bluuebunny/crossref_metadata_2025 huggingface dataset:
Glacial Lake Saskatchewan and Lake Agassiz deltas in east-central Saskatchewan with special emphasis on the Nipawin delta
Authors: Christiansen E. A. , Sauer E. Karl , Schreiner Bryan T.
Published: August 2009

The Nipawin delta extends eastward from the town of Nipawin in east-central Saskatchewan. The Prince Albert and Fort à la Corne deltas formed in Lake Saskatchewan at the mouths of the South and North Saskatchewan rivers, whereas the Nipawin and Mossy vale deltas formed in Lake Agassiz at the mouth of the Saskatchewan River. These deltas became lower in elevation and younger eastward. Clays beneath the Nipawin and Mossyvale deltas can be traced beneath the Prince Albert and Fort à la Corne deltas with little change in thickness, suggesting that most of the clays beneath the Nipawin and Mossyvale deltas were deposited during the formation of the Prince Albert and Fort à la Corne deltas. The Nipawin delta formed between 10 200 and 9500 BP. The Campbell strandline (Emerson phase) was the shoreline of the Nipawin delta. The Mossyvale delta formed about 9500 BP. The surface of the Mossyvale delta (McCauleyville level) is about 40 m below the surface of the Nipawin delta (Campbell level).
ON THE TRANSITION TO METALLIC CONDUCTION IN SEMICONDUCTORS
Authors: Mott N. F.
Published: August 2009

A discussion is given of the conductivity to be expected from a crystalline array of atoms when the interatomic distance a is varied. It is shown that both for monovalent atoms and divalent atoms the conductivity is zero at T = 0 when a is large, the wave function of the system being real so that no current is possible. In both types of atom a discontinuous transition to a state showing metallic conductivity is predicted at a definite value of a. For divalent atoms calculations using Bloch orbitals and localized Wannier functions give essentially the same result; for monovalent metals they do not, and correspond to physically different states of the system. Applications are made to impurity-band conduction in semiconductors, the impurity centers being treated by the usual model as expanded atoms in a uniform dielectric. It is shown that the concentrations at which "metallic" conductivity sets in are not unexpected, but that it is difficult to understand impurity band conduction at lower concentrations unless the semiconductors are "compensated", either chemically or through the presence of dislocations.
THE CHEMICAL BOND IN SEMICONDUCTORS: THE GROUP V B TO VII B ELEMENTS AND COMPOUNDS FORMED BETWEEN THEM
Authors: Mooser E. , Pearson W. B.
Published: August 2009

A brief review is first given of the developments which led to an understanding of the important role played by chemical bonding in semiconductors. The properties of the Group V B to VII B elements and of some compounds formed between these elements are then considered according to the valence bond model of Pauling. This leads to the conclusion that the band scheme in these substances is somewhat different to that which has been generally accepted, and we discuss the new model in relation to their electrical and optical properties.
DYNAMIC SPACE WARPING OF STROKES FOR RECOGNITION OF ONLINE HANDWRITTEN CHARACTERS
Authors: SEN AMRIK , ANANTHAKRISHNAN G. , SUNDARAM SURESH , RAMAKRISHNAN A. G.
Published: August 2009

This paper suggests a scheme for classifying online handwritten characters, based on dynamic space warping of strokes within the characters. A method for segmenting components into strokes using velocity profiles is proposed. Each stroke is a simple arbitrary shape and is encoded using three attributes. Correspondence between various strokes is established using Dynamic Space Warping. A distance measure which reliably differentiates between two corresponding simple shapes (strokes) has been formulated thus obtaining a perceptual distance measure between any two characters. Tests indicate an accuracy of over 85% on two different datasets of characters.
CLASSIFIER COMBINATION BY BAYESIAN NETWORKS FOR HANDWRITING RECOGNITION
Authors: DE STEFANO CLAUDIO , D'ELIA CIRO , DI FRECA ALESSANDRA SCOTTO , MARCELLI ANGELO
Published: August 2009

In the field of handwriting recognition, classifier combination received much more interest than the study of powerful individual classifiers. This is mainly due to the enormous variability among the patterns to be classified, that typically requires the definition of complex high dimensional feature spaces: as the overall complexity increases, the risk of inconsistency in the decision of the classifier increases as well. In this framework, we propose a new combining method based on the use of a Bayesian Network. In particular, we suggest to reformulate the classifier combination problem as a pattern recognition one in which each input pattern is associated to a feature vector composed by the output of the classifiers to be combined. A Bayesian Network is then used to automatically infer the probability distribution for each class and eventually to perform the final classification. Experiments have been performed by using two different pools of classifiers, namely an ensemble of Learning Vector Quantization neural networks and an ensemble of Back Propagation neural networks, and handwritten specimen from the UCI Machine Learning Repository. The obtained performance has been compared with those exhibited by multi-classifier systems adopting the classifiers, but three of the most effective and widely used combining rules: the Majority Vote, the Weighted Majority Vote and the Borda Count.
FEATURE SELECTION FOR HMM AND BLSTM BASED HANDWRITING RECOGNITION OF WHITEBOARD NOTES
Authors: LIWICKI MARCUS , BUNKE HORST
Published: August 2009

