bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcγ receptor binding properties
Authors: Nordstrom Jeffrey L , Gorlatov Sergey , Zhang Wenjun , Yang Yinhua , Huang Ling , Burke Steve , Li Hua , Ciccarone Valentina , Zhang Tengfei , Stavenhagen Jeffrey , Koenig Scott , Stewart Stanford J , Moore Paul A , Johnson Syd , Bonvini Ezio
Published: December 2011

Introduction

Response to trastuzumab in metastatic breast cancer correlates with expression of the high binding variant (158V) of the activating Fcγ receptor IIIA (CD16A). We engineered MGAH22, a chimeric anti-HER2 monoclonal antibody with specificity and affinity similar to trastuzumab, with an Fc domain engineered for increased binding to both alleles of human CD16A.

Methods

MGAH22 was compared to an identical anti-HER2 mAb except for a wild type Fc domain. Antibody-dependent cell cytotoxicity (ADCC) assays were performed with HER2-expressing cancer cells as targets and human PBMC or purified NK cells as effectors. Xenograft studies were conducted in mice with wild type murine FcγRs; in mice lacking murine CD16; or in mice lacking murine CD16 but transgenic for human CD16A-158F, the low-binding variant. The latter model reproduces the differential binding between wild type and the Fc-optimized mAb for human CD16A. The JIMT-1 human breast tumor line, derived from a patient that progressed on trastuzumab therapy, was used in these studies. Single and repeat dose toxicology studies with MGAH22 administered intravenously at high dose were conducted in cynomolgus monkeys.

Results

The optimized Fc domain confers enhanced ADCC against all HER2-positive tumor cells tested, including cells resistant to trastuzumab's anti-proliferative activity or expressing low HER2 levels. The greatest improvement occurs with effector cells isolated from donors homozygous or heterozygous for CD16A-158F, the low-binding allele. MGAH22 demonstrates increased activity against HER2-expressing tumors in mice transgenic for human CD16A-158F. In single and repeat-dose toxicology studies in cynomolgus monkeys, a species with a HER2 expression pattern comparable to that in humans and Fcγ receptors that exhibit enhanced binding to the optimized Fc domain, MGAH22 was well tolerated at all doses tested (15-150 mg/kg) and exhibited pharmacokinetic parameters similar to that of other anti-HER2 antibodies. Induction of cytokine release by MGAH22 in vivo or in vitro was similar to that induced by the corresponding wild type mAb or trastuzumab.

Conclusions

The data support the clinical development of MGAH22, which may have utility in patients with low HER2 expressing tumors or carrying the CD16A low-binding allele.
FGF/MAPK signaling is required in the gastrula epiblast for avian neural crest induction
Authors: Stuhlmiller Timothy J. , García-Castro Martín I.
Published: December 2011

Neural crest induction involves the combinatorial inputs of the FGF, BMP and Wnt signaling pathways. Recently, a two-step model has emerged where BMP attenuation and Wnt activation induces the neural crest during gastrulation, whereas activation of both pathways maintains the population during neurulation. FGF is proposed to act indirectly during the inductive phase by activating Wnt ligand expression in the mesoderm. Here, we use the chick model to investigate the role of FGF signaling in the amniote neural crest for the first time and uncover a novel requirement for FGF/MAPK signaling. Contrary to current models, we demonstrate that FGF is required within the prospective neural crest epiblast during gastrulation and is unlikely to operate through mesodermal tissues. Additionally, we show that FGF/MAPK activity in the prospective neural plate prevents the ectopic expression of lateral ectoderm markers, independently of its role in neural specification. We then investigate the temporal participation of BMP/Smad signaling and suggest a later involvement in neural plate border development, likely due to widespread FGF/MAPK activity in the gastrula epiblast. Our results identify an early requirement for FGF/MAPK signaling in amniote neural crest induction and suggest an intriguing role for FGF-mediated Smad inhibition in ectodermal development.
Theosr1andosr2genes act in the pronephric anlage downstream of retinoic acid signaling and upstream ofwnt2bto maintain pectoral fin development
Authors: Neto Ana , Mercader Nadia , Gómez-Skarmeta José Luis
Published: December 2011

Vertebrate odd-skipped related genes (Osr) have an essential function during the formation of the intermediate mesoderm (IM) and the kidney structures derived from it. Here, we show that these genes are also crucial for limb bud formation in the adjacent lateral plate mesoderm (LPM). Reduction of zebrafish Osr function impairs fin development by the failure of tbx5a maintenance in the developing pectoral fin bud. Osr morphant embryos show reduced wnt2b expression, and increasing Wnt signaling in Osr morphant embryos partially rescues tbx5a expression. Thus, Osr genes control limb bud development in a non-cell-autonomous manner, probably through the activation of Wnt2b. Finally, we demonstrate that Osr genes are downstream targets of retinoic acid (RA) signaling. Therefore, Osr genes act as a relay within the genetic cascade of fin bud formation: by controlling the expression of the signaling molecule Wnt2ba in the IM they play an essential function transmitting the RA signaling originated in the somites to the LPM.
Oxidative stress-related enzyme gene polymorphisms and susceptibility to breast cancer in non-smoking, non-alcohol-consuming Taiwanese women: a case-control study
Authors: Tsai Shih-Meng , Wu Szu-Hsien , Hou Ming-Feng , Chen Yueh-Ling , Ma Hsu , Tsai Li-Yu
Published: December 2011

Background

Mitochondrial manganese superoxide dismutase (MnSOD) converts superoxide anion into H2O2, which is neutralized sequentially by either catalase (CAT) or glutathione peroxidase 1 (Gpx 1) into water or converted into highly reactive hypochlorous acid by myeloperoxidase (MPO). We hypothesize that gene variants for these enzymes might be associated with the risk of breast cancer in non-smoking, non-alcohol-consuming women.

