique generates keyphrases that match those selected by human judges. Crowdsourced ratings of tag cloud visualizations rank our approach above other automatic techniques. Finally, we discuss the role of HCI methods in developing new algorithmic techniques suitable for user-facing applications.
Strong concepts
Authors: Höök Kristina , Löwgren Jonas
Published: November 2012

Design-oriented research practices create opportunities for constructing knowledge that is more abstracted than particular instances, without aspiring to be at the scope of generalized theories. We propose an intermediate design knowledge form that we namestrong conceptsthat has the following properties: is generative and carries a core design idea, cutting across particular use situations and even application domains; concerned with interactive behavior, not static appearance; is a design element and a part of an artifact and, at the same time, speaks of a use practice and behavior over time; and finally, resides on an abstraction level above particular instances. We present two strong concepts—social navigation and seamfulness—and discuss how they fulfil criteria we might have on knowledge, such as being contestable, defensible, and substantive. Our aim is to foster an academic culture of discursive knowledge construction of intermediate-level knowledge and of how it can be produced and assessed in design-oriented HCI research.
Essential AOP
Authors: De Fraine Bruno , Ernst Erik , Südholt Mario
Published: November 2012

Aspect-oriented programming (AOP) has produced interesting language designs, but also ad hoc semantics that needs clarification. We contribute to this clarification with a calculus that models essential AOP, both simpler and more general than existing formalizations. In AOP,
advice
may intercept method invocations, and
proceed
executes the suspended call. Proceed is an ad hoc mechanism, only usable inside advice bodies. Many pointcut mechanisms, for example, wildcards, also lack regularity. We model proceed using first-class closures, and shift complexity from pointcuts to ordinary object-oriented code. Two well-known pointcut categories,
call
and
execution
, are commonly considered similar. We formally expose their differences, and resolve the associated soundness problem. Our calculus includes
type ranges
, an intuitive and concise alternative to explicit type variables that allows advice to be polymorphic over intercepted methods. We use calculus parameters to cover type safety for a wide design space of other features. Type soundness is verified in Coq.
Multivariate amortized resource analysis
Authors: Hoffmann Jan , Aehlig Klaus , Hofmann Martin
Published: November 2012

We study the problem of automatically analyzing the worst-case resource usage of procedures with several arguments. Existing automatic analyses based on amortization or sized types bound the resource usage or result size of such a procedure by a sum of unary functions of the sizes of the arguments.

In this article we generalize this to arbitrary multivariate polynomial functions thus allowing bounds of the form
mn
which had to be grossly overestimated by
m
2
+
n
2
before. Our framework even encompasses bounds like ∑

i,j≤ n
m
i
m
j

where the

m
i

are the sizes of the entries of a list of length
n
.

This allows us for the first time to derive useful resource bounds for operations on matrices that are represented as lists of lists and to considerably improve bounds on other superlinear operations on lists such as longest common subsequence and removal of duplicates from lists of lists. Furthermore, resource bounds are now closed under composition which improves accuracy of the analysis of composed programs when some or all of the components exhibit superlinear resource or size behavior.

The analysis is based on a novel multivariate amortized resource analysis. We present it in form of a type system for a simple first-order functional language with lists and trees, prove soundness, and describe automatic type inference based on linear programming.

We have experimentally validated the automatic analysis on a wide range of examples from functional programming with lists and trees. The obtained bounds were compared with actual resource consumption. All bounds were asymptotically tight, and the constants were close or even identical to the optimal ones.
Delivery of adiponectin gene to skeletal muscle using ultrasound targeted microbubbles improves insulin sensitivity and whole body glucose homeostasis
Authors: Vu Vivian , Liu Ying , Sen Sanjana , Xu Aimin , Sweeney Gary
Published: November 2012