In this paper, we describe feature selection experiments for online handwriting recognition. We investigated a set of 25 online and pseudo-offline features to find out which features are important and which features may be redundant. To analyze the saliency of the features, we applied a sequential forward and a sequential backward search on the feature set. A hidden Markov model and a neural network based recognizer have been used as recognition engines. In our experiments, we obtained interesting results. Using a set of only five features, we achieved a performance similar to that of the reference system that uses all 25 features. The five selected features have a low correlation and have been the top choices during the first iterations of the forward search with both recognizers. Furthermore, for both recognizers, subsets have been identified that outperform the reference system with statistical significance. In order to assess the results more rigorously, we have compared our recognizer with the widely used commercial recognizer from Microsoft.
A MECHANISM FOR FILTERING DISTRACTORS FOR DOODLE PASSWORDS
Authors: POET RON , RENAUD KAREN
Published: August 2009

Graphical authentication holds some potential as an alternative to the ubiquitous password. Graphical authentication mechanisms typically present users with one or more challenge sets composed of a number of images: one target image surrounded by distractor images. Unfortunately, this means it tends to be more time-consuming than password entry and to alleviate this, we need to streamline the process as much as possible to maximize efficiency. The distractors must be chosen with care so as to ensure that users do not become confused by similarities with the target image. It is especially challenging to achieve this filtering with minimalist image types, such as hand-drawn doodles.

This paper explores the issues related to filtering the distractor images used in graphical authentication mechanisms using minimalist images. We present an algorithm for automatically classifying minimalist images in terms of visual similarity. The principles outlined here can also be used to assess the similarity of other minimalist image types such as signatures and handwritten numerals.
WORD EXTRACTION ASSOCIATED WITH A CONFIDENCE INDEX FOR ONLINE HANDWRITTEN SENTENCE RECOGNITION
Authors: QUINIOU SOLEN , BOUTERUCHE FRANÇOIS , ANQUETIL ERIC
Published: August 2009

This paper presents a word extraction approach based on the use of a confidence index to limit the total number of segmentation hypotheses in order to further extend our online sentence recognition system to perform "on-the-fly" recognition. Our initial word extraction task is based on the characterization of the gap between each couple of consecutive strokes from the online signal of the handwritten sentence. A confidence index is associated to the gap classification result in order to evaluate its reliability. A reconsideration process is then performed to create additional segmentation hypotheses to ensure the presence of the correct segmentation among the hypotheses. In this process, we control the total number of segmentation hypotheses to limit the complexity of the recognition process and thus the execution time. This approach is evaluated on a test set of 425 English sentences written by 17 writers, using different metrics to analyze the impact of the word extraction task on the whole sentence recognition system performances. The word extraction task using the best reconsideration strategy achieves a 97.94% word extraction rate and a 84.85% word recognition rate which represents a 33.1% word error rate decrease relatively to the initial word extraction task (with no segmentation hypothesis reconsideration).
A GENERAL METHOD TO FIND PROPER CHANNEL FOR THREE-QUBIT STATE TELEPORTATION
Authors: TIAN XIU-LAO , XI XIAO-QIANG
Published: August 2009

Based on tensor analysis and Bell basis measurement, we propose a general method to find proper channel for successful teleportation of an unknown three-qubit state. Instead of starting from "the proper channel" as that of the previous work, we begin from the successful teleportation then trace back to find which channel is proper and why it is proper for successful teleportation. At last, we give the necessary and sufficient condition for three-qubit perfect teleportation. This condition can guide us to design the corresponding channel for realizing the teleportation. Furthermore, the description of teleporting process with the help of tensor analysis is more compact and clear. Our method can also be generalized to find the channel for N-qubit successful teleportation.
TIGHT QUANTUM BOUNDS FOR COMPUTATIONAL GEOMETRY PROBLEMS
Authors: VOLPATO NILTON , MOURA ARNALDO
Published: August 2009

We present new quantum lower bounds and upper bounds for several computational geometry problems. The bounds presented here improve on currently known results in a number of ways. We give asymptotically optimal bounds for one of the problems considered, and we provide, up to logarithmic factors, optimal bounds for a number of other problems and, in particular, we settle an open problem of Bahadur et al. Some of these new bounds are obtained using a general algorithm for finding a minimum pair over a given arbitrary order relation.
DOES BLACK HOLE EVAPORATION IMPLY THAT PHYSICS IS NONUNITARY, AND IF SO, WHAT MUST THE LAWS OF PHYSICS LOOK LIKE?
Authors: GIELEN STEFFEN
Published: August 2009

Stephen Hawking's discovery of black hole evaporation has the remarkable consequence that information is destroyed by a black hole, which can only be accommodated by modifying the laws of quantum mechanics. Different attempts to evade the information loss paradox were subsequently suggested, apparently without a satisfactory resolution of the paradox. On the other hand, attempting to include nonunitarity in quantum mechanics might lead to laws predicting observable consequences such as nonlocality or violation of energy–momentum conservation; but it may be possible to circumvent these obstacles. Recent developments seem to require a different view on quantum gravity and suggest that ideas about locality in physics and Hawking's semiclassical approximation are misleading. An accurate description may show unitary evolution and no information loss after all.
ONE DIMENSIONAL SCATTERING PROBLEM IN BOHMIAN QUANTUM MECHANICS
Authors: MOHAMMADI S.
Published: August 2009

