bluuebunny/crossref_metadata_2025 huggingface dataset:
Once-Yearly Administered Intravenous Zoledronic Acid for Postmenopausal Osteoporosis
Authors: Woodis C Brock
Published: May 2008

Objective:

To review studies that investigated the use of once-yearly administered intravenous zoledronic acid (or the treatment of postmenopausal osteoporosis.

Data Sources:

Searches of MEDLINE (1966–February 2008) and EMBASE (1974–February 2008) were conducted using the terms zoledronic acid, once-yearly, and postmenopausal osteoporosis. Literature review was limited to human studies.

Study Selection and Data Extraction:

All literature Identified from the data sources was evaluated for review inclusion. Studies investigating the use of zoledronic add in conditions other than postmenopausal osteoporosis, including malignant hypercalcemia, multiple myeloma, and Paget's disease, were excluded. Five randomized controlled studies were included in this review.

Data Synthesis:

Oral bisphosphonates represent one of the most commonly prescribed drug classes for the treatment of postmenopausal osteoporosis. However, due to poor gastrointestinal absorption and poor patient adherence to bisphosphonate therapy, once-yearly intravenous zoledronic add may be a more attractive option for some patients. Once-yearly zoledronic add has been shown to decrease bone turnover markers such as serum C-tolopeptide by 49-52%, decrease the vertebral fracture rate by approximately 70%, and significantly increase bone mineral density at total hip, femoral neck, and lumbar spine by 6.02%, 5.06%, and 6.71 %, respectively. Furthermore, some women may prefer the convenience of once-yearly intravenous zoledronic add to daily or weekly oral bisphosphonates. In clinical trials that compared once-yearly zoledronic add Infusion with weekly oral alendronate, participants preferred zoledronic add and found its adverse effect profile to be more favorable.

Conclusions:

Based on available evidence, once-yearly zoledronic acid Is an efficacious treatment option for postmenopausal women with osteoporosis. However, lack of head-to-head studies with oral bisphosphonates is a limitation In evaluating its clinical utility. Additional studies investigating zoledronic acid against oral bisphosphonates, specifically looking at rates and types of fractures, are needed to fully determine its place In postmenopausal osteoporosis treatment.
Values for free/total prostate-specific antigen ratio as a function of age: necessity of reference validation in a Turkish population
Authors: Mungan A. Gorkem , Erol Bulent , Akduman Bulent , Bozdogan Gurdal , Kiran Sibel , Yesilli Cetin , Mungan N. Aydin
Published: May 2008

Clin Chem Lab Med 2007;45:912–6.
First characterization of the development of bleached kraft softwood pulp fiber interfaces during drying and rewetting using FRET microscopy
Authors: Thomson Cameron I. , Lowe Robert M. , Ragauskas Arthur J.
Published: May 2008

Cellulosic fiber interfaces are critical to the material properties of paper. Likewise, the presence of water in a paper sheet is an important property, because paper is a wet-laid structure and the cellulosic fibers that compose it are hygroscopic. This work uses a fluorescence microscopy technique established by the authors to study the development of individual bleached kraft pulp fiber crossings in situ during drying and through a cycle of rewetting and wet pressing. The results indicate that coalescence of the fiber-fiber interface occurs during drying and that the fluorescence resonance energy transfer (FRET) response, which is proportional to the distance between fiber components, increases logarithmically with time. The FRET signal of once-dried fiber crossings increases dramatically after rewetting and wet pressing for a second time. This indicates that fiber bonds are still compliant after a single drying cycle and that the interactions between fiber components are likely reversible at the solids content present in bleached kraft pulp fiber crossings dried at 25°C and 50% relative humidity.
Evaluation on structural performance of compressed wood as shear dowel
Authors: Jung Kiho , Kitamori Akihisa , Komatsu Kohei
Published: May 2008

