bluuebunny/crossref_metadata_2025 huggingface dataset:
Forest management effects on carabid beetle communities in coniferous and broadleaved forests: implications for conservation
Authors: FULLER REBECCA J. , OLIVER TOM H. , LEATHER SIMON R.
Published: August 2010

Abstract. Carabid beetles (Carabidae, Coleoptera) were sampled by pitfall trapping to determine the effects of plantation forest management on beetle abundance, diversity and community composition. Five habitats were chosen for study to represent the different environments created by the clear‐fell and re‐plant forestry cycle: clear‐fell, new‐plant, mixed (conifer and broadleaved) and mature stage conifer plantation. The results from these sites were compared with semi‐natural deciduous woodland. Beetles were trapped for 6 weeks during June and July 2005. At each site, a range of environmental parameters were measured; soil pH, soil organic matter content, soil water content, percentage canopy cover, amount of dead wood, leaf‐litter depth, tree species present, tree diameter at breast height and percentage cover of ground vegetation. These were used to interpret differences in carabid abundance, diversity and community assemblage. Beetle abundance was highest in the deciduous habitat, but species diversity was not significantly different between any of the sites, except the clear‐fell habitat which was less diverse. Carabid community assemblages of forest specialist, forest generalist and open‐habitat species were investigated. Only the broadleaved deciduous woodland contained large populations of forest specialist species. These results suggest inclusion of purely broadleaved stands in the forest landscape is necessary to maximise diversity at the landscape scale and enhance the overall conservation potential of managed forest land. Within habitats the amount of dead wood, number of tree species present, percentage canopy cover and leaf‐litter depth were significant determinants of carabid abundance and diversity.
A conversation with Joseph Stiglitz1
Authors: Stiglitz Joseph
Published: August 2010

Joseph Stiglitz launched his new book Making Globalization Work at the Said Business School on 4 September. In this interview with OES he explains how he thinks globalization should be governed, discusses policies for economic development, and suggests some directions for future research.
MONITORING REGIONAL GERIATRIC ASSESSMENT TEAMS: ANALYSIS OF CLIENT FLOWS AND OUTCOMES
Authors: Dudgeon Paul , Howe Anna L.
Published: August 2010

The Commonwealth Government funding of the Geriatric Assessment Program began in 1984. The Program included an evaluation component, and this paper reports findings for three Regional Geriatric Assessment Teams (RGATs) in Victoria focusing on (1) the identification of different starting points in the flow of clients to the RGATs, (2) the relationships between different starting points and (3) recommended care plans, and the relationships between (2) and final outcome, particularly whether or not this involved admission to nursing home care.

The role performed by RGATs is reviewed in the context of introducing mandatory assessment, the success of which will depend on the effectiveness of RGATs not only in differentiating need for and securing admission to nursing home care but also in assessing for, accessing and initiating alternative services.
Using blocks of linked single nucleotide polymorphisms as highly polymorphic genetic markers for parentage analysis
Authors: JONES BEATRIX , WALSH DANIEL , WERNER LILLIAN , FIUMERA ANTHONY
Published: August 2010

Single nucleotide polymorphisms (SNPs) are plentiful in most genomes and amenable to high throughput genotyping, but they are not yet popular for parentage or paternity analysis. The markers are bi‐allelic, so individually they contain little information about parentage, and in nonmodel organisms the process of identifying large numbers of unlinked SNPs can be daunting. We explore the possibility of using blocks of between three and 26 linked SNPs as highly polymorphic molecular markers for reconstructing male genotypes in polyandrous organisms with moderate (five offspring) to large (25 offspring) clutches of offspring. Haplotypes are inferred for each block of linked SNPs using the programs Haplore and Phase 2.1. Each multi‐SNP haplotype is then treated as a separate allele, producing a highly polymorphic, ‘microsatellite‐like’ marker. A simulation study is performed using haplotype frequencies derived from empirical data sets from Drosophila melanogaster and Mus musculus populations. We find that the markers produced are competitive with microsatellite loci in terms of single parent exclusion probabilities, particularly when using six or more linked SNPs to form a haplotype. These markers contain only modest rates of missing data and genotyping or phasing errors and thus should be seriously considered as molecular markers for parentage analysis, particularly when the study is interested in the functional significance of polymorphisms across the genome.
On the Existence of the Shuangtsüan Series and its Triassic Flora in Hsishan or the Western Hills of Peiping.1
Authors: Chi Y. S. , Fan C. H.
Published: August 2010

The Shuangtsüan Series is a new name used for a subdivision of rocks comprising, in general, sandstones, shales, conglomerates and sometimes shales with a thin bad coal seam, with a total thickness of about 150–200 meters. The fine green and purple colors of the sandstone and shale in alteration, and variegated thin conglomerates, the frequent diabase intrusion in this series which cause the rocks of this series subjected to metamorphism, are the most characteristic features. Fossil plants collected from the shales near die coal seam at the middle part comprise the species: Psygmophyllum multipartitum Halle, Pecopteris (Asterotheca) orientalis (Schenk) Potonie, Peconteris lativenosa Halle, Newropteridium coreanicam Koiwai, Nephropsis cf. integerrima (Schmalhausen). Taeniospteris spatulata (McClelland), Nilssonia cf. simplex Oishi, cf. Danœopsis hughesi Feistm,? Albertia sp. nov., Lobatannularia heianensis (Kodaira) and Podozamites distans? (Presl.) According to the above mentioned flora, it is most probable that the Shuangtsiian Series is Lower Triassic in age. This series is sometimes overlain by the Mentoukou Coal Series or unconformably overlain by the Kiulungshan Series, and in several places it even becomes very thin or wanting, making the Hungmiaoling Sandstone directly overlain by the Mentoukou Coal Series or sometimes by the Kiulungshan Series.
The Granitisation Of China
Authors: Teilhard de Chardin P.
Published: August 2010