According to Standard Quantum Mechanics (SQM), known as the Copenhagen Interpretation, the complete description of a system of particles is provided by its wave function. However, in the de Broglie-Bohm theory of Bohmian Quantum Mechanics (BQM), the additional element which is introduced apart from the wave function is the particle position, conceived in the classical sense as pursuing a definite continuous track in space-time. In BQM formulation, depending on the configuration of the potential barrier and the energy of the packet, the particle trajectories have been shown to take distinct paths. We will consider several barrier heights and show that in a Bohmian interpretation of the problem, there is no such thing as Quantum Tunnelling.
ENTANGLEMENT DYNAMICS IN THE THREE-ATOM TAVIS-CUMMINGS MODEL
Authors: ZHANG JIAN-SONG , CHEN AI-XI
Published: August 2009

We investigate the entanglement dynamics in a quantum system consisting of three two-level atoms resonantly coupled to a single mode electromagnetic field in a cavity. An explicit analytical solution of the system is obtained and the entanglement of the system is studied with the help of the concurrence and tangle. It is also shown that the W states could be generated if the interaction time of the two-level atoms and the cavity field is chosen appropriately.
ENTANGLEMENT ENHANCES THE SECURITY OF ARBITRATED QUANTUM SIGNATURE
Authors: LI QIN , DU RUI-GANG , LONG DONG-YANG , WANG CHANG-JI , CHAN WAI-HONG
Published: August 2009

We show that quantum entanglement is helpful in improving the security of arbitrated quantum signature (AQS). Using the properties of quantum entanglement, a potential forgery which might occur in arbitrated quantum signature schemes without using them can be avoided. The fact is illustrated by relevant schemes.
Collective Cell Migration
Authors: Rørth Pernille
Published: August 2009

For all animals, cell migration is an essential and highly regulated process. Cells migrate to shape tissues, to vascularize tissues, in wound healing, and as part of the immune response. Unfortunately, tumor cells can also become migratory and invade surrounding tissues. Some cells migrate as individuals, but many cell types will, under physiological conditions, migrate collectively in tightly or loosely associated groups. This includes invasive tumor cells. This review discusses different types of collective cell migration, including sheet movement, sprouting and branching, streams, and free groups, and highlights recent findings that provide insight into cells' organization and behavior. Cells performing collective migration share many cell biological characteristics with independently migrating cells but, by affecting one another mechanically and via signaling, these cell groups are subject to additional regulation and constraints. New properties that emerge from this connectivity can contribute to shaping, guiding, and ultimately ensuring tissue function.
Vertebrate Endoderm Development and Organ Formation
Authors: Zorn Aaron M. , Wells James M.
Published: August 2009

The endoderm germ layer contributes to the respiratory and gastrointestinal tracts and to all of their associated organs. Over the past decade, studies in vertebrate model organisms, including frog, fish, chick, and mouse, have greatly enhanced our understanding of the molecular basis of endoderm organ development. We review this progress with a focus on early stages of endoderm organogenesis including endoderm formation, gut tube morphogenesis and patterning, and organ specification. Lastly, we discuss how developmental mechanisms that regulate endoderm organogenesis are used to direct differentiation of embryonic stem cells into specific adult cell types, which function to alleviate disease symptoms in animal models.
Genetic and metabolic effects on skeletal muscle AMPK in young and older twins
Authors: Mortensen Brynjulf , Poulsen Pernille , Wegner Lise , Stender-Petersen Kirstine L. , Ribel-Madsen Rasmus , Friedrichsen Martin , Birk Jesper B. , Vaag Allan , Wojtaszewski Jørgen F. P.
Published: August 2009

The protein complex AMP-activated protein kinase (AMPK) is believed to play an important role in the regulation of skeletal muscle glucose and lipid metabolism. Defects in the AMPK system might therefore be an important factor in the pathogenesis of type 2 diabetes. We aimed to identify genetic and environmental mechanisms involved in the regulation of AMPK expression and activity and to examine the association between AMPK protein levels and activity on the one hand, and glucose and fat metabolism on the other. We investigated skeletal muscle biopsies from 100 young and 82 older mono- and dizygotic nondiabetic twins excised during the basal and insulin-stimulated states of a physiological hyperinsulinemic-euglycemic clamp. AMPKα1, -α2, and -γ3 mRNA expression was investigated using real-time PCR, and Western blotting was employed to measure protein levels. Multiple regression analyses indicated that skeletal muscle AMPK mRNA and protein expression as well as activity were regulated by sex, age, obesity, and aerobic capacity. Comparison of intraclass correlations on AMPK measurements from mono- and dizygotic twins suggested that skeletal muscle AMPK expression was under minor genetic influence. AMPKγ3 protein expression and activity were negatively related to whole body glucose uptake through the nonoxidative metabolic pathway and positively related to phosphorylation of glycogen synthase. Our results suggest that skeletal muscle AMPK expression is under minor genetic control but regulated by age and sex and associated with obesity and aerobic capacity. Furthermore, our results indicate a role for γ3-containing AMPK complexes in downregulation of insulin-stimulated nonoxidative glucose metabolism possibly through inhibition of glycogen synthase activity.
Role of CYP27A1 in progesterone metabolism in vitro and in vivo
Authors: Escher Geneviève , Vögeli Isabelle , Escher Robert , Tuckey Robert C. , Erickson Sandra , Krozowski Zygmunt , Frey Felix J.
Published: August 2009