Methods

Genotypes of oxidative stress-related enzymes ( MnSOD1183T>C, MPO-463G>A, GPx1Pro198Leu and CAT-262C>T) were analysed in 260 non-smoking and non-alcohol-consuming female patients with breast cancer and 224 habit-matched controls.

Results

Subjects with the MnSOD1183T>C C carrier or those with the GPx1Pro198Leu CT genotype had significantly decreased age-adjusted risks (odds ratio [OR]: 0.56 and 0.16 with 95% confidence intervals [95% CI]: 0.38–0.83 and 0.08–0.29, respectively) for breast cancer. Certain combined genotypes of the polymorphisms also significantly modulated the age-adjusted risk.

Conclusions

We conclude that oxidative stress-related enzyme genetic variants, especially GPx1Pro198Leu CT, modify the risk of breast cancer development in non-smoking and non-alcohol-consuming women. The role of unidentified environmental factors predisposing to breast cancer development through an oxidative stress mechanism merits further investigation.
Adsorption/Desorption Equilibria and Kinetics at Reconstructible Surfaces
Authors: Cerofolini G.F.
Published: December 2011

A general kinetic theory, which takes explicit account of the phenomena occurring at reconstructible surfaces while adsorption or desorption proceed, is proposed. The theory contains a few free parameters which specify the adsorption and desorption rate constants, and the reconstruction and irreversibility degrees of the process.
On the Adsorption Kinetics and Equilibrium of Polyaromatic Hydrocarbons from Aqueous Solution
Authors: Haro Marta , Cabal Belén , Parra José B. , Ania Conchi O.
Published: December 2011

The purpose of the present work was to explore the removal of three polycyclic aromatic hydrocarbons (naphthalene, fluorene and acenaphtene) (PAHs) from aqueous solution onto an activated carbon. The adsorption performance of these compounds (both kinetic and equilibrium) has been discussed in terms of their chemical and physical properties. The results showed that the rate of adsorption was strongly dependent on the molecular size of the hydrocarbons. Thus, for example, steric hindrances associated with acenaphthene inhibited the accessibility of this compound to the high-energy sites. Under equilibrium conditions, the uptake seemed to be governed by the carbon–PAH affinity, as the lowest uptake was obtained for naphthalene which displayed the fastest adsorption rate. The interactions between the studied pollutants and the activated carbon seemed to be controlled by two factors, viz. aromaticity and water solubility. As a general rule, the higher the number of aromatic rings in the polycyclic hydrocarbon, the more favoured the adsorbate–carbon interactions. Analysis of the carbon after adsorption of the studied hydrocarbons indicated that the accessibility restrictions to the porosity of the carbon can also lead to weaker interactions with the activated carbon.
Biosorption of Heavy Metal Ions: Ion-Exchange versus Adsorption and the Heterogeneity of Binding Sites
Authors: Plazinski Wojciech , Rudziński Wladyslaw
Published: December 2011

Surface heterogeneity-related effects have been studied in the context of biosorption systems designed for the removal of bivalent heavy metal ions from aqueous systems. The research was focused on incorporating these effects into the concept of the ion-exchange (IE) constant. Cases of both correlated and uncorrelated values of the affinity constants towards metal ions and protons were considered. When strong correlations were assumed, the dispersion of the IE constant was smaller (or, in the limiting case, the same) in comparison to the dispersions of the affinity constants. In contrast, when no correlation was assumed, the dispersion of the IE constant was greater than those corresponding to any of the affinity constants. The dispersion of the IE constant could be additionally enhanced by the existence of multi-dentate binding modes related to the metal ions.
Adsorption of Pb(II) Ions from Aqueous Solutions by Pyrolusite-Modified Activated Carbon Prepared from Sewage Sludge
Authors: Fan Lu , Chen Yao , Wang Li , Jiang Wenju
Published: December 2011

In this study, activated carbons were prepared from sewage sludge by chemical activation, and modified with pyrolusite as a catalyst during activation and carbonization. The influence of the addition of the mineral on the properties of the produced activated carbons was evaluated. The modified activated carbons exhibited BET surface areas which were 11.31% higher than ordinary sludge-based activated carbons and had larger pore volumes. The results of adsorption experiments showed that the pyrolusite-added adsorbents performed better towards the removal of Pb(II) ions than those without pyrolusite addition. At an initial pH of 5.4 for the Pb(II) ion solution, addition of the pyrolusite-added activated carbon led to the effective removal of Pb(II) ions with an adsorption capacity of ca. 70 mg/g. The adsorption capacity towards Pb(II) ion removal also increased with increasing contact time and adsorbent dosage. Compared to adsorbents derived from various other materials, the pyrolusite-modified adsorbent had a relatively high Pb(II) ion adsorption capacity. Adsorption isotherm and kinetics studies showed that the adsorption of Pb(II) ions onto the pyrolusite-modified adsorbent was well fitted by the Langmuir isotherm and could be described by the pseudo-second-order kinetic model.
Thermo-Mechanical Analysis of 2D-FGM Thick Hollow Cylinder Using Graded Finite Elements
Authors: Asgari M. , Akhlaghi M.
Published: December 2011