Numerous studies have shown that adiponectin confers antidiabetic effects via both insulin-like and insulin-sensitizing actions. The majority of adiponectin in circulation is derived from adipocytes; however, other tissues such as skeletal muscle can produce adiponectin. This study was designed to investigate the functional significance of adiponectin produced by skeletal muscle. We encapsulated the adiponectin gene in lipid-coated microspheres filled with octafluoropropane gas that were injected into the systemic circulation and destroyed within the microvasculature of skeletal muscle using ultrasound. We first demonstrated safe and successful targeting of luciferase and green fluorescent protein reporter genes to skeletal muscle using this approach and then confirmed efficient overexpression of adiponectin mRNA and oligomeric protein forms. Glucose tolerance test indicated that overexpression of adiponectin in skeletal muscle was able to improve glucose intolerance induced by feeding mice a high-fat diet (HFD), and this correlated with improved skeletal muscle insulin signaling. We then performed hyperinsulinemic-euglycemic clamp studies and demonstrated that adiponectin overexpression attenuated the decreases in glucose infusion rate, glucose disposal, and increase in glucose appearance induced by HFD. Ultrasound-targeted microbubble destruction (UTMD) delivery of adiponectin to skeletal muscle also enhanced serum adiponectin levels and improved hepatic insulin sensitivity. In conclusion, our data show that UTMD efficiently delivers adiponectin to skeletal muscle and that this improves insulin sensitivity and glucose homeostasis.
Enhanced cardiac protein glycosylation (O-GlcNAc) of selected mitochondrial proteins in rats artificially selected for low running capacity
Authors: Johnsen Virginia L. , Belke Darrell D. , Hughey Curtis C. , Hittel Dustin S. , Hepple Russell T. , Koch Lauren G. , Britton Steven L. , Shearer Jane
Published: November 2012

O-linked β-N-acetyl glucosamine (O-GlcNAc) is a posttranslational modification consisting of a single N-acetylglucosamine moiety attached by an O-β-glycosidic linkage to serine and threonine residues of both nuclear and cytosolic proteins. Analogous to phosphorylation, the modification is reversible and dynamic, changing in response to stress, nutrients, hormones, and exercise. Aims of this study were to examine differences in O-GlcNAc protein modification in the cardiac tissue of rats artificially selected for low (LCR) or high (HCR) running capacity. Hyperinsulinemic-euglycemic clamps in conscious animals assessed insulin sensitivity while 2-[14C] deoxyglucose tracked both whole body and tissue-specific glucose disposal. Immunoblots of cardiac muscle examined global O-GlcNAc modification, enzymes that control its regulation (OGT, OGA), and specific proteins involved in mitochondrial oxidative phosphorylation. LCR rats were insulin resistant disposing of 65% less glucose than HCR. Global tissue O-GlcNAc, OGT, OGA, and citrate synthase were similar between groups. Analysis of cardiac proteins revealed enhanced O-GlcNAcylation of mitochondrial Complex I, Complex IV, VDAC, and SERCA in LCR compared with HCR. These results are the first to establish an increase in specific protein O-GlcNAcylation in LCR animals that may contribute to progressive mitochondrial dysfunction and the pathogenesis of insulin resistance observed in the LCR phenotype.
Evaluating Genetic Risk for Prostate Cancer among Japanese and Latinos
Authors: Cheng Iona , Chen Gary K. , Nakagawa Hidewaki , He Jing , Wan Peggy , Laurie Cathy C. , Shen Jess , Sheng Xin , Pooler Loreall C. , Crenshaw Andrew T. , Mirel Daniel B. , Takahashi Atsushi , Kubo Michiaki , Nakamura Yusuke , Al Olama Ali Amin , Benlloch Sara , Donovan Jenny L. , Guy Michelle , Hamdy Freddie C. , Kote-Jarai Zsofia , Neal David E. , Wilkens Lynne R. , Monroe Kristine R. , Stram Daniel O. , Muir Kenneth , Eeles Rosalind A. , Easton Douglas F. , Kolonel Laurence N. , Henderson Brian E. , Le Marchand Loïc , Haiman Christopher A.
Published: November 2012

Background: There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos.