If they are separated according to their geological age and reported on a map, the post‐Palaeozoic granites of China seem to betray a regular distribution in space and time. They emerge along a definite net of tectonic fissures; and they shift gradually eastward toward the pacific margin of the land.

This peculiar distribution suggests that granitisation is a specific and perennial geological process, possibly playing a fundamental part in the building of continents.
Stratigraphical Development in Kwangsi
Authors: CHAO KINGKOO
Published: August 2010

In summarizing the geological events, it is revealed that the main structur in Kwangsi, the Epsilon structure, was not accomplished to its present status in one orogeny, but in successive periods. The early stages, although rudimentary, served a postive controlling factor on sedimentation. Eight stages can be recognized in the history of development:

1. Caledonian Movement. Elevation of the Kiangnania in northern Kwangsi (part) and the depression of the Cathaysian geosyncline. The southern end of the Kiangnania is responsible for the formation of the backbone of the Kwangsi system.,

2. Liukiang Movement. First appearence of the western wing as a barrier in the Tuyang range and a similar land trending east and west in north central Kwangsi.

3. Huainan Movement. Uplift ot the western and southern regions of Kwangsi along the positions of the western and frontal parts of the arc structure.

4. Tungwu Movement. Formation of the basin in central Kwangsi and the elevation of western part of the province, as has happened in the Huainan Movement.

5. Suwan Movement. Repetation of the Huainan and Suwan Movements, but more conspicuous.

6. Huaiyang Movement. Rejuvenation of the preceding movement and the formation of basins inside of the arc.

7. Nanhsiang Movement. Strong folding.

8. Yenshan Movement. The chief and final orogeny. Formation of the Epsilon structure to its present status.
How to critically appraise and apply meta‐analyses in clinical practice
Authors: HO Roger C. M. , ONG Hatta S. , KUDVA Kundadak G. , CHEUNG Mike W. L. , MAK Anselm
Published: August 2010

Aim:  Prompted by a clinical question, we critically appraised a meta‐analysis of efficacy and safety of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC) in the treatment of proliferative lupus nephritis.

Methods:  Systemic reviews and a meta‐analysis are introduced to the reader in the perspective of a clinical scenario that raises questions about applicability of certain treatment options in clinical practice. Critical appraisal of meta‐analysis addresses three questions. (i) What are the results? (ii) Are the results valid? (iii) How can I apply the results to my patient care?

Results:  A meta‐analysis paper titled ‘Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta‐analysis and meta‐regression’by Mak et al. (2009) was selected. Our critical appraisal identified several strengths of the paper, such as having a clearly focused clinical question, considering clinically important outcomes, using appropriate inclusion criteria to select primary studies, assessing quality of selected papers, good reproducibility in the assessment of primary studies and performing sensitivity analysis and meta‐regression to account for heterogeneity. Nevertheless, we also identified several weaknesses, such as possibly missing out other relevant studies, possible selection bias, low quality of some primary studies used and lack of data on cost effectiveness.

Conclusion:  Meta‐analyses have an important role in the implementation of evidence‐based practice and shaping of future research. Despite the undoubted advantages, meta‐analyses are no panacea. Caution, therefore, has to be applied when using the results of meta‐analyses in clinical practice, due to methodological limitations of the meta‐analyses and limitations in the primary studies used.
Recent Development and Applications of Bulk Glassy Alloys
Authors: Inoue Akihisa , Takeuchi Akira
Published: August 2010

This paper reviews past developments and the present understanding of the physical and mechanical properties of glass alloys, with an emphasis on recent results obtained since around 1990, together with applications of bulk glassy alloys achieved mainly in Tohoku University. After introducing the fundamental concepts around glassy alloys in the first section, the second section describes the relationships between structural relaxation and the discoveries of glassy alloys with a large supercooled liquid region. The third section reviews the history of bulk glassy alloy development, followed by the bulk glassy alloy systems and their features in the fourth section and the features of a glassy structure in the fifth section. The sixth, seventh, and eighth sections summarize the engineering and standardization of Zr‐based bulk glassy alloys. Section nine and the 10th focus on the glass‐forming ability of Zr‐based hypoeutectic glassy alloys and Cu–Zr–Al–Ag bulk glassy alloys. The mechanical properties of Ni‐based bulk glass alloys at low temperatures are shown in the 11th section, whereas the 12th section describes the formation and properties of Ni‐free Ti‐based bulk glassy alloys. The 13th and 14th sections deal with porous Zr‐based bulk glassy alloys including spherical pores and commercialized Fe‐based glassy alloys, respectively, whereas the 15th section reviews supercoold liquid forming. Finally, applications for Zr‐, Ti‐, and Fe‐based glassy alloys are described in the 16th section. In conclusion, the 17th section attempts to assess the present knowledge of the structure and physical properties and identify some outstanding problems for future work.
The Influence of Residual Rolling Stresses on the Strength of Cylindrical Pressure Vessels Under External Loading
Authors: Lunchick M. E.
Published: August 2010