In the kidney, progesterone is inactivated to 20α-dihydro-progesterone (20α-DH-progesterone) to protect the mineralocorticoid receptor from progesterone excess. In an attempt to clone the enzyme with 20α-hydroxysteroid activity using expression cloning in CHOP cells and a human kidney expression library, serendipitously cDNA encoding CYP27A1 was isolated. Overexpression of CYP27A1 in CHOP cells decreased progesterone conversion to 20α-DH-progesterone in a dose-dependent manner, an effect enhanced by cotransfection with adrenodoxin and adrenodoxin reductase. Incubation of CHOP cells with 27-hydroxycholesterol, a product of CYP27A1, increased the ratio of progesterone to 20α-DH-progesterone in a concentration-dependent manner, indicating that the effect of CYP27A1 overexpression was mediated by 27-hydroxycholesterol. To analyze whether these observations are relevant in vivo, progesterone and 20α-DH-progesterone were measured by gas chromatography-mass spectometry in 24-h urine of CYP27A1 gene knockout (ko) mice and their control wild-type and heterozygote littermates. In CYP27A1 ko mice, urinary progesterone concentrations were decreased, 20α-DH-progesterone increased, and the progesterone-to-20α-DH-progesterone ratio decreased threefold ( P < 0.001). Thus CYP27A1 modulates progesterone concentrations. The underlying mechanism is inhibition of 20α-hydroxysteroid dehydrogenase by 27-hydroxycholesterol.
Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice
Authors: Stoller Douglas , Pytel Peter , Katz Sophie , Earley Judy U. , Collins Keith , Metcalfe Jamie , Lang Roberto M. , McNally Elizabeth M.
Published: August 2009

By sensing intracellular energy levels, ATP-sensitive potassium (KATP) channels help regulate vascular tone, glucose metabolism, and cardioprotection. SUR2 mutant mice lack full-length KATP channels in striated and smooth muscle and display a complex phenotype of hypertension and coronary vasospasm. SUR2 mutant mice also display baseline cardioprotection and can withstand acute sympathetic stress better than normal mice. We now studied response to a form of chronic stress, namely that induced by 4 wk of daily exercise on SUR2 mutant mice. Control mice increased exercise capacity by 400% over the training period, while SUR2 mutant mice showed little increase in exercise capacity. Unexercised SUR2 mutant showed necrotic and regenerating fibers in multiple muscle skeletal muscles, including quadriceps, tibialis anterior, and diaphragm muscles. Unlike exercised control animals, SUR2 mutant mice did not lose weight, presumably due to less overall exertion. Unexercised SUR2 mutant mice showed a trend of mildly reduced cardiac function, measured by fractional shortening, (46 ± 4% vs. 57 ± 7% for SUR2 mutant and control, respectively), and this decrease was not exacerbated by chronic exercise exposure. Despite an improved response to acute sympathetic stress and baseline cardioprotection, exercise intolerance results from lack of SUR2 KATP channels in mice.
Synchronization of GABAergic Inputs to CA3 Pyramidal Cells Precedes Seizure-Like Event Onset in Juvenile Rat Hippocampal Slices
Authors: Lasztóczi Bálint , Nyitrai Gabriella , Héja László , Kardos Julianna
Published: August 2009

Here we address how dynamics of glutamatergic and GABAergic synaptic input to CA3 pyramidal cells contribute to spontaneous emergence and evolution of recurrent seizure-like events (SLEs) in juvenile (P10-13) rat hippocampal slices bathed in low-[Mg2+] artificial cerebrospinal fluid. In field potential recordings from the CA3 pyramidal layer, a short epoch of high-frequency oscillation (HFO; 400–800 Hz) was observed during the first 10 ms of SLE onset. GABAergic synaptic input currents to CA3 pyramidal cells were synchronized and coincided with HFO, whereas the glutamatergic input lagged by ∼10 ms. If the intracellular [Cl−] remained unperturbed (cell-attached recordings) or was set high with whole cell electrode solution, CA3 pyramidal cell firing peaked with HFO and GABAergic input. By contrast, with low intracellular [Cl−], spikes of CA3 pyramidal cells lagged behind HFO and GABAergic input. This temporal arrangement of HFO, synaptic input sequence, synchrony of GABAergic currents, and pyramidal cell firing emerged gradually with preictal discharges until the SLE onset. Blockade of GABAA receptor-mediated currents by picrotoxin reduced the inter-SLE interval and the number of preictal discharges and did not block recurrent SLEs. Our data suggest that dynamic changes of the functional properties of GABAergic input contribute to ictogenesis and GABAergic and glutamatergic inputs are both excitatory at the instant of SLE onset. At the SLE onset GABAergic input contributes to synchronization and recruitment of pyramidal cells. We conjecture that this network state is reached by an activity-dependent shift in GABA reversal potential during the preictal phase.
What’s New About Osmotic Regulation of Glycerophosphocholine
Authors: Gallazzini Morgan , Burg Maurice B.
Published: August 2009

Glycerophosphocholine is an abundant renal medullary organic osmolyte that protects renal medullary cells from the high interstitial concentrations of NaCl and urea to which they are normally exposed. We consider the metabolism of glycerophosphocholine, its osmotic regulation, and the recently discovered molecular identity of the enzymes that osmoregulate its abundance.
The Mammalian Urine Concentrating Mechanism: Hypotheses and Uncertainties
Authors: Layton Anita T. , Layton Harold E. , Dantzler William H. , Pannabecker Thomas L.
Published: August 2009