In this paper a thick hollow circular cylinder with finite length made of two-dimensional functionally graded material (2D-FGM) and subjected to steady state thermal and mechanical loadings is considered. The volume fraction distribution of materials, geometry and thermo-mechanical load are assumed to be axisymmetric but not uniform along the axial direction. The finite element method with graded material properties within each element (graded finite elements) is used to model the structure. The effects of variation of materials distribution in two radial and axial directions on the temperature, displacements and stress distributions are studied. Also the effectiveness of the graded finite elements on accuracy of the stresses is investigated. The achieved results show that using 2D-FGM leads to a more flexible design so that behavior of structure, maximum amplitude of stresses and uniformity of temperature and stress distributions can be modified to a required manner by selecting suitable material distribution profiles in two directions. Also for identical meshes, the graded element formulations do better than conventional homogeneous elements.
Approximate Analysis of Simply Supported Composite Beams with Partial Interaction
Authors: Kim Sung-Hoon , Choi Jun-Hyeok
Published: December 2011

An approximate analysis method was presented for the analysis and design of a simply supported composite beam with partial interaction. To solve the governing differential equation in linear elastic partial interaction theory, the internal axial force was approximated by Fourier series. In case studies, the internal axial force, slip and displacement of the beam were obtained for some load cases such as temperature load, end moment, point load and uniformly distributed load. From the study for convergence of the approximate solution, the relative error for the displacement was converged below about 0.1% at more than the fifth order of Fourier series. This method can be applied to arbitrary loading conditions. Also, the results are sufficiently accurate for determining the behavior of the composite beam with partial interaction for the design purpose.
Seismic Retrofit of Deficient RC Structures with Internal Steel Frames
Authors: Ozcelik Ramazan , Akpınar Uğur , Binici Baris
Published: December 2011

This paper describes an experimental study on internal steel frames (ISFs) to retrofit seismically deficient reinforced concrete (RC) frames. One reference and six strengthened frame specimens were tested under constant gravity load and cyclic lateral displacement excursions. Installation of the ISF with and without anchors to the RC frame was examined. Test results showed that the snug tight ISF installed inside an RC frame may suffice to realize the benefit of implementing ISFs. If the horizontal shear strength of the RC beam-column joint is smaller than the target lateral strength enhancement, anchors should be used between the RC and ISF members to provide an additional load path for the lateral load and limit the force demand on the RC beam-column joint. A case study building was analyzed to demonstrate the performance of an ISF retrofitted deficient RC frame by using a numerical model calibrated with cyclic test results.
Compressive Strength of Concrete in Flexural Critical Region of Reinforced Concrete Beam-Column Members
Authors: Cho Chang-Geun , Hotta Hisato , Takiguchi Katsuki
Published: December 2011

The compressive strength of concrete in flexural critical regions of reinforced concrete beam-column members is investigated experimentally and in terms of three-dimensional finite element predictions. Reinforced concrete beam-column members subjected to an axial load combined with single or double curvature bending were manufactured with special stirrups that minimize the confining effect of concrete by stirrups. Due to the existence of a beam-column joint near the flexural critical section at both ends of the members, the concrete on the compression fibers around the joint is subject to multiaxial compressive stress states; and the compressive stress in the region exceeds the uniaxial compressive strength of concrete. In the case of double curvature bending, the load-carrying capacities of the beam-column members which are measured experimentally and predicted by means of finite element analysis greatly exceed the moment and axial force interaction curve obtained from the uniaxial stress-strain curve of concrete.
Characterization of Adhesive Joints for Hybrid Steel-Glass Beams by Means of Simplified Small Scale Tests
Authors: Feldmann M. , Abeln B. , Preckwinkel E.
Published: December 2011

In the recent past there have been calls for transparent and filigree structures in the building industry. Therefore, glass plays an increasing role not only in a classic way, as a space enclosing element, but also more and more in terms of offering load carrying functions. Glass beams for façade elements or floor girders, glass columns, or bracing façade elements are examples of this. To realize such architecturally attractive structures, bonded hybrid steel-glass elements have been developed in which each material is used in an optimized way according to its material properties. Promising examples for such bonded structures are I-beams in which steel flanges and glass webs are connected by linear adhesive bonds. The shear force is carried by the glass web, whereas the bending capacity of the hybrid beam is significantly increased by slender steel flanges compared to the pure glass pane. The shear forces between steel and glass are sustained only by the adhesive between them. In order to maximize the exploitation of both steel and glass, the adhesive on the one hand has to ensure an adequate stiffness but on the other hand has to be flexible enough to allow for a reduction or redistribution of local stress peaks, as well as other constraints such as thermal dilatation. However, the load-bearing capacity of such beams is governed, besides by the mechanical and geometrical characteristics of the adhesive joint, by aging, temperature, and creeping. In this contribution, an approach is shown for characterizing the adhesive joints for hybrid steel-glass beams by means of simplified small-scale tests. Standardized specimens (block shear and tension bulk specimens) and small-scale push-out tests are used to derive adequate mechanical values for analytical and numerical calculations, allowing one to draw conclusions regarding the general load carrying behavior of large-scale hybrid steel-glass beams. The results show that full-scale hybrid steel-glass beams, especially those with butt splice bonded and U-bonded geometries, are feasible using new structural adhesives, predominantly elasto-plastics such as polyurethanes or epoxy resins.
Highwire Regulates Guidance of Sister Axons in theDrosophilaMushroom Body
Authors: Shin Jung Eun , DiAntonio Aaron
Published: December 2011