The residual stresses induced by cold-rolling flat plate to a cylindrical shell are investigated for initially elastic, perfectly plastic materials. Expressions for the nonlinear stress-strain curves induced by the residual stresses that are effective in the rolled condition are derived by theory. By means of the effective stress-strain curves reductions in the collapse pressure of cylindrical pressure vessels formed by rolling are calculated.
Stress and Displacement Analysis of a Shell Intersection
Authors: Pan K. C. , Beckett R. E.
Published: August 2010

The problem of two normally intersecting cylindrical shells subjected to internal pressure is considered. The differential equations used for the shells are solved subject to the boundary conditions imposed along the intersection between the two cylinders. Details of a procedure for obtaining a numerical solution are given. Numerical results for a radius ratio of 1:2 are presented. Problems encountered in the numerical computation are discussed and the results of the analysis are compared with experiment.
Bending of a Cracked Plate With Arbitrary Stress Distribution Across the Thickness
Authors: Sih G. C.
Published: August 2010

A theoretical study is carried out to examine the influence of plate thickness on the stress state ahead of a through crack in a bent plate of infinite extent. The approach used rests on a theory in which no restrictions are placed on the mode of the stress distribution across the thickness of the plate. A knowledge of the local stresses or moments of the ensuing stress or moment intensity factor is held important in connection with modern views on the theory of crack propagation. The results show that the bending stresses local to the crack tip are drastically changed when the plate thickness increases from zero to some infinite, but small value. This is evidenced by the high elevation of the local moments as the ratio of plate thickness to crack length is perturbed slightly from zero.
The Development of a New Design for Railroad Flatcar to Carry Cargo Containers and Highway Trailers Interchangeably
Authors: Brodeur R. H.
Published: August 2010

With the growth in the use of standardized freight containers by the maritime operators along with increased use in domestic rail freight operations, a need developed for a rail freight car to handle this traffic interchangeably with domestic piggyback traffic. This paper reviews the approach that was taken to evolve this design by (a) the initial writing of a short set of general specifications, (b) the purchase from each of four car builders of a prototype which embodied their individual ideas, (c) the laboratory testing of each prototype under one testing specification, (d) a period of service testing for each prototype, (e) the writing of final specifications for a production car on the basis of that which was learned during the laboratory and service testing, (f) the final performance testing of the production model. Data on end wall force measurements on containers, longitudinal restraint force, and trailer kingpin forces at various speeds of coupling impacts are presented for the final production design as well as for the tests on the four prototypes.
Deformation Characteristics and Ductile Fracture of 1040 Steel in Simple Upsetting of Solid Cylinders and Rings
Authors: Kobayashi Shiro
Published: August 2010

Experiments were conducted involving the upsetting of solid cylinders and rings of annealed SAE 1040 steel at room temperature for various end conditions. Measurements were made on the displacement distributions at the tool-workpiece interface, and on the development of barreling and strain variations at the free surface. Crack formation at the free surface was observed. The relationship between friction at the interface, deformation characteristics, and fracturing is discussed, and a tentative analysis is given for formulating the strains at the free surface, based on the experimental measurements for upsetting solid cylinders.
Pressure-Induced Ductility
Authors: Avitzur Boaz , Avitzur Betzalel
Published: August 2010

The deformability of brittle composites, including a fiber-reinforced material, and the effect of plastic deformation on the tensile strength of such materials is investigated. The materials of interest are high-strength steel, carbide, and a composite of aluminum reinforced by 10 vol percent of Al3Ni fibers of 0.7 to 0.8 μ diameter. The Al-Ni composite was produced by unidirectional solidification. The plastic deformation was performed by hydrostatic extrusion into a receiver pressure. The effect of environmental pressure in inducing sound flow in otherwise brittle material is presented. When 50 percent reduction in area in the fibrous material was introduced by extruding into a receiver pressure of at least 150,000 psi, a sound product resulted. The micrographs indicate that the voids formed by fracture of the fibers were healed by flow of the aluminum matrix. For evaluation of the tensile test results, a strength equation for fibrous materials was introduced. This equation, developed by the upper bound approach, predicts both the strength of the composite and whether fibers will fracture. Both the strength and the fracture criterion are functions of volume ratio, strength ratio of the two constituents, geometry, and environmental pressure. The upper bound equation is general and includes the “rule of mixtures” as a special case. Correlation was found between predicted and measured strength for the billets tested. In general, the fibrous material after extrusion is more ductile than “as solidified” but has a lower strength. Shorter fibers are expected to yield lower strength and increased ductility.
COMPLETE PERIODIC SYNCHRONIZATION OF DELAYED NEURAL NETWORKS WITH DISCONTINUOUS ACTIVATIONS
Authors: LIU XIAOYANG , CAO JINDE , HUANG GAN
Published: August 2010