The urine concentrating mechanism of the mammalian kidney, which can produce a urine that is substantially more concentrated than blood plasma during periods of water deprivation, is one of the enduring mysteries in traditional physiology. Owing to the complex lateral and axial relationships of tubules and vessels, in both the outer and inner medulla, the urine concentrating mechanism may only be fully understood in terms of the kidney’s three-dimensional functional architecture and its implications for preferential interactions among tubules and vessels.
Phosphoinositide Signaling: New Tools and Insights
Authors: Balla Tamas , Szentpetery Zsofia , Kim Yeun Ju
Published: August 2009

Phosphoinositides constitute only a small fraction of cellular phospholipids, yet their importance in the regulation of cellular functions can hardly be overstated. The rapid metabolic response of phosphoinositides after stimulation of certain cell surface receptors was the first indication that these lipids could serve as regulatory molecules. These early observations opened research areas that ultimately clarified the plasma membrane role of phosphoinositides in Ca2+signaling. However, research of the last 10 years has revealed a much broader range of processes dependent on phosphoinositides. These lipids control organelle biology by regulating vesicular trafficking, and they modulate lipid distribution and metabolism more generally via their close relationship with lipid transfer proteins. Phosphoinositides also regulate ion channels, pumps, and transporters as well as both endocytic and exocytic processes. The significance of phosphoinositides found within the nucleus is still poorly understood, and a whole new research concerns the highly phosphorylated inositols that also appear to control multiple nuclear processes. The expansion of research and interest in phosphoinositides naturally created a demand for new approaches to determine where, within the cell, these lipids exert their effects. Imaging of phosphoinositide dynamics within live cells has become a standard cell biological method. These new tools not only helped us localize phosphoinositides within the cell but also taught us how tightly phosphoinositide control can be linked with distinct effector protein complexes. The recent progress allows us to understand the underlying causes of certain human diseases and design new strategies for therapeutic interventions.
Transcriptome analysis reveals an unexpected role of a collagen tyrosine kinase receptor gene,Ddr2,as a regulator of ovarian function
Authors: Matsumura Hirokazu , Kano Kiyoshi , de Evsikova Caralina Marín , Young James A. , Nishina Patsy M. , Naggert Jürgen K. , Naito Kunihiko
Published: August 2009

Mice homozygous for the smallie ( slie) mutation lack a collagen receptor, discoidin domain receptor 2 (DDR2), and are dwarfed and infertile due to peripheral dysregulation of the endocrine system of unknown etiology. We used a systems biology approach to identify biological networks affected by Ddr2slie/sliemutation in ovaries using microarray analysis and validate findings using molecular, cellular, and functional biological assays. Transcriptome analysis indicated several altered gene categories in Ddr2slie/sliemutants, including gonadal development, ovulation, antiapoptosis, and steroid hormones. Subsequent biological experiments confirmed the transcriptome analysis predictions. For instance, a significant increase of TUNEL-positive follicles was found in Ddr2slie/sliemutants vs. wild type, which confirm the transcriptome prediction for decreased chromatin maintenance and antiapoptosis. Decreases in gene expression were confirmed by RT-PCR and/or qPCR; luteinizing hormone receptor and prostaglandin type E and F receptors in Ddr2slie/sliemutants, compared with wild type, confirm hormonal signaling pathways involved in ovulation. Furthermore, deficiencies in immunohistochemistry for DDR2 and luteinizing hormone receptor in the somatic cells, but not the oocytes, of Ddr2slie/sliemutant ovaries suggest against an intrinsic defect in germ cells. Indeed, Ddr2slie/sliemutants ovulated significantly fewer oocytes; their oocytes were competent to complete meiosis and fertilization in vitro. Taken together, our convergent data signify DDR2 as a novel critical player in ovarian function, which acts upon classical endocrine pathways in somatic, rather than germline, cells.
Clinical and molecular characterizations of novelPOU3F4mutations reveal that DFN3 is due to null function of POU3F4 protein
Authors: Lee Hee Keun , Song Mee Hyun , Kang Myengmo , Lee Jung Tae , Kong Kyoung-Ah , Choi Su-Jin , Lee Kyu Yup , Venselaar Hanka , Vriend Gert , Lee Won-Sang , Park Hong-Joon , Kwon Taeg Kyu , Bok Jinwoong , Kim Un-Kyung
Published: August 2009

X-linked deafness type 3 (DFN3), the most prevalent X-linked form of hereditary deafness, is caused by mutations in the POU3F4 locus, which encodes a member of the POU family of transcription factors. Despite numerous reports on clinical evaluations and genetic analyses describing novel POU3F4 mutations, little is known about how such mutations affect normal functions of the POU3F4 protein and cause inner ear malformations and deafness. Here we describe three novel mutations of the POU3F4 gene and their clinical characterizations in three Korean families carrying deafness segregating at the DFN3 locus. The three mutations cause a substitution (p.Arg329Pro) or a deletion (p.Ser310del) of highly conserved amino acid residues in the POU homeodomain or a truncation that eliminates both DNA-binding domains (p.Ala116fs). In an attempt to better understand the molecular mechanisms underlying their inner ear defects, we examined the behavior of the normal and mutant forms of the POU3F4 protein in C3H/10T1/2 mesodermal cells. Protein modeling as well as in vitro assays demonstrated that these mutations are detrimental to the tertiary structure of the POU3F4 protein and severely affect its ability to bind DNA. All three mutated POU3F4 proteins failed to transactivate expression of a reporter gene. In addition, all three failed to inhibit the transcriptional activity of wild-type proteins when both wild-type and mutant proteins were coexpressed. Since most of the mutations reported for DFN3 thus far are associated with regions that encode the DNA binding domains of POU3F4, our results strongly suggest that the deafness in DFN3 patients is largely due to the null function of POU3F4.
MultiPoint BVPs for Second‐Order Functional Differential Equations with Impulses
Authors: Yang Xuxin , He Zhimin , Shen Jianhua
Published: August 2009