Axons often form synaptic contacts with multiple targets by extending branches along different paths. PHR (Pam/Highwire/RPM-1) family ubiquitin ligases are important regulators of axon development, with roles in axon outgrowth, target selection, and synapse formation. Here we report the function of Highwire, theDrosophilamember of the PHR family, in promoting the segregation of sister axons during mushroom body (MB) formation. Loss ofhighwireresults in abnormal development of the axonal lobes in the MB, leading to thinned and shortened lobes. Thehighwiredefect is attributable to guidance errors after axon branching, in which sister axons that should target different lobes instead extend together into the same lobe. Thehighwiremutant MB displays elevation in the level of the MAPKKK Wallenda/DLK (dual leucine zipper kinase), a previously identified substrate of Highwire, and genetic suppression studies show that Wallenda/DLK is required for thehighwireMB phenotype. Thehighwirelobe defect is limited to α/β lobe axons, but transgenic expression ofhighwirein the pioneering α′/β′ neurons rescues the phenotype. Mosaic analysis further shows that α/β axons ofhighwiremutant clones develop normally, demonstrating a non-cell-autonomous role of Highwire for axon guidance. Genetic interaction studies suggest that Highwire and Plexin A signals may interact to regulate normal morphogenesis of α/β axons.
SIRT1 Modulates Aggregation and Toxicity through Deacetylation of the Androgen Receptor in Cell Models of SBMA
Authors: Montie Heather L. , Pestell Richard G. , Merry Diane E.
Published: December 2011

Posttranslational protein modifications can play a major role in disease pathogenesis; phosphorylation, sumoylation, and acetylation modulate the toxicity of a variety of proteotoxic proteins. The androgen receptor (AR) is substantially modified, in response to hormone binding, by phosphorylation, sumoylation, and acetylation; these modifications might thus contribute to DHT-dependent polyglutamine (polyQ)-expanded AR proteotoxicity in spinal and bulbar muscular atrophy (SBMA). SIRT1, a nuclear protein and deacetylase of the AR, is neuroprotective in many neurodegenerative disease models. Our studies reveal that SIRT1 also offers protection against polyQ-expanded AR by deacetylating the AR at lysines 630/632/633. This finding suggested that nuclear AR acetylation plays a role in the aberrant metabolism and toxicity of polyQ-expanded AR. Subsequent studies revealed that the polyQ-expanded AR is hyperacetylated and that pharmacologic reduction of acetylation reduces mutant AR aggregation. Moreover, genetic mutation to inhibit polyQ-expanded AR acetylation of lysines 630/632/633 substantially decreased its aggregation and completely abrogated its toxicity in cell lines and motor neurons. Our studies also reveal one means by which the AR acetylation state likely modifies polyQ-expanded AR metabolism and toxicity, through its effect on DHT-dependent AR stabilization. Overall, our findings reveal a neuroprotective function of SIRT1 that operates through its deacetylation of polyQ-expanded AR and highlight the potential of both SIRT1 and AR acetylation as powerful therapeutic targets in SBMA.
Patterns of Presynaptic Activity and Synaptic Strength Interact to Produce Motor Output
Authors: Wright Terrence Michael , Calabrese Ronald L.
Published: December 2011

Motor neuron activity is coordinated by premotor networks into a functional motor pattern by complex patterns of synaptic drive. These patterns combine both the temporal pattern of spikes of the premotor network and the profiles of synaptic strengths (i.e., conductances). Given the complexity of premotor networks in vertebrates, it has been difficult to ascertain the relative contributions of temporal patterns and synaptic strength profiles to the motor patterns observed in these animals. Here, we use the leech (Hirudosp.) heartbeat central pattern generator (CPG), in which we can measure both the temporal pattern and the synaptic strength profiles of the entire premotor network and the motor outflow in individual animals. In this system, a series of motor neurons all receive input from the same premotor interneurons of the CPG but must be coordinated differentially to produce a functional pattern. These properties allow a theoretical and experimental dissection of the rules that govern how temporal patterns and synaptic strength profiles are combined in motor neurons so that functional motor patterns emerge, including an analysis of the impact of animal-to-animal variation in input to such variation in output. In the leech, segmental heart motor neurons are coordinated alternately in a synchronous and peristaltic pattern. We show that synchronous motor patterns result from a nearly synchronous premotor temporal pattern produced by the leech heartbeat CPG. For peristaltic motor patterns, the staggered premotor temporal pattern determines the phase range over which segmental motor neurons can fire while synaptic strength profiles define the intersegmental motor phase progression realized.
Synaptic Stimulation of mTOR Is Mediated by Wnt Signaling and Regulation of Glycogen Synthetase Kinase-3
Authors: Ma Tao , Tzavaras Nikos , Tsokas Panayiotis , Landau Emmanuel M. , Blitzer Robert D.
Published: December 2011