Recently, the synchronization issue in chaotic systems has become a hot topic in nonlinear dynamics and has aroused great interest among researchers due to the theoretical significance and potential applications. In this paper, complete periodic synchronization is considered for the delayed neural networks with discontinuous activation functions. Under the framework of Filippov solution, a novel control method is presented by using differential inclusions theory, nonsmooth Lyapunov method and linear matrix inequality (LMI) approach. Based on a newly obtained necessary and sufficient condition, several criteria are derived to ensure the global asymptotical stability of the error system, and thus the response system synchronizes with the drive system. Moreover, the estimation gains are obtained. With these new and effective methods, complete synchronization is achieved. Simulation results are given to illustrate the theoretical results.
ENHANCED FLUORESCENCE IMAGING WITH DMSO-MEDIATED OPTICAL CLEARING
Authors: KARMA SANJEEV , HOMAN JAMES , STOIANOVICI CHARLES , CHOI BERNARD
Published: August 2010

Recent studies have demonstrated that topical application of glycerol on intact skin does not affect its optical scattering properties. Investigators from our research group recently revisited the use of dimethyl sulfoxide (DMSO) as an agent with optical clearing potential. We address the use of optical clearing to enhance quantitation of subsurface fluorescence emission. We employed both in vitro and in vivo model systems to study the effect of topical DMSO application on fluorescence emission. Our in vitro experiments performed on a tissue-simulating phantom suggest that DMSO-mediated optical clearing enables enhanced characterization of subsurface fluorophores. With topical DMSO application, a marked increase in fluorescence emission was observed. After 30 min, the fluorescence signal at the DMSO-treated site was 9× greater than the contralateral saline-treated site. This ratio increased to 13× at 105 min after agent application. In summary, DMSO is an effective optical clearing agent for improved fluorescence emission quantitation and warrants further study in preclinical in vivo studies. Based on outcomes from previous clinical studies on the toxicity profile of DMSO, we postulate that clinical application of DMSO as an optical clearing agent, can be performed safely, although further study is warranted.
ASSESSMENT OF OPTICAL CLEARING AGENTS USING REFLECTANCE-MODE CONFOCAL SCANNING LASER MICROSCOPY
Authors: SAMATHAM RAVIKANT , PHILLIPS KEVIN G. , JACQUES STEVEN L.
Published: August 2010

The mechanism of action of clearing agents to improve optical imaging of mouse skin during reflectance-mode confocal microscopy was tested. The dermal side of excised dorsal mouse skin was exposed for one hour to saline, glycerin, or 80% DMSO, then the clearing agent was removed and the dermis placed against a glass cover slip through which a confocal microscope measured reflectance at 488 nm wavelength. An untreated control was also measured. The axial attenuation of reflectance signal, R(zf) versus increasing depth of focus zf behaved as R = ρ exp (-μzf2G), where ρ is tissue reflectivity and μ is attenuation [cm-1]. The factor 2G accounts for the in/out path of photons, and the numerical aperture of the lens. The ρ, μ data were mapped to values of scattering coefficient (μs [cm-1]) and anisotropy of scattering (g). Images showed that glycerin significantly increased the g of dermis from about 0.7 to about 0.99, with little change in the μs of dermis at about 300 cm-1. DMSO and saline had only slight and inconsistent effects on g and μs.
Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring
Authors: Abbott David H. , Bruns Cristin R. , Barnett Deborah K. , Dunaif Andrea , Goodfriend Theodore L. , Dumesic Daniel A. , Tarantal Alice F.
Published: August 2010

Discrete fetal androgen excess during early gestation in rhesus monkeys ( Macaca mulatta ) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155–175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in pancreatic function in PA infants, suggesting in this nonhuman primate model that differential programming of insulin action and secretion may precede adult metabolic dysfunction.
Activation and repression of glucose-stimulated ChREBP requires the concerted action of multiple domains within the MondoA conserved region
Authors: Davies Michael N. , O'Callaghan Brennon L. , Towle Howard C.
Published: August 2010

Carbohydrate response element-binding protein (ChREBP) is a glucose-dependent transcription factor that stimulates the expression of glycolytic and lipogenic genes in mammals. Glucose regulation of ChREBP has been mapped to its conserved NH2-terminal region of 300 amino acids, designated the MondoA conserved region (MCR). Within the MCR, five domains (MCR1–5) have a particularly high level of conservation and are likely to be important for glucose regulation. We carried out a large-scale deletion and substitution mutational analysis of the MCR domain of ChREBP. This analysis revealed that MCRs 1–4 function in a concerted fashion to repress ChREBP activity in basal (nonstimulatory) conditions. Deletion of the entire MCR1–4 segment or the combination of four specific point mutations located across this region leads to a highly active, glucose-independent form of ChREBP. However, deletion of any individual MCR domain and the majority of point mutations throughout MCR1–4 rendered ChREBP inactive. These observations suggest that the MCR1–4 region interacts with an additional coregulatory factor required for activation. This possibility is supported by the observation that the MCR1–4 region can compete for activity with wild-type ChREBP in stimulatory conditions. In contrast, mutations in the MCR5 domain result in increased activity, suggesting that this domain may be the target of intramolecular repression in basal conditions. Thus, the MCR domains act in a complex and coordinated manner to regulate ChREBP activity in response to glucose.
PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop
Authors: Lavi-Moshayoff Vardit , Wasserman Gilad , Meir Tomer , Silver Justin , Naveh-Many Tally
Published: August 2010