This study addresses the application of compressed wood (CW) made of Japanese cedar, as a substitute for high-density hardwood, to shear dowel. A double wood-to-wood shear test was performed to evaluate the mechanical shear properties of CW perpendicular to the grain, and the results were compared with those of several types of dowel material. CW with its annual ring radial to loading direction (0°) had a unique double shear performance characteristic, and showed good properties as a dowel material by virtue of its strength and rich ductility. In contrast, CW with its annual ring tangential to loading direction (90°) and maple exhibited brittle failure. While thickness of the base member was varied, the ductility of the joint became stable for diameter over 36 mm and 24 mm thickness for the main and side members, respectively. When the density of the base member increased, its stiffness, yield load, and maximum load exhibited proportional improvement with different inclinations; however, in the case of a maple dowel, the increases were small. When the density of the base member was increased, the ultimate load had positive linear tendency, whereas plastic modulus decreased. Consequently, almost constant energy absorption was observed in spite of the increased density. The optimum load-carrying capacity and ductility of a compressed wooden dowel joint could be designed by introducing an appropriate base member.
Challenging social hierarchy: Playing with oppositional identities in family talk
Authors: Bani-Shoraka Helena
Published: May 2008

This study examines how bilingual family members use language choice and language alternation as a local scheme of interpretation to distinguish different and often contesting social identities in interaction. It is argued that the playful creation of oppositional identities in interaction relieves the speakers from responsibility and creates a safe environment for challenging otherwise strict social hierarchies. The data are drawn from ethnographic research and informal conversations audio recorded in bilingual and multigenerational Azerbaijani families in Tehran, Iran. The methods of analysis integrate a sequential analysis with membership categorization analysis and ethnography. This paper also highlights the need for a multilayered analysis in order to approach the issue of social order as a product of participants' situated conduct.
Automatic Semantic Analysis for NLP Applications
Authors: Glückner Ingo , Hartrumpf Sven , Helbig Hermann , Leveling Johannes , Osswald Rainer
Published: May 2008

In this article, we describe a long-term enterprise at the FernUniversität in Hagen to develop systems for the automatic semantic analysis of natural language. We introduce the underlying semantic framework and give an overview of several recent activities and projects covering natural language interfaces to information providers on the web, automatic knowledge acquisition, and textual inference.
Repräsentation und Verknüpfung allgemeinsprachlicher und terminologischer Wortnetze in OWL
Authors: Kunze Claudia , Lemnitzer Lothar , Lüngen Harald , Storrer Angelika
Published: May 2008

This paper describes an approach to modelling a general-language wordnet, GermaNet, and a domain-specific wordnet, TermNet, in the web ontology language OWL. While the modelling process for GermaNet adopts relevant recommendations with respect to the English Princeton WordNet, for TermNet an alternative modelling concept is developed that considers the special characteristics of domain-specific terminologies. We present a proposal for linking a general-language wordnet and a terminological wordnet within the framework of OWL and on this basis discuss problems and alternative modelling approaches.
Suggesting Error Corrections of Path Expressions and Categories for Tree-Mapping Grammars
Authors: Brück Tim Vor Der , Busemann Stephan
Published: May 2008

Tree mapping grammars are used in natural language generation (NLG) to map non-linguistic input onto a derivation tree from which the target text can be trivially read off as the terminal yield. Such grammars may consist of a large number of rules. Finding errors is quite tedious and sometimes very time-consuming. Often the generation fails because the relevant input subtree is not specified correctly. This work describes a method to detect and correct wrong assignments of input subtrees to grammar categories by cross-validating grammar rules with the given input structures. The method also detects and corrects the usage of a category in a grammar rule. The result is implemented in a grammar development workbench and accelerates the grammar writer's work considerably. The paper suggests the algorithms can be ported to other areas in which tree mapping is required.
Produktivität und Idiomatizität von Präposition-Substantiv-Sequenzen
Authors: Kiss Tibor
Published: May 2008

The present paper discusses two fundamental properties of so-called determinerless PPs, their idiomaticity and productivity. Combining evidence from German newspaper corpora with methods from statistical natural language processing, we can show that determinerless PPs are no more idiomatic that ordinary phrasal combinations in general. From an empirical point of view determinerless PPs can be classified as productive. Consequently determinerless PPs should not be treated as idiomatic exceptions, which can be covered by finite lists.
Abstracting Suffixes: A Morphophonemic Approach to Polish Morphological Analysis
Authors: Zeldes Amir
Published: May 2008

This paper presents a morphophonology-based Item-and-Process approach to the finite-state lemmatization and morphological analysis of Polish. Unlike current text-based techniques, which search for all possible orthographic representations of Polish morphological suffixes, the multilevel phonological feature based algorithm presented here extracts morphophoneme arrays from graphemic word forms, allowing the extraction of abstract suffixes, independent of their surface representation. This makes it possible to use a simple mono-lemmatic dictionary, as well as to distinguish between homographic suffixes, and to carry out various phonological and morphological investigations using suffix fields in corpora.
Spray Adjuvant Effects on Droplet Size Spectra Measured by Three Laser-Based Systems in a High-Speed Wind Tunnel
Authors: Hoffmann W. Clint , Hewitt A. J. , Ross J. B. , Bagley W. E. , Martin D. E. , Fritz B. K.
Published: May 2008