The persistent or “late” phase of long-term potentiation (L-LTP), which requires protein synthesis, can be induced by relatively intense synaptic activity. The ability of such strong synaptic protocols to engage the translational machinery and produce plasticity-related proteins, while weaker protocols activate only posttranslational processes and transient potentiation (early LTP; E-LTP), is not understood. Among the major translation control pathways in neurons, the stimulation of mammalian target of rapamycin (mTOR) is a key event in the induction of L-LTP. We report that mTOR is tonically suppressed in rat hippocampus under resting conditions, a consequence of the basal activity of glycogen synthetase kinase 3 (GSK3). This suppression could be overcome by weak synaptic stimulation in the presence of the β-adrenergic agonist isoproterenol, a combination that induced L-LTP, and activation of mTOR coincided with the Akt-mediated phosphorylation of GSK3. Surprisingly, while isoproterenol alone elevated Akt activity, it failed to increase GSK3 phosphorylation or mTOR signaling, showing that Akt was uncoupled from these effectors in the absence of synaptic stimulation. With the addition of weak stimulation, Akt signaled to GSK3 and mTOR, a gating effect that was mediated by voltage-dependent Ca2+channels and the Wnt pathway. mTOR could be stimulated by pharmacological inhibition, enabling weak HFS to induce L-LTP. These results establish GSK3 as an integrator of Akt and Wnt signals and suggest that overcoming GSK3-mediated suppression of mTOR is a key event in the induction of L-LTP by synaptic activity.
Striatal Dysfunctions Associated with Mitochondrial DNA Damage in Dopaminergic Neurons in a Mouse Model of Parkinson's Disease
Authors: Pickrell Alicia M. , Pinto Milena , Hida Aline , Moraes Carlos T.
Published: December 2011

Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders, characterized by resting tremor, rigidity, bradykinesia, and postural instability. These symptoms are associated with massive loss of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) causing an estimated 70–80% depletion of dopamine (DA) in the striatum, where their projections are located. Although the etiology of PD is unknown, mitochondrial dysfunctions have been associated with the disease pathophysiology. We used a mouse model expressing a mitochondria-targeted restriction enzyme, PstI or mito-PstI, to damage mitochondrial DNA (mtDNA) in dopaminergic neurons. The expression of mito-PstI induces double-strand breaks in the mtDNA, leading to an oxidative phosphorylation deficiency, mostly due to mtDNA depletion. Taking advantage of a dopamine transporter (DAT) promoter-driven tetracycline transactivator protein (tTA), we expressed mito-PstI exclusively in dopaminergic neurons, creating a novel PD transgenic mouse model (PD-mito-PstI mouse). These mice recapitulate most of the major features of PD: they have a motor phenotype that is reversible withl-DOPA treatment, a progressive neurodegeneration of the SN dopaminergic population, and striatal DA depletion. Our results also showed that behavioral phenotypes in PD-mito-PstI mice were associated with striatal dysfunctions preceding SN loss of tyrosine hydroxylase-positive neurons and that other neurotransmitter systems [noradrenaline (NE) and serotonin (5-HT)] were increased after the disruption of DA neurons, potentially as a compensatory mechanism. This transgenic mouse model provides a novel model to study the role of mitochondrial defects in the axonal projections of the striatum in the pathophysiology of PD.
Identifying Specific Light Inputs for Each Subgroup of Brain Clock Neurons inDrosophilaLarvae
Authors: Klarsfeld André , Picot Marie , Vias Carine , Chélot Elisabeth , Rouyer François
Published: December 2011

InDrosophila, opsin visual photopigments as well as blue-light-sensitive cryptochrome (CRY) contribute to the synchronization of circadian clocks. We focused on the relatively simple larval brain, with nine clock neurons per hemisphere: five lateral neurons (LNs), four of which express the pigment-dispersing factor (PDF) neuropeptide, and two pairs of dorsal neurons (DN1s and DN2s). CRY is present only in the PDF-expressing LNs and the DN1s. The larval visual organ expresses only two rhodopsins (RH5 and RH6) and projects onto the LNs. We recently showed that PDF signaling is required for light to synchronize the CRY−larval DN2s. We now show that, in the absence of functional CRY, synchronization of the DN1s also requires PDF, suggesting that these neurons have no direct connection with the visual system. In contrast, the fifth (PDF−) LN does not require the PDF-expressing cells to receive visual system inputs. All clock neurons are light-entrained by light–dark cycles in therh52;cryb,rh61cryb, andrh52;rh61double mutants, whereas the triple mutant is circadianly blind. Thus, any one of the three photosensitive molecules is sufficient, and there is no other light input for the larval clock. Finally, we show that constant activation of the visual system can suppress molecular oscillations in the four PDF-expressing LNs, whereas, in the adult, this effect of constant light requires CRY. A surprising diversity and specificity of light input combinations thus exists even for this simple clock network.
Algorithm Engineering Challenges in Multicore and Manycore Systems
Authors: Kang Seunghwa , Ediger David , Bader David A.
Published: December 2011