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) target the kidney to cause a phosphaturia. FGF23 also acts on the parathyroid to decrease PTH expression, but in chronic kidney disease (CKD) there are high-serum PTH and FGF23 levels and resistance of the parathyroid to FGF23. We now report that PTH acts on bone to increase FGF23 expression and characterize the signal transduction pathway whereby PTH increases FGF23 expression. Remarkably, we show that PTH is necessary for the high-FGF23 levels of early kidney failure due to an adenine high-phosphorus diet. Parathyroidectomy before the diet totally prevented the fivefold increase in FGF23 levels in kidney failure rats. Moreover, parathyroidectomy of early kidney failure rats corrected their high-FGF23 levels. Therefore, in early kidney failure, the high-FGF23 levels are dependent on the high-PTH levels. PTH infusion for 3 days to mice with normal renal function increased serum FGF23 and calvaria FGF23 mRNA levels. To demonstrate a direct effect of PTH on FGF23, we added PTH to rat osteoblast-like UMR106 cells. PTH increased FGF23 mRNA levels (4-fold) and this effect was mimicked by a PKA activator, forskolin. PTH also decreased SOST mRNA levels (3-fold). SOST codes for sclerostin, a Wnt pathway inhibitor, which is a PTH receptor (PTH1R) target. The effect of PTH was prevented by added sclerostin. Therefore, PTH increases FGF23 expression which involves the PKA and Wnt pathways. The effect of PTH on FGF23 completes a bone-parathyroid endocrine feedback loop. Importantly, secondary hyperparathyroidism is essential for the high-FGF23 levels in early CKD.
On the Origin of the Extracellular Field Potential in the Nucleus Laminaris of the Barn Owl (Tyto alba)
Authors: Kuokkanen Paula T. , Wagner Hermann , Ashida Go , Carr Catherine E. , Kempter Richard
Published: August 2010

The neurophonic is a sound-evoked, frequency-following potential that can be recorded extracellularly in nucleus laminaris of the barn owl. The origin of the neurophonic, and thus the mechanisms that give rise to its exceptional temporal precision, has not yet been identified. Putative generators of the neurophonic are the activity of afferent axons, synaptic activation of laminaris neurons, or action potentials in laminaris neurons. To identify the generators, we analyzed the neurophonic in the high-frequency (>2.5 kHz) region of nucleus laminaris in response to monaural pure-tone stimulation. The amplitude of the neurophonic is typically in the millivolt range. The signal-to-noise ratio reaches values beyond 30 dB. To assess which generators could give rise to these large, synchronous extracellular potentials, we developed a computational model. Spike trains were produced by an inhomogeneous Poisson process and convolved with a spike waveform. The model explained the dependence of the simulated neurophonic on parameters such as the mean rate, the vector strength of phase locking, the number of statistically independent sources, and why the signal-to-noise ratio is independent of the spike waveform and subsequent filtering of the signal. We found that several hundred sources are needed to reach the observed signal-to-noise ratio. The summed coherent signal from the densely packed afferent axons and activation of their synapses on laminaris neurons are alone sufficient to explain the measured properties of the neurophonic.
Postsynaptic Cell Type–Dependent Cholinergic Regulation of GABAergic Synaptic Transmission in Rat Insular Cortex
Authors: Yamamoto Kiyofumi , Koyanagi Yuko , Koshikawa Noriaki , Kobayashi Masayuki
Published: August 2010

The cerebral cortex consists of multiple neuron subtypes whose electrophysiological properties exhibit diverse modulation patterns in response to neurotransmitters, including noradrenaline and acetylcholine (ACh). We performed multiple whole cell patch-clamp recording from layer V GABAergic interneurons and pyramidal cells of rat insular cortex (IC) to examine whether cholinergic effects on unitary inhibitory postsynaptic currents (uIPSCs) are differentially regulated by ACh receptors, depending on their presynaptic and postsynaptic cell subtypes. In fast-spiking (FS) to pyramidal cell synapses, carbachol (10 μM) invariably decreased uIPSC amplitude by 51.0%, accompanied by increases in paired-pulse ratio (PPR) of the second to first uIPSC amplitude, coefficient of variation (CV) of the first uIPSC amplitude, and failure rate. Carbachol-induced uIPSC suppression was dose dependent and blocked by atropine, a muscarinic ACh receptor antagonist. Similar cholinergic suppression was observed in non-FS to pyramidal cell synapses. In contrast, FS to FS/non-FS cell synapses showed heterogeneous effects on uIPSC amplitude by carbachol. In roughly 40% of pairs, carbachol suppressed uIPSCs by 35.8%, whereas in a similar percentage of pairs uIPSCs were increased by 34.8%. Non-FS to FS/non-FS cell synapses also showed carbachol-induced uIPSC facilitation by 29.2% in about half of the pairs, whereas nearly 40% of pairs showed carbachol-induced suppression of uIPSCs by 40.3%. Carbachol tended to increase uIPSC amplitude in interneuron-to-interneuron synapses with higher PPR, suggesting that carbachol facilitates GABA release in interneuron synapses with lower release probability. These results suggest that carbachol-induced effects on uIPSCs are not homogeneous but preiotropic: i.e., cholinergic modulation of GABAergic synaptic transmission is differentially regulated depending on postsynaptic neuron subtypes.
Derived Categories and the Analytic Approach to General Reciprocity Laws: Part III
Authors: Berg Michael C.
Published: August 2010