Spray droplet size has long been recognized as the most important variable that aerial applicators can influence to mitigate spray drift from the application site. There are several different technologies that are used by researchers to measure droplet size from spray nozzles. The objective of these studies was to determine the influence of eight spray adjuvants on the droplet size spectrum produced by two nozzles in a high-speed wind tunnel when characterized using three different droplet size measurement systems. The adjuvant, nozzles, and airspeeds used in these studies are commonly used by aerial applicators. Three droplet sizing systems (Malvern laser diffraction, PMS optical array probe, and LaVision laser imaging) were simultaneously operated to measure the spray droplet size spectra for each adjuvant, airspeed, and nozzle combination. Two spray nozzles (a D6-46 nozzle and a D2 straight stream nozzle) were evaluated in a high-speed wind tunnel at airspeeds of 45 and 58 m/sec. There were significant differences in the droplet size spectra produced by the eight spray adjuvants tested. There were also significant differences between the droplet size values reported by the three measurement systems (Malvern, LaVision, and PMS) evaluated; however, there was considerable agreement trendwise. In general, the Malvern reported smaller spray droplet size spectra values than the LaVision, while the PMS system generally reported the largest spray droplet size spectra values. These tests are the first reported studies where all three droplet sizing systems were operated simultaneously.
The Best Disease-Linked Cl−ChannelhBest1Regulates CaV1 (L-type) Ca2+Channels via src-Homology-Binding Domains
Authors: Yu Kuai , Xiao Qinghuan , Cui Guiying , Lee Amy , Hartzell H. Criss
Published: May 2008

Mutations in the bestrophin-1 (Best1) gene are linked to several kinds of macular degeneration in both humans and dogs. Although bestrophins have been shown clearly to be Cl−ion channels, it is controversial whether Cl−channel dysfunction can explain the diseases. It has been suggested that bestrophins are multifunctional proteins: they may regulate voltage-gated Ca2+channels in addition to functioning as Cl−channels. Here, we show that humanBest1gene (hBest1) differentially modulates CaV1.3 (L-type) voltage-gated Ca2+channels through association with the CaVβ subunit. In transfected human embryonic kidney 293 cells, hBest1 inhibited CaV1.3. Inhibition of CaV1.3 was not observed in the absence of the β subunit. Also, the hBest1 C terminus binds to CaVβ subunits, suggesting that the effect of hBest1 was mediated by the CaVβ subunit. The region of hBest1 responsible for the effect was localized to a region (amino acids 330–370) in the cytoplasmic C terminus that contains a predicted src-homology-binding domain that is not present in other bestrophin subtypes. Mutation of Pro330and Pro334abolished the effects of hBest1 on CaV1.3. The effect was specific to hBest1; it was not observed with mouse Best1 (mBest1), mBest2, or mBest3. Wild-type hBest1 and the disease-causing mutants R92S, G299R, and D312N inhibited CaVcurrents the same amount, whereas the A146K and G222E mutants were less effective. We propose that hBest1 regulates CaVchannels by interacting with the CaVβ subunit and altering channel availability. Our findings reveal a novel function of bestrophin in regulation of CaVchannels and suggest a possible mechanism for the role of hBest1 in macular degeneration.
Mechanisms Underlying Functional Changes in the Primary Motor Cortex Ipsilateral to an Active Hand
Authors: Perez Monica A. , Cohen Leonardo G.
Published: May 2008