Modern multicore and manycore systems have the strong potential to deliver both high performance and high power efficiency. The large variance in memory access latency, resource sharing, and the heterogeneity of processor architectures in modern multicore and manycore systems raise significant algorithm engineering challenges. In this article, we overview important algorithm engineering issues for modern multicore and manycore systems, and we present algorithm engineering techniques to address such problems as a guideline for practitioners.
Internationale Zertifizierung der industriellen Prozessmesstechnik
Authors: Klotz-Engmann Gerold , Klausmeyer Uwe
Published: December 2011

Sensoren der industriellen Prozessmesstechnik werden in verschiedensten Branchen und globalen Märkten eingesetzt. Daraus entstehen weitreichende Anforderungen an Produktzertifizierungen. Grundsätzlich muss jedes Messgerät, das in den Europäischen Mitgliedsländern in Verkehr gebracht wird, den zutreffenden Europäischen Richtlinien entsprechen. Der Hersteller bestätigt die Einhaltung aller Anforderungen mit der Ausstellung einer EG-Konformitätserklärung und der CE-Kennzeichnung des Geräts. Voraussetzung ist bei einigen Richtlinien die Produktzertifizierung durch eine “benannte Stelle”. Werden Geräte international vermarktet, dann müssen sehr viele länderspezifische Zertifizierungen außerhalb Europas durchgeführt werden, z. B. in Nordamerika, Russland, China, Japan oder Australien. Mittlerweile werden diese Zertifizierungen teilweise durch internationale Zertifizierungssysteme harmonisiert.
Patterning of the Adult Mandibulate Mouthparts in the Red Flour Beetle, Tribolium castaneum
Authors: Angelini David R , Smith Frank W , Aspiras Ariel C , Kikuchi Moto , Jockusch Elizabeth L
Published: December 2011

Specialized insect mouthparts, such as those of Drosophila, are derived from an ancestral mandibulate state, but little is known about the developmental genetics of mandibulate mouthparts. Here, we study the metamorphic patterning of mandibulate mouthparts of the beetle Tribolium castaneum, using RNA interference to deplete the expression of 13 genes involved in mouthpart patterning. These data were used to test three hypotheses related to mouthpart development and evolution. First, we tested the prediction that maxillary and labial palps are patterned using conserved components of the leg-patterning network. This hypothesis was strongly supported: depletion of Distal-less and dachshund led to distal and intermediate deletions of these structures while depletion of homothorax led to homeotic transformation of the proximal maxilla and labium, joint formation required the action of Notch signaling components and odd-skipped paralogs, and distal growth and patterning required epidermal growth factor (EGF) signaling. Additionally, depletion of abrupt or pdm/nubbin caused fusions of palp segments. Second, we tested hypotheses for how adult endites, the inner branches of the maxillary and labial appendages, are formed at metamorphosis. Our data reveal that Distal-less, Notch signaling components, and odd-skipped paralogs, but not dachshund, are required for metamorphosis of the maxillary endites. Endite development thus requires components of the limb proximal–distal axis patterning and joint segmentation networks. Finally, adult mandible development is considered in light of the gnathobasic hypothesis. Interestingly, while EGF activity is required for distal, but not proximal, patterning of other appendages, it is required for normal metamorphic growth of the mandibles.
A dynamic explanation of size–density scaling in carnivores
Authors: DeLong John P. , Vasseur David A.
Published: December 2011

Population abundance is negatively related to body size for many types of organisms. Despite the ubiquity of size–density scaling relationships, we lack a general understanding of the underlying mechanisms. Although dynamic models suggest that it is possible to predict the intercept and slope of the scaling relationship from prior observations, this has never been empirically attempted. Here we fully parameterize a set of consumer–resource models for mammalian carnivores and successfully predict the size–density scaling relationship for this group without the use of free parameters. All models produced similar predictions, but comparison of nested models indicated that the primary factors generating size–density scaling in mammalian carnivores are prey productivity, predator–prey size ratios, and consumer area of capture.
Not just the usual suspects: Insect herbivore populations and communities are associated with multiple plant nutrients
Authors: Joern Anthony , Provin Tony , Behmer Spencer T.
Published: December 2011

The relationship between plant nutrient content and insect herbivore populations and community structure has long interested ecologists. Insect herbivores require multiple nutrients, but ecologists have focused mostly on nitrogen (an estimate of plant protein content), and more recently phosphorus (P); other nutrients have received little attention. Here we document nutrient variation in grass and forb samples from grassland habitats in central Nebraska using an elemental approach; in total we measured foliar concentrations of 12 elements (N and P, plus S, B, Ca, Mg, Na, K, Zn, Fe, Mn, and Cu). We detected significant variability among sites for N, P, Mg, Na, K, and Cu. We next used a model selection approach to explore how this nutritional variation and plant biomass correlate with grasshopper densities (collectively and at the feeding‐guild level), and principal component analysis to explore nutrient correlations with grasshopper community species composition. When all grasshoppers were pooled, densities varied among sites, but only P was associated with abundance of the elements shown to vary between sites. Different responses occurred at the feeding‐guild level. For grass specialists, densities were associated with N, plus P, Mg, and Na. For forb specialists, N and P were often associated with density, but associations with Na and K were also observed. Finally, mixed‐feeder abundance was strongly associated with biomass, and to a lesser extent P, Mg, Na, and Cu. At the community level, B, Ca, Zn, and Cu, plus biomass, explained >30% of species composition variation. Our results confirm the positive association of N and P with insect herbivore populations, while suggesting a potential role for Mg, Na, and K. They also demonstrate the importance of exploring effects at the feeding‐guild level. We hope our data motivate ecologists to think beyond N and P when considering plant nutrient effects on insect herbivores, and make a call for studies to examine functional responses of insect herbivores to dietary manipulation of Mg, Na, and K. Finally, our results demonstrate correlations between variation in nutrients and species assemblages, but factors not linked to plant nutrient quality or biomass likely explain most of the observed variation.
Invasive salmonids and lake order interact in the decline of puye grande Galaxias platei in western Patagonia lakes
Authors: Correa Cristian , Hendry Andrew P.
Published: December 2011