Building on the scaffolding constructed in the first two articles in this series, we now proceed to the geometric phase of our sheaf (‐complex) theoretic quasidualization of Kubota′s formalism for n‐Hilbert reciprocity. Employing recent work by Bridgeland on stability conditions, we extend our yoga of t‐structures
situated above diagrams of specifically designed derived categories to arrangements of metric spaces or complex manifolds. This prepares the way for proving
n‐Hilbert reciprocity by means of singularity analysis.
A Comparative Analysis of the Value of Information in a Continuous Time Market Model with Partial Information: The Cases of Log‐Utility and CRRA
Authors: Yang Zhaojun , Ewald Christian-Oliver , Wang Wen-Kai
Published: August 2010

We study the question what value an agent in a generalized Black‐Scholes model with partial information attributes to the
complementary information. To do this, we study the utility maximization problems from terminal wealth for the two cases partial information and full information. We assume that the drift term of the risky asset is a dynamic process of general linear type and that the two levels of observation correspond to whether this drift term is observable or not. Applying methods from stochastic filtering theory we derive an analytical tractable formula for the value of information in the case of logarithmic utility. For the case of constant relative risk aversion (CRRA) we derive a semianalytical formula, which uses as an input the numerical solution of a system of ODEs. For both cases we present a comparative analysis.
Anti–Placental Growth Factor Reduces Bone Metastasis by Blocking Tumor Cell Engraftment and Osteoclast Differentiation
Authors: Coenegrachts Lieve , Maes Christa , Torrekens Sophie , Van Looveren Riet , Mazzone Massimiliano , Guise Theresa A. , Bouillon Roger , Stassen Jean-Marie , Carmeliet Peter , Carmeliet Geert
Published: August 2010

Treatment of bone metastases is largely symptomatic and is still an unmet medical need. Current therapies mainly target the late phase of tumor-induced osteoclast activation and hereby inhibit further metastatic growth. This treatment method is, however, less effective in preventing initial tumor engraftment, a process that is supposed to depend on the bone microenvironment. We explored whether bone-derived placental growth factor (PlGF), a homologue of vascular endothelial growth factor-A, regulates osteolytic metastasis. Osteogenic cells secrete PlGF, the expression of which is enhanced by bone-metastasizing breast tumor cells. Selective neutralization of host-derived PlGF by anti-mouse PlGF (αPlGF) reduced the incidence, number, and size of bone metastases, and preserved bone mass. αPlGF did not affect metastatic tumor angiogenesis but inhibited osteoclast formation by preventing the upregulation of the osteoclastogenic cytokine receptor activator of NF-κB ligand in osteogenic cells, as well as by blocking the autocrine osteoclastogenic activity of PlGF. αPlGF also reduced the engraftment of tumor cells in the bone and inhibited their interaction with matrix components in the metastatic niche. αPlGF therefore inhibits not only the progression of metastasis but also the settlement of tumor in the bone. These findings identify novel properties of PlGF and suggest that αPlGF might offer opportunities for adjuvant therapy of bone metastasis. Cancer Res; 70(16); 6537–47. ©2010 AACR.
Gene Array and Fluorescence In situ Hybridization Biomarkers of Activity of Saracatinib (AZD0530), a Src Inhibitor, in a Preclinical Model of Colorectal Cancer
Authors: Arcaroli John J. , Touban Basel M. , Tan Aik Choon , Varella-Garcia Marileila , Powell Rebecca W. , Eckhardt S. Gail , Elvin Paul , Gao Dexiang , Messersmith Wells A.
Published: August 2010

Purpose: To evaluate the efficacy of saracatinib (AZD0530), an oral Src inhibitor, in colorectal cancer (CRC) and to identify biomarkers that predict antitumor activity.

Experimental Design: Twenty-three CRC cell lines were exposed to saracatinib, and baseline gene expression profiles of three sensitive and eight resistant cell lines in vitro and in vivo were used to predict saracatinib sensitivity in an independent group of 10 human CRC explant tumors using the gene array K-Top Scoring Pairs (K-TSP) method. In addition, fluorescence in situ hybridization (FISH) and immunoblotting determined both Src gene copy number and activation of Src, respectively.

Results: Two of 10 explant tumors were determined to be sensitive to saracatinib. The K-TSP classifier (TOX>GLIS2, TSPAN7>BCAS4, and PARD6G>NXN) achieved 70% (7 of 10) accuracy on the test set. Evaluation of Src gene copy number by FISH showed a trend toward significance (P = 0.066) with respect to an increase in Src gene copy and resistance to saracatinib. Tumors sensitive to saracatinib showed an increase in the activation of Src and FAK when compared with resistant tumors.

Conclusions: Saracatinib significantly decreased tumor growth in a subset of CRC cell lines and explants. A K-TSP classifier (TOX>GLIS2, TSPAN7>BCAS4, and PARD6G>NXN) was predictive for sensitivity to saracatinib. In addition, increased activation of the Src pathway was associated with sensitivity to saracatinib. These results suggest that FISH, a K-TSP classifier, and activation of the Src pathway have potential in identifying CRC patients that would potentially benefit from treatment with saracatinib. Clin Cancer Res; 16(16); OF1–12. ©2010 AACR. Clin Cancer Res; 16(16); 4165–77. ©2010 AACR.
The Oncoprotein SF2/ASF Promotes Non–Small Cell Lung Cancer Survival by Enhancing Survivin Expression
Authors: Ezponda Teresa , Pajares María J. , Agorreta Jackeline , Echeveste José I. , López-Picazo José M. , Torre Wenceslao , Pio Ruben , Montuenga Luis M.
Published: August 2010

Purpose: SF2/ASF is a splicing factor recently described as an oncoprotein. In the present work, we examined the role of SF2/ASF in human non–small cell lung cancer (NSCLC) and analyzed the molecular mechanisms involved in SF2/ASF-related carcinogenesis.