Methods: Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls = 1,043/1,057) from the Multiethnic Cohort (MEC). Significant associations from stage I (P < 1.0 × 10−4) were examined in silico in GWAS of prostate cancer (stage II) in Japanese (cases/controls = 1,583/3,386) and Europeans (cases/controls = 1,854/1,894).

Results: No novel stage I single-nucleotide polymorphism (SNP) outside of known risk regions reached genome-wide significance. For Japanese, in stage I, the most notable putative novel association was seen with 10 SNPs (P ≤ 8.0 × 10−6) at chromosome 2q33; however, this was not replicated in stage II. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage I: OR = 1.45; P = 7.01 × 10−5 and stage II: OR = 1.58; P = 3.05 × 10−7). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele = 1.10; P = 2.71 × 10−25 and OR = 1.07; P = 1.02 × 10−16 for Japanese and Latinos, respectively).

Conclusion and Impact: Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings show that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos. Cancer Epidemiol Biomarkers Prev; 21(11); 2048–58. ©2012 AACR.
Biomarkers for Screening, Diagnosis, and Monitoring of Ovarian Cancer
Authors: Kobayashi Eiji , Ueda Yutaka , Matsuzaki Shinya , Yokoyama Takuhei , Kimura Toshihiro , Yoshino Kiyoshi , Fujita Masami , Kimura Tadashi , Enomoto Takayuki
Published: November 2012

Serum tumor markers have a major role in the screening, diagnosis, and monitoring of most of the gynecologic cancers. Ovarian cancer is one of the deadliest of the group because it is so frequently asymptomatic until it has advanced to an untreatable stage. Even serum cancer antigen-125 (CA-125), clinically one of the most reliable serum markers for ovarian cancer, is elevated in only half of early-stage still-treatable tumors. Because of the very low prevalence of ovarian cancer in the general population, at present, there is no cost-effective imaging or simple microscopic screening test for ovarian cancer as there is for breast and cervical cancers. However, recent proteomics and nucleic acid–based analyses have shown great promise for the discovery of new and more useful serum biomarkers, which cumulatively might provide such a screening tool. In this review, we will discuss both the currently used serum tumor markers for screening, diagnosis, monitoring of ovarian cancer, and the novel biomarkers that are now under investigation and validation. Cancer Epidemiol Biomarkers Prev; 21(11); 1902–12. ©2012 AACR.
The Association between NSAID Use and Colorectal Cancer Mortality: Results from the Women's Health Initiative
Authors: Coghill Anna E. , Phipps Amanda I. , Bavry Anthony A. , Wactawski-Wende Jean , Lane Dorothy S. , LaCroix Andrea , Newcomb Polly A.
Published: November 2012

Background: Randomized trial evidence shows that nonsteroidal anti-inflammatory drug (NSAID) use, particularly long-term use, reduces the incidence of colorectal neoplasia. Recent data also suggests an inverse association between NSAID use and death due to colorectal cancer (CRC).

Methods: We examined the association between NSAID use and CRC mortality among 160,143 postmenopausal women enrolled in the Women's Health Initiative. Women provided details on medication use at baseline and three years after enrollment. Reported CRC cases were locally confirmed and centrally adjudicated; cause of death was determined according to centralized medical record and death certificate review. Cox regression was used to investigate the association between NSAID use and CRC mortality.

Results: Overall, NSAID use at baseline was not associated with CRC mortality [HR: 0.93; 95% confidence interval (CI) 0.76, 1.14]. However, women who reported NSAID use at both baseline and year 3 experienced reductions in CRC mortality (HR: 0.72; 95% CI 0.54, 0.95) compared with nonusers.

Conclusion: Results suggest that NSAID use is associated with lower CRC mortality among postmenopausal women who use these medications more consistently over time.