This paper is concerned about the existence of extreme solutions of multipoint boundary value problem for a class of second‐order impulsive functional differential
equations. We introduce a new concept of lower and upper solutions. Then, by using the
method of upper and lower solutions introduced and monotone iterative technique, we obtain
the existence results of extreme solutions.
A New Mechanical Model for Particle Transport by Surface Waves and Applications
Authors: Ragulskis Minvydas , Sakyte Edita , Seoane Jesús M. , Sanjuán Miguel A. F.
Published: August 2009

We present a study of the behavior of a ball under the influence of gravity on a platform. A propagating surface wave travels on the surface of the platform while the platform remains motionless. This is a modification of the classical bouncing ball problem and describes the transport of particles by surface waves. Phase and velocity maps cannot be expressed in the explicit form due to implicit formulations, and no formal analytical analyses is possible. Numerical analysis shows that the transition to chaos is produced via a period doubling routewhich is a common property for classical bouncers. These numerical analysis have been carried out for the conservative and for the viscous cases and also for elastic and for inelastic collisions. The bouncing process can be sensitive to the initial conditions and can be useful for control techniques which can dramatically increase the effectiveness of particle transport in practical applications. Finally, we also consider the mechanical model of a particle sliding on a surface which is also important because it has important physical implications such as the transportation of thin films in biomedical applications, among others.
A 3D Multiport Scattering Matrix Based‐Method for Educing Wall Impedance of Cylindrical Lined Duct Section: Simulation and Error Evaluation
Authors: Taktak Mohamed , Ville Jean-Michel , Haddar Mohamed , Gabard Gwénaël , Foucart Felix
Published: August 2009

The first step to achieve the development of an original indirect method to educe the wall normalized acoustic impedance of a cylindrical lined duct section which includes frequency and modal content pressure field dependence is introduced. It is based on the minimization of the difference between numerical and experimental acoustic power dissipations deduced from the 3D numerical and experimental scattering matrices of a lined duct element. The work presented in this paper is a step toward conducting experiments with a flow duct facility developed during the European DUCAT program. To validate this eduction technique, a simulation of the experiment is performed for no flow conditions assuming an axi‐symmetric wall lined with a locally reacting material whose impedance was measured with the two microphone method (TMM). The simulation conducted for two incident pressure vectors with a Monte Carlo′s technique also provides an assessment of the uncertainty in three predominant experimental parameters on the scattering matrix coefficients, the acoustic power dissipation, and the educed impedance whose results will be useful during the experiments being conducted.
Advances in Maize Genomics and Their Value for Enhancing Genetic Gains from Breeding
Authors: Xu Yunbi , Skinner Debra J. , Wu Huixia , Palacios-Rojas Natalia , Araus Jose Luis , Yan Jianbing , Gao Shibin , Warburton Marilyn L. , Crouch Jonathan H.
Published: August 2009

Maize is an important crop for food, feed, forage, and fuel across tropical and temperate areas of the world. Diversity studies at genetic, molecular, and functional levels have revealed that, tropical maize germplasm, landraces, and wild relatives harbor a significantly wider range of genetic variation. Among all types of markers, SNP markers are increasingly the marker‐of‐choice for all genomics applications in maize breeding. Genetic mapping has been developed through conventional linkage mapping and more recently through linkage disequilibrium‐based association analyses. Maize genome sequencing, initially focused on gene‐rich regions, now aims for the availability of complete genome sequence. Conventional insertion mutation‐based cloning has been complemented recently by EST‐ and map‐based cloning. Transgenics and nutritional genomics are rapidly advancing fields targeting important agronomic traits including pest resistance and grain quality. Substantial advances have been made in methodologies for genomics‐assisted breeding, enhancing progress in yield as well as abiotic and biotic stress resistances. Various genomic databases and informatics tools have been developed, among which MaizeGDB is the most developed and widely used by the maize research community. In the future, more emphasis should be given to the development of tools and strategic germplasm resources for more effective molecular breeding of tropical maize products.
Inhibition of Activator Protein-1 by Sulforaphane Involves Interaction with Cysteine in the cFos DNA-Binding Domain: Implications for Chemoprevention of UVB-Induced Skin Cancer
Authors: Dickinson Sally E. , Melton Tania F. , Olson Erik R. , Zhang Jian , Saboda Kathylynn , Bowden G. Timothy
Published: August 2009