Experimental Design: SF2/ASF protein levels were analyzed in 81 NSCLC patients by immunohistochemistry. SF2/ASF downregulation cellular models were generated using small interfering RNAs, and the effects on proliferation and apoptosis were evaluated. Survivin and SF2/ASF expression in lung tumors was analyzed by Western blot and immunohistochemistry. Survival curves and log-rank test were used to identify the association between the expression of the proteins and time to progression.

Results: Overexpression of SF2/ASF was found in most human primary NSCLC tumors. In vitro downregulation of SF2/ASF induced apoptosis in NSCLC cell lines. This effect was associated with a reduction in the expression of survivin, an antiapoptotic protein widely upregulated in cancer. In fact, SF2/ASF specifically bound survivin mRNA and enhanced its translation, via a mammalian target of rapamycin complex 1 (mTORC1) pathway-dependent mechanism, through the phosphorylation and inactivation of the translational repressor 4E-BP1. Moreover, SF2/ASF promoted the stability of survivin mRNA. A strong correlation was observed between the expression of SF2/ASF and survivin in tumor biopsies from NSCLC patients, supporting the concept that survivin expression levels are controlled by SF2/ASF. Furthermore, combined expression of these proteins was associated with prognosis.

Conclusion: This study provides novel data on the mTORC1- and survivin-dependent mechanisms of SF2/ASF-related carcinogenic potential, and shows that SF2/ASF and survivin expression is involved in NSCLC progression. Clin Cancer Res; 16(16); 4113–25. ©2010 AACR.
Inhibition of Hypoxia Inducible Factor-1α by Dihydroxyphenylethanol, a Product from Olive Oil, Blocks Microsomal Prostaglandin-E Synthase-1/Vascular Endothelial Growth Factor Expression and Reduces Tumor Angiogenesis
Authors: Terzuoli Erika , Donnini Sandra , Giachetti Antonio , Iñiguez Miguel A. , Fresno Manuel , Melillo Giovanni , Ziche Marina
Published: August 2010

Purpose: 2-(3,4-dihydroxyphenil)-ethanol (DPE), a polyphenol present in olive oil, has been found to attenuate the growth of colon cancer cells, an effect presumably related to its anti-inflammatory activity.

Experimental Design: To further explore the effects of DPE on angiogenesis and tumor growth we investigated the in vivo efficacy of DPE in a HT-29 xenograft model and in vitro activities in colon cancer cells exposed to interleukin-1β (IL-1β) and prostaglandin E-2 (PGE-2).

Results: DPE (10 mg/kg/day for 14 days) inhibited tumor growth, reducing vessel lumina and blood perfusion to tumor, and diminished expression of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and microsomal prostaglandin-E synthase-1 (mPGEs-1). In vitro, DPE (100 μmol/L) neither affected cell proliferation nor induced apoptosis in HT-29 and WiDr cells. DPE prevented the IL-1β–mediated increase of mPGEs-1 expression and PGE-2 generation, as it did the silencing of HIF-1α. Moreover, DPE blocked mPGEs-1–dependent expression of VEGF and inhibited endothelial sprouting induced by tumor cells in a coculture system. PGE-2 triggers a feed-forward loop involving HIF-1α, which impinges on mPGEs-1 and VEGF expression, events prevented by DPE via extracellular signal–related kinase 1/2. The reduction of PGE-2 and VEGF levels, caused by DPE, was invariably associated with a marked decrease in HIF-1α expression and activity, independent of proteasome activity, indicating that the DPE effects on tumor growth and angiogenesis are dependent on the inhibition of HIF-1α translation.

Conclusions: We show that the in vivo DPE antitumor effect is associated with anti-inflammatory and antiangiogenic activities resulting from the downregulation of the HIF-1α/mPGEs-1/VEGF axis. Clin Cancer Res; 16(16); 4207–16. ©2010 AACR.
SMAD4 Immunohistochemistry Reflects Genetic Status in Juvenile Polyposis Syndrome
Authors: Langeveld Danielle , van Hattem W. Arnout , de Leng Wendy W.J. , Morsink Folkert H. , ten Kate Fiebo J.W. , Giardiello Francis M. , Offerhaus G. Johan A. , Brosens Lodewijk A.A.
Published: August 2010

Purpose: Juvenile polyposis syndrome (JPS) can be caused by a germline defect of the SMAD4 gene. Somatic inactivation of SMAD4 occurs in pancreatic and colorectal cancers and is reflected by loss of SMAD4 immunohistochemistry. Here, SMAD4 immunohistochemistry as a marker of SMAD4 gene status and the role of SMAD4 in the adenoma-carcinoma sequence in neoplastic progression in JPS are studied.