Salmonid fishes, native to the northern hemisphere, have become naturalized in many austral countries and appear linked to the decline of native fishes, particularly galaxiids. However, a lack of baseline information and the potential for confounding anthropogenic stressors have led to uncertainty regarding the association between salmonid invasions and galaxiid declines, especially in lakes, as these have been much less studied than streams. We surveyed 25 lakes in the Aysén region of Chilean Patagonia, including both uninvaded and salmonid‐invaded lakes. Abundance indices (AI) of Galaxias platei and salmonids (Salmo trutta and Oncorhynchus mykiss) were calculated using capture‐per‐unit‐effort data from gillnets, minnow traps, and electrofishing. We also measured additional environmental variables, including deforestation, lake morphometrics, altitude, and hydrological position (i.e., lake order). An information‐theoretic approach to explaining the AI of G. platei revealed that by far the strongest effect was a negative association with the AI of salmonids. Lake order was also important, and using structural equation modeling, we show that this is an indirect effect naturally constraining the salmonid invasion success in Patagonia. Supporting this conclusion, an analysis of an independent data set from 106 mountain lakes in western Canada showed that introduced salmonids are indeed less successful in low‐order lakes. Reproductive failure due to insufficient spawning habitat and harsh environmental conditions could be the cause of these limits to salmonid success. The existence of this effect in Chilean Patagonia suggests that low‐order lakes are likely to provide natural ecological refugia for G. platei. Finally, pristine, high‐order lakes should be actively protected as these have become rare and irreplaceable unspoiled references of the most diverse, natural lake ecosystems in Patagonia.
REPLICATIONS AND EXTENSIONS IN AROUSAL ASSESSMENT FOR SEX OFFENDERS WITH DEVELOPMENTAL DISABILITIES
Authors: Reyes Jorge R. , Vollmer Timothy R. , Hall Astrid
Published: December 2011

Three adult male sex offenders with developmental disabilities participated in phallometric assessments that involved repeated measures of arousal when exposed to various stimuli. Arousal assessment outcomes were similar to those obtained by Reyes et al. (2006). Additional data‐analysis methods provided further information about sexual preferences, thus replicating and extending previous research. The results provide preliminary data for establishing a preference gradient by age. Implications for the use of repeated measures and preference gradients in arousal assessments are discussed.
ESTABLISHING COMPLIANCE WITH LIQUID MEDICATION ADMINISTRATION IN A CHILD WITH AUTISM
Authors: Schiff Averil , Tarbox Jonathan , Lanagan Taira , Farag Peter
Published: December 2011

Children with autism often display difficulty with swallowing pills and liquid medications. In the current study, stimulus fading and positive reinforcement established compliance with liquid medication administration in a young boy with autism. The boy's mother eventually administered liquid medication on her own.
An epizootic of rabies in Maryland, 1982-84.
Authors: Beck A M , Felser S R , Glickman L T
Published: December 2011

The number of reported rabid raccoons increased by 617 per cent in Maryland from 1982 to 1984. The per cent of raccoons that tested positive for rabies increased from 7.9 per cent in 1982 to 57 per cent in 1984. During this period of time, more than 74 per cent of human exposures to rabid animals involved raccoons. Reports of animal bites of humans, however, showed only a 2.6 per cent increase. The raccoon rabies epizootic has had significant public health impact in terms of human rabies postexposure prophylaxis and rabies control programs.
The effect of a patient education program on emergency room use for inner-city children with asthma.
Authors: Shields M C , Griffin K W , McNabb W L
Published: December 2011

An educational program for children with asthma designed to reduce emergency room (ER) use enrolled all eligible children (n = 253 primarily low-income Black) within a health maintenance organization (HMO) who had used the hospital or ER for asthma during the pre-enrollment period and randomized them into two groups. Twenty-four of the experimental group patients had 55 ER visits and 18 of the control patients had 39 ER visits during the first 12 months post-intervention. This program did not achieve its goal.
Infant formula promotion and the health sector in the Philippines.
Authors: Popkin B M , Fernandez M E , Avila J L
Published: December 2011