Impact: Our results support prolonged NSAID use in postmenopausal women for the prevention of poor CRC outcomes. Cancer Epidemiol Biomarkers Prev; 21(11); 1966–73. ©2012 AACR.
A Pooled Analysis of Smoking and Colorectal Cancer: Timing of Exposure and Interactions with Environmental Factors
Authors: Gong Jian , Hutter Carolyn , Baron John A. , Berndt Sonja , Caan Bette , Campbell Peter T. , Casey Graham , Chan Andrew T. , Cotterchio Michelle , Fuchs Charles S. , Gallinger Steven , Giovannucci Edward , Harrison Tabitha , Hayes Richard , Hsu Li , Jiao Shuo , Lin Yi , Lindor Noralane M. , Newcomb Polly , Pflugeisen Bethann , Phipps Amanda I. , Rohan Thomas , Schoen Robert , Seminara Daniela , Slattery Martha L. , Stelling Deanna , Thomas Fridtjof , Warnick Greg , White Emily , Potter John , Peters Ulrike
Published: November 2012

Background: Considerable evidence suggests that cigarette smoking is associated with a higher risk of colorectal cancer (CRC). What is unclear, however, is the impact of quitting smoking on risk attenuation and whether other risk factors for CRC modify this association.

Methods: We conducted a pooled analysis of eight studies, including 6,796 CRC cases and 7,770 controls, to evaluate the association between cigarette smoking history and CRC risk and to investigate potential effect modification by other risk factors.

Results: Current smokers [OR, 1.26; 95% confidence interval (CI), 1.11–1.43] and former smokers (OR, 1.18; 95% CI, 1.09–1.27), relative to never smokers, showed higher risks of CRC. Former smokers remained at higher CRC risk, relative to never smokers, for up to about 25 years after quitting. The impact of time since quitting varied by cancer subsite: The excess risk due to smoking decreased immediately after quitting for proximal colon and rectal cancer but not until about 20 years post-quitting for distal colon cancer. Furthermore, we observed borderline statistically significant additive interactions between smoking status and body mass index [BMI; relative excess risk due to interaction (RERI]), 0.15; 95% CI, −0.01 to 0.31; P = 0.06] and significant additive interaction between smoking status and fruit consumption (RERI, 0.16; 95% CI, 0.01–0.30; P = 0.04).

Conclusion: CRC risk remained increased for about 25 years after quitting smoking, and the pattern of decline in risk varied by cancer subsite. BMI and fruit intake modified the risk associated with smoking.

Impact: These results contribute to a better understanding of the mechanisms through which smoking impacts CRC etiology. Cancer Epidemiol Biomarkers Prev; 21(11); 1974–85. ©2012 AACR.
Bile Acid Promotes Intestinal Metaplasia and Gastric Carcinogenesis
Authors: Tatsugami Masana , Ito Masanori , Tanaka Shinji , Yoshihara Masaharu , Matsui Hirofumi , Haruma Ken , Chayama Kazuaki
Published: November 2012

Background: Bile acid and Helicobacter pylori (H. pylori) are important toxic factors for gastric mucosal injury. We examined the role of bile acid in promoting histologic gastritis and gastric carcinoma in Japanese patients.

Methods: A total of 767 patients (452 men, mean age 51.1 years) were studied. Gastric juice was collected by gastro-endoscopic examination, and the bile acid concentration was examined by enzymatic method. The grade of histologic gastritis was evaluated by gastric biopsies, and the relationship between the bile acid concentration and the gastritis score was examined. The occurrence of gastric cancer was examined by a retrospective cohort study. CDX2/CINC1 expression in RGM-1 cells was evaluated by real-time PCR.

Results: In H. pylori–positive patients, we found significant positive correlation between the bile acid concentration and the grades of atrophy/intestinal metaplasia (P < 0.01). However, we found significant negative associations between the bile acid concentrations and the histologic scores of mononuclear cell/neutrophil infiltrations (P < 0.01). Patients with a high concentration of bile acid developed gastric cancer more frequently than those with a low concentration (P < 0.05). Cholic acid treatment significantly increased CDX2 expression in RGM-1 cells. CINC1 expression in RGM-1 cell was significantly induced by coculture with H. pylori, and the induction was reduced by glycochenodeoxycholic acid treatment.