Experimental Design: Twenty polyps with a SMAD4 germline defect and 38 control polyps were studied by SMAD4 immunohistochemistry. Inactivation of the SMAD4 wild-type allele was studied in dysplastic epithelium and in areas with aberrant SMAD4 expression. APC, β-catenin, p53, and K-ras were studied to evaluate the adenoma-carcinoma sequence.

Results: Nine of 20 polyps with a SMAD4 germline defect showed loss of epithelial SMAD4 expression. Loss of heterozygosity of SMAD4 was found in five polyps and a somatic stop codon mutation was found in two polyps without loss of heterozygosity. Remarkably, somatic inactivation of epithelial SMAD4 did not always coincide with dysplasia and aberrant p53 staining was found in four of six dysplastic polyps with normal SMAD4 staining. One K-ras mutation was found in nine juvenile polyps with dysplasia. No evidence for Wnt activation was found.

Conclusions: SMAD4 immunohistochemistry mirrors genetic status and provides a specific adjunct in the molecular diagnosis of JPS. However, epithelial SMAD4 inactivation is not required for polyp formation and is not obligatory for neoplastic progression in JPS. Instead, different routes to neoplasia in JPS caused by germline SMAD4 mutation seem to be operative, including somatic loss of SMAD4 and p53 inactivation without somatic loss of SMAD4. Clin Cancer Res; 16(16); 4126–34. ©2010 AACR.
Genomic Profiling Reveals Alternative Genetic Pathways of Meningioma Malignant Progression Dependent on the UnderlyingNF2Status
Authors: Goutagny Stéphane , Yang Hong Wei , Zucman-Rossi Jessica , Chan Jennifer , Dreyfuss Jonathan M. , Park Peter J. , Black Peter M. , Giovannini Marco , Carroll Rona S. , Kalamarides Michel
Published: August 2010

Purpose: Meningiomas are the most common central nervous system tumors in the population of age 35 and older. WHO defines three grades predictive of the risk of recurrence. Clinical data supporting histologic malignant progression of meningiomas are sparse and underlying molecular mechanisms are not clearly depicted.

Experimental Design: We identified genetic alterations associated with histologic progression of 36 paired meningioma samples in 18 patients using 500K SNP genotyping arrays and NF2 gene sequencing.

Results: The most frequent chromosome alterations observed in progressing meningioma samples are early alterations (i.e., present both in lower- and higher-grade samples of a single patient). In our series, NF2 gene inactivation was an early and frequent event in progressing meningioma samples (73%). Chromosome alterations acquired during progression from grade I to grade II meningioma were not recurrent. Progression to grade III was characterized by recurrent genomic alterations, the most frequent being CDKN2A/CDKN2B locus loss on 9p.

Conclusion: Meningiomas displayed different patterns of genetic alterations during progression according to their NF2 status: NF2-mutated meningiomas showed higher chromosome instability during progression than NF2-nonmutated meningiomas, which had very few imbalanced chromosome segments. This pattern of alterations could thus be used as markers in clinical practice to identify tumors prone to progress among grade I meningiomas. Clin Cancer Res; 16(16); 4155–64. ©2010 AACR.
Phase II Trial to Evaluate Gemcitabine and Etoposide for Locally Advanced or Metastatic Pancreatic Cancer
Authors: Melnik Marianne K. , Webb Craig P. , Richardson Patrick J. , Luttenton Charles R. , Campbell Alan D. , Monroe Thomas J. , O'Rourke Timothy J. , Yost Kathleen J. , Szczepanek Connie M. , Bassett Michelle R. , Truszkowski Kimberly J. , Stein Phyllis , Van Brocklin Matthew W. , Davis Alan T. , Bedolla Gabriela , Vande Woude George F. , Koo Han-Mo
Published: August 2010

Prior studies suggest that tumor cell lines harboring RAS mutations display remarkable sensitivity to gemcitabine and etoposide. In a phase II clinical trial of patients with locally advanced or metastatic pancreatic cancer, we evaluated the response rate to a combination of these drugs. Forty chemo-naïve patients with nonresectable and histologically confirmed pancreatic cancer were accrued. Patients received gemcitabine 1,000 mg/m2 (days 1 and 8) and etoposide 80 mg/m2 (days 8, 9, and 10; 21-day cycle). The primary end point was radiological response rate. Secondary objectives were determination of overall survival, response duration (time to progression), quality of life, toxicity, and CA 19-9 biomarker response. In 35 evaluable patients, 10 exhibited a radiological partial response and 12 had stable disease in response to treatment. Twenty patients exhibited a >20% decrease in CA 19-9 biomarker levels. Median overall survival was 6.7 months for all patients (40) and 7.2 months for evaluable patients (35). Notably, four patients survived for longer than 1 year, with two patients surviving for more than 2 years. Median time to progression for evaluable patients was 3.1 months. The median overall survival for locally advanced patients was 8.8 months and 6.75 months for metastatic patients. One-year survival was 10% for all patients and 11.4% for evaluable patients. Quality of life improved in 12 patients and remained stable in 3 of the evaluable patients. The primary dose-limiting toxicities were hematologic toxicity and fatigue. These results show that the gemcitabine and etoposide combination is generally well-tolerated and exhibits a response rate similar to other published studies. Mol Cancer Ther; 9(8); 2423–9. ©2010 AACR.