Sulforaphane is an isothiocyanate derived from cruciferous vegetables that has been linked to decreased risk of certain cancers. Although the role of sulforaphane in the induction of the transcription factor Nrf2 has been studied extensively, there is also evidence that inhibition of the transcription factor activator protein-1 (AP-1) may contribute to the chemopreventive properties of this compound. In this study, we show for the first time that sulforaphane is effective at reducing the multiplicity and tumor burden of UVB-induced squamous cell carcinoma in a mouse model using cotreatment with the compound and the carcinogen. We also show that sulforaphane pretreatment is able to reduce the activity of AP-1 luciferase in the skin of transgenic mice after UVB. Chromatin immunoprecipitation analysis verified that a main constituent of the AP-1 dimer, cFos, is inhibited from binding to the AP-1 DNA binding site by sulforaphane. Electrophoretic mobility shift assay analysis of nuclear proteins also shows that sulforaphane and diamide, both known to react with cysteine amino acids, are effective at inhibiting AP-1 from binding to its response element. Using truncated recombinant cFos and cJun, we show that mutation of critical cysteines in the DNA-binding domain of these proteins (Cys154 in cFos and Cys272 in cJun) results in loss of sensitivity to both sulforaphane and diamide in electrophoretic mobility shift assay analysis. Together, these data indicate that inhibition of AP-1 activity may be an important molecular mechanism in chemoprevention of squamous cell carcinoma by sulforaphane. [Cancer Res 2009;69(17):7103–10]
Consensus Recommendations to Accelerate Clinical Trials for Neurofibromatosis Type 2
Authors: Evans D. Gareth , Kalamarides Michel , Hunter-Schaedle Kim , Blakeley Jaishri , Allen Jeffrey , Babovic-Vuskanovic Dusica , Belzberg Allan , Bollag Gideon , Chen Ruihong , DiTomaso Emmanuelle , Golfinos John , Harris Gordon , Jacob Abraham , Kalpana Ganjam , Karajannis Matthias , Korf Bruce , Kurzrock Razelle , Law Meng , McClatchey Andrea , Packer Roger , Roehm Pamela , Rubenstein Allan , Slattery William , Tonsgard James H. , Welling D. Bradley , Widemann Brigitte , Yohay Kaleb , Giovannini Marco
Published: August 2009

Purpose: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need.

Experimental Design: Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials.

Results: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2.

Conclusions: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics. (Clin Cancer Res 2009;15(16):5032–9)
Evaluation of a 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid–Conjugated Bombesin-Based Radioantagonist for the Labeling with Single-Photon Emission Computed Tomography, Positron Emission Tomography, and Therapeutic Radionuclides
Authors: Mansi Rosalba , Wang Xuejuan , Forrer Flavio , Kneifel Stefan , Tamma Maria-Luisa , Waser Beatrice , Cescato Renzo , Reubi Jean Claude , Maecke Helmut R.
Published: August 2009

Purpose: G protein–coupled receptor agonists are being used as radiolabeled vectors for in vivo localization and therapy of tumors. Recently, somatostatin-based antagonists were shown to be superior to agonists. Here, we compare the new [111In/68Ga]-labeled bombesin-based antagonist RM1 with the agonist [111In]-AMBA for targeting the gastrin-releasing peptide receptor (GRPR).

Experimental Design: IC50, Kd values, and antagonist potency were determined using PC-3 and HEK-GRPR cells. Biodistribution and imaging studies were done in nude mice transplanted with the PC-3 tumor. The antagonist potency was assessed by evaluating the effects on calcium release and on receptor internalization monitored by immunofluorescence microscopy.

Results: The IC50 value of [natIn]-RM1 was 14 ± 3.4 nmol/L. [nat/111In]-RM1 was found to bind to the GRPR with a Kd of 8.5 ± 2.7 nmol/L compared with a Kd of 0.6 ± 0.3 nmol/L of [111In]-AMBA. A higher maximum number of binding site value was observed for [111In]-RM1 (2.4 ± 0.2 nmol/L) compared with [111In]-AMBA (0.7 ± 0.1 nmol/L). [natLu]-AMBA is a potent agonist in the immunofluorescence-based internalization assay, whereas [natIn]-RM1 is inactive alone but efficiently antagonizes the bombesin effect. These data are confirmed by the calcium release assay. The pharmacokinetics showed a superiority of the radioantagonist with regard to the high tumor uptake (13.4 ± 0.8% IA/g versus 3.69 ± 0.75% IA/g at 4 hours after injection. as well as to all tumor-to-normal tissue ratios.

Conclusion: Despite their relatively low GRPR affinity, the antagonists [111In/68Ga]-RM1 showed superior targeting properties compared with [111In]-AMBA. As found for somatostatin receptor–targeting radiopeptides, GRP-based radioantagonists seem to be superior to radioagonists for in vivo imaging and potentially also for targeted radiotherapy of GRPR-positive tumors. (Clin Cancer Res 2009;15(16):5240–9)
Antiangiogenic and Antitumor Activity of 6-(2-Aminoethyl)Amino-5-Chlorouracil, a Novel Small-Molecule Inhibitor of Thymidine Phosphorylase, in Combination with the Vascular Endothelial Growth Factor-Trap
Authors: Lu Haiyan , Klein Robert S. , Schwartz Edward L.
Published: August 2009

Purpose: Tumors produce multiple proangiogenic factors, making it unlikely that agents targeting a single angiogenic pathway will be sufficient to treat the spectrum of tumors that occur clinically. Platelet-derived endothelial cell growth factor has angiogenic activity in vitro and in vivo and is overexpressed in most human cancers, where its expression has been correlated with increased microvessel density, more aggressive tumors, and poorer patient prognosis. Platelet-derived endothelial cell growth factor is identical to the enzyme thymidine phosphorylase (TP), and unlike other angiogenic factors, the proangiogenic actions of TP are dependent on its enzyme activity.