Conclusion: The bile acid in gastric juice contributes to the progression of histologic atrophy and intestinal metaplasia without inflammatory cell infiltration, followed by carcinogenesis in H. pylori–positive patients.

Impact: Bile acid promotes intestinal metaplasia and gastric carcinogenesis without inflammatory cell infiltration. Cancer Epidemiol Biomarkers Prev; 21(11); 2101–7. ©2012 AACR.
Stichoposide C Induces Apoptosis through the Generation of Ceramide in Leukemia and Colorectal Cancer Cells and Shows In Vivo Antitumor Activity
Authors: Yun Seong-Hoon , Park Eun-Seon , Shin Sung-Won , Na Yong-Woo , Han Jin-Yeong , Jeong Jin-Sook , Shastina Valeria V. , Stonik Valentin A. , Park Joo-In , Kwak Jong-Young
Published: November 2012

Purpose: Marine triterpene glycosides that are physiologically active natural compounds isolated from sea cucumbers (holothurians) and sponges have antifungal, cytotoxic, and antitumor activities, whose specific molecular mechanisms remain to be elucidated. In this study, we examined if and through which mechanisms stichoposide C (STC) from Thelenota anax (family Stichopodidae) induces apoptosis in leukemia and colorectal cancer cells.

Experimental Design: We examined STC-induced apoptosis in human leukemia and colorectal cancer cells in the context of mitochondrial injury and signaling pathway disturbances, and investigated the antitumor effect of STC in mouse CT-26 subcutaneous tumor and HL-60 leukemia xenograft models.

Results: We found that STC induces apoptosis in these cells in a dose-dependent manner and leads to the activation of Fas and caspase-8, cleavage of Bid, mitochondrial damage, and activation of caspase-3. STC activates acid sphingomyelinase (SMase) and neutral SMase, which resulted in the generation of ceramide. Specific inhibition of acid SMase or neutral SMase and siRNA knockdown experiments partially blocked STC-induced apoptosis. Moreover, STC markedly reduced tumor growth of HL-60 xenograft and CT-26 subcutaneous tumors and increased ceramide generation in vivo.

Conclusions: Ceramide generation by STC, through activation of acid and neutral SMase, may in part contribute to STC-induced apoptosis and antitumor activity. Thus, STC may have therapeutic relevance for human leukemia and colorectal cancer. Clin Cancer Res; 18(21); 5934–48. ©2012 AACR.
Reversing Effect of Ring Finger Protein 43 Inhibition on Malignant Phenotypes of human Hepatocellular Carcinoma
Authors: Xing Chunyang , Zhou Wuhua , Ding Songming , Xie Haiyang , Zhang Wu , Yang Zhe , Wei Bajin , Chen Kangjie , Su Rong , Cheng Jun , Zheng Shusen , Zhou Lin
Published: November 2012

It has been shown that Ring finger protein 43 (RNF43) is overexpressed in colorectal cancer and mediates cancer cell proliferation; however, its role in hepatocellular carcinoma (HCC) remains unknown. In this study, we found that RNF43 was frequently overexpressed in HCCs, and this overexpression was correlated with positive vascular invasion, poor tumor differentiation, and advanced tumor stage. Functional studies showed that knockdown of RNF43 could induce apoptosis and inhibit proliferation, invasion, colony formation, and xenograft growth of HCCs. Microarray-based gene profiling showed a total of 229 genes differentially expressed after RNF43 knockdown, many of which are involved in oncogenic processes such as cell proliferation, cell adhesion, cell motility, cell death, DNA repair, and so on. These results suggest that RNF43 is involved in tumorigenesis and progression of HCCs and that antagonism of RNF43 may be beneficial for HCC treatment. Mol Cancer Ther; 12(1); 94–103. ©2012 AACR.