We use data collected in 1984, 1986, and 1988 from public and private health facilities in the Metropolitan Cebu area of the Philippines to assess effects of World Health Organization and Government of the Philippines Codes of Marketing of Breast Milk Substitutes on distribution of formula supplies. Distribution of free and low-cost infant formula declined drastically between 1986 and 1988. Industry compliance was almost complete.
Telephone health surveys: potential bias from noncompletion.
Authors: Mishra S I , Dooley D , Catalano R , Serxner S
Published: December 2011

OBJECTIVES. Little is known about the effect of noncompletion on telephone surveys of health issues. This paper identifies a little-studied source of noncompletion, passive refusal, and evaluates its contribution to noncompletion bias along with two other sources: noncooperation and noncontact. Passive refusals include respondents who repeatedly request callbacks and households where interviewers repeatedly encounter an answering machine. METHODS. Measures of noncompletion (noncooperation, passive refusal, and noncontact), demographic and socioeconomic characteristics, health risk factors, and indicators of health care access and health status were collected through the Orange County Health Surveys on 4893 respondents. The surveys sampled by random-digit dialing and interviewed by computer-assisted telephone. RESULTS. Passive refusals have a substantial impact on completion rates and bias due to noncompletion. Commonly used definitions for completion rates may underestimate the bias due to noncompletion because they omit passive refusals. After we controlled for demographic and socioeconomic factors, few noncompletion biases appeared on selected health indicators. CONCLUSIONS. These results suggest improved reporting of completion rates and support a multivariate framework for studying noncompletion in telephone health surveys.
Assessment of a severe-weather warning system and disaster preparedness, Calhoun County, Alabama, 1994.
Authors: Liu S , Quenemoen L E , Malilay J , Noji E , Sinks T , Mendlein J
Published: December 2011

Tornado preparedness warning system effectiveness, and shelter-seeking behavior were examined in two Alabama areas after tornado warnings. In the area without sirens, only 28.9% of 194 respondents heard a tornado warning of these, 73.2% first received the warning from radios or television. In the area with sirens, 88.1% of 193 respondents heard a warning, and 61.8% first received the warning from a siren. Knowledge of warnings, access to shelter, and education were key predictors for seeking shelter. Our findings indicate that installing sirens, providing access to shelter, and teaching appropriate responses to warnings are important elements of an effective disaster prevention system.
Homicide risk among immigrants in California, 1970 through 1992.
Authors: Sorenson S B , Shen H
Published: December 2011

According to the death certificates of the 65,510. California residents who died of homicide from 1970 through 1992, foreign-born persons are overrepresented in the homicides of California residents. Analysis of homicide data for 15- to 34-year-olds (n = 38,774), who account for a majority of all homicide victims indicated that immigrant-to-nonimmigrant risk patterns differed by ethnicity and across time. During the 23-year study period, foreign-born Whites, Hispanics, and Asians and others were at significantly higher risk and foreign-born Blacks were at a statistically similar risk of homicide compared with their US-born counterparts (risk ratio = 2.12, 1.24, 1.72, and 0.60, respectively).
Assessing prenatal hepatitis B screening in Illinois with an inexpensive study design adaptable to other jurisdictions.
Authors: Barr D , Hershow R , Furner S , Handler A , Levy P
Published: December 2011

OBJECTIVES: This study estimated, using an economical survey design adaptable to other jurisdictions, the proportion of birth admissions in Illinois hospitals in which mothers were not screened for hepatitis B surface antigen prior to delivery. It also identified factors associated with lack of screening. METHODS: Based on a cluster sampling design, 1372 birth records were sampled, and data were abstracted by local personnel at 56 hospitals. Selected data elements were reabstracted on a subsample to evaluate recording errors. RESULTS: Reabstracted data demonstrated 95% agreement among reviewers. Hepatitis B surface antigen screening was documented for 90.7% of mothers; 11% of responding hospitals accounted for 45% of nonscreened mothers. Risk factors for not being screened included no prenatal care, Medicaid or no insurance, and delivery at a hospital lacking a written hepatitis B surface antigen policy. CONCLUSIONS: In Illinois, prenatal hepatitis B surface antigen screening rates were high and similar to those in other states. Births without screening or transferred information clustered in a few hospitals. The methods used here can economically identify underscreened populations by sampling a large number of hospitals within designated areas.
Syringe exchange in the United States, 1996: a national profile.
Authors: Paone D , Clark J , Shi Q , Purchase D , Des Jarlais D C
Published: December 2011

OBJECTIVES: This paper provides 1996 information on the status of US syringe exchange programs and compares these findings with data from our 1994 survey. METHODS: In November 1996, questionnaires were mailed to 101 syringe exchange programs. Program directors were contacted to conduct telephone interviews based on the mailed questionnaires. Data collected included number of syringes exchanged, syringe exchange program operations, legal status, and services offered. RESULTS: Eighty-seven programs participated in the survey. A total of 46 (53%) were legal, 20 (23%) were illegal but tolerated, and 21 (24%) were illegal-underground. Since 1994, there has been a 54% increase in the number of cities and a 38% increase in the number of states with syringe exchange programs. Eighty-four programs reported exchanging approximately 14 million syringes, a 75% increase from 1994. Syringe exchange programs also provided a variety of other services and supplies, and legal programs were more likely than illegal ones to provide these services. CONCLUSION: Despite continued lack of federal funding, syringe exchange programs expanded in terms of the number of syringes exchanged, the geographic distribution of programs, and the range of services offered.