Experimental Design: A potent and specific small-molecule inhibitor of the catalytic activity of TP, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), was tested for antiangiogenic and antitumor activity in human cancer xenografts in vivo.

Results: Oral administration of AEAC caused 40% to 50% reductions in the growth of A549 non–small cell lung cancer and PANC-1 pancreatic cancer xenografts, but it was not active against a second pancreatic tumor, BxPC-3. AEAC reduced the microvessel density in the tumors, providing evidence for an antiangiogenic action. Equal or better activity was seen when the mice were treated with the vascular endothelial growth factor (VEGF)-Trap, a soluble VEGF decoy receptor, and the combination of AEAC and VEGF-Trap produced additive antitumor activity that was significantly greater than the VEGF-Trap alone. In the A549 tumors, the combination produced tumor regressions.

Conclusion: These studies show antitumor activity for a drug targeting TP and suggest that inhibitors of TP could be used to augment the clinical efficacy of drugs targeting the VEGF pathway. (Clin Cancer Res 2009;15(16):5136–44)
Visualizing Implanted Tumors in Mice with Magnetic Resonance Imaging Using Magnetotactic Bacteria
Authors: Benoit Michael R. , Mayer Dirk , Barak Yoram , Chen Ian Y. , Hu Wei , Cheng Zhen , Wang Shan X. , Spielman Daniel M. , Gambhir Sanjiv S. , Matin A.
Published: August 2009

Purpose: To determine if magnetotactic bacteria can target tumors in mice and provide positive contrast for visualization using magnetic resonance imaging.

Experimental Design: The ability of the magnetotactic bacterium, Magnetospirillum magneticum AMB-1 (referred to from here as AMB-1), to confer positive magnetic resonance imaging contrast was determined in vitro and in vivo. For the latter studies, AMB-1 were injected either i.t. or i.v. Bacterial growth conditions were manipulated to produce small (∼25-nm diameter) magnetite particles, which were observed using transmission electron microscopy. Tumor targeting was confirmed using 64Cu-labeled bacteria and positron emission tomography and by determination of viable cell counts recovered from different organs and the tumor.

Results: We show that AMB-1 bacteria with small magnetite particles generate T1-weighted positive contrast, enhancing in vivo visualization by magnetic resonance imaging. Following i.v. injection of 64Cu-labeled AMB-1, positron emission tomography imaging revealed increasing colonization of tumors and decreasing infection of organs after 4 hours. Viable cell counts showed that, by day 6, the bacteria had colonized tumors but were cleared completely from other organs. Magnetic resonance imaging showed a 1.22-fold (P = 0.003) increased positive contrast in tumors on day 2 and a 1.39-fold increase (P = 0.0007) on day 6.

Conclusion: Magnetotactic bacteria can produce positive magnetic resonance imaging contrast and colonize mouse tumor xenografts, providing a potential tool for improved magnetic resonance imaging visualization in preclinical and translational studies to track cancer. (Clin Cancer Res 2009;15(16):5170–7)
Elevated Cutaneous Smad Activation Associates with Enhanced Skin Tumor Susceptibility in Organ Transplant Recipients
Authors: Harradine Kelly A. , Ridd Katie , Saunier Elise F. , Clermont Frederic F. , Perez-Losada Jesus , Moore Dan H. , Epstein Ervin H. , Bastian Boris C. , Akhurst Rosemary J.
Published: August 2009

Purpose: Nonmelanoma skin cancer incidence is enhanced >50-fold in patients taking antirejection drugs (ARD) following organ transplantation. Preclinical studies suggest that ARD treatment increases transforming growth factor-β1 (TGF-β1) levels, which contribute to enhanced tumor susceptibility independent of the immunosuppressive effects of ARDs. This study investigates whether TGF-β signaling is elevated in transplant patients.

Experimental Design: Immunohistochemical tissue microarray analysis was used to determine the levels of TGF-β1, TGF-β2, TGF-β3, TβRII, and activated P-Smad2/3 and P-Smad1/5/8, which are phosphorylated directly by distinct TGF-β/BMP receptor complexes. We analyzed >200 cutaneous lesions and adjacent nonlesional skin samples from 87 organ transplant recipients, and 184 cutaneous lesions and adjacent skin samples from 184 individuals who had never received ARDs.

Results: We found significantly higher levels of P-Smad2 in both nonlesional and lesional tissue from transplant recipients compared with those not exposed to ARDs (P ≤ 0.001). In contrast, P-Smad1/5/8, a marker of activation of the bone morphogenetic protein signaling pathway, was generally not expressed at higher levels in patients taking ARDs, including analysis of nonlesional skin, actinic keratoses, carcinoma in situ, or squamous cell carcinoma but was differentially expressed between keratoacanthoma from transplant recipients compared with those from non–transplant recipients (P ≤ 0.005).

Conclusions: Observation of elevated P-Smad2 levels in transplant recipients is consistent with the notion that elevated TGF-β signaling may contribute to malignancy in organ transplant recipients. Disparate P-Smad1/5/8 expression levels between keratoacanthoma from the two patient groups might reflect the distinct BMP-responsive cell of origin for this hair follicle–derived lesion. (Clin Cancer Res 2009;15(16):5101–7)