Performance of a unimanual hand motor task results in functional changes in both primary motor cortices (M1ipsilateraland M1contralateral). The neuronal mechanisms controlling the corticospinal output originated in M1ipsilateraland the resting hand during a unimanual task remain unclear. Here, we assessed functional changes within M1ipsilateraland in interhemispheric inhibition (IHI) associated with parametric increases in unimanual force. We measured motor-evoked potential (MEP) recruitment curves (RCs) and short-interval intracortical inhibition (SICI) in M1ipsilateral, IHI from M1contralateralto M1ipsilateral, and the influence of IHI over SICI using transcranial magnetic stimulation at rest and during 10, 30, and 70% of maximal right wrist flexion force. EMG from the left resting flexor carpi radialis (FCR) muscle was comparable across conditions. Left FCR MEP RCs increased, and SICI decreased with increasing right wrist force. Activity-dependent (rest and 10, 30, and 70%) left FCR maximal MEP size correlated with absolute changes in SICI. IHI decreased with increasing force at matched conditioned MEP amplitudes. IHI and SICI were inversely correlated at increasing forces. In the presence of IHI, SICI decreased at rest and 70% force. In summary, we found activity-dependent changes in (1) SICI in M1ipsilateral, (2) IHI from M1contralateralto M1ipsilateral, and (3) the influence of IHI over SICI in the left resting hand during force generation by the right hand. Our findings indicate that interactions between GABAergic intracortical circuits mediating SICI and interhemispheric glutamatergic projections between M1s contribute to control activity-dependent changes in corticospinal output to a resting hand during force generation by the opposite hand.
Stress Induces a Switch of Intracellular Signaling in Sensory Neurons in a Model of Generalized Pain
Authors: Khasar Sachia G. , Burkham Jennifer , Dina Olayinka A. , Brown Adrienne S. , Bogen Oliver , Alessandri-Haber Nicole , Green Paul G. , Reichling David B. , Levine Jon D.
Published: May 2008

Stress dramatically exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, but the underlying mechanisms are unknown. We tested the hypothesis that stress causes generalized hyperalgesia by enhancing pronociceptive effects of immune mediators. Rats exposed to nonhabituating sound stress exhibited no change in mechanical nociceptive threshold, but showed a marked increase in hyperalgesia evoked by local injections of prostaglandin E2or epinephrine. This enhancement, which developed more than a week after exposure to stress, required concerted action of glucocorticoids and catecholamines at receptors located in the periphery on sensory afferents. The altered response to pronociceptive mediators involved a switch in coupling of their receptors from predominantly stimulatory to inhibitory G-proteins (Gsto Gi), and for prostaglandin E2, emergence of novel dependence on protein kinase Cε. Thus, an important mechanism in generalized pain syndromes may be stress-induced coactivation of the hypothalamo-pituitary-adrenal and sympathoadrenal axes, causing a long-lasting alteration in intracellular signaling pathways, enabling normally innocuous levels of immune mediators to produce chronic hyperalgesia.
Feedback from Horizontal Cells to Rod Photoreceptors in Vertebrate Retina
Authors: Thoreson Wallace B. , Babai Norbert , Bartoletti Theodore M.
Published: May 2008

Retinal horizontal cells (HCs) provide negative feedback to cones, but, largely because annular illumination fails to evoke a depolarizing response in rods, it is widely believed that there is no feedback from HCs to rods. However, feedback from HCs to cones involves small changes in the calcium current (ICa) that do not always generate detectable depolarizing responses. We therefore recordedICadirectly from rods to test whether they were modulated by feedback from HCs. To circumvent problems presented by overlapping receptive fields of HCs and rods, we manipulated the membrane potential of voltage-clamped HCs while simultaneously recording from rods in a salamander retinal slice preparation. Like HC feedback in cones, hyperpolarizing HCs from −14 to −54, −84, and −104 mV increased the amplitude ofICarecorded from synaptically connected rods and caused hyperpolarizing shifts inICavoltage dependence. These effects were blocked by supplementing the bicarbonate-buffered saline solution with HEPES. In rods lacking light-responsive outer segments, hyperpolarizing neighboring HCs with light caused a negative activation shift and increased the amplitude ofICa. These changes inICawere blocked by HEPES and by inhibiting HC light responses with a glutamate antagonist, indicating that they were caused by HC feedback. These results show that rods, like cones, receive negative feedback from HCs that regulates the amplitude and voltage dependence ofICa. HC-to-rod feedback counters light-evoked decreases in synaptic output and thus shapes the transmission of rod responses to downstream visual neurons.
Noradrenergic Innervation of the Dorsal Medial Prefrontal Cortex Modulates Hypothalamo-Pituitary-Adrenal Responses to Acute Emotional Stress
Authors: Radley Jason J. , Williams Brandon , Sawchenko Paul E.
Published: May 2008

The medial prefrontal cortex (mPFC) has been proposed to play a role in the inhibition of hypothalamo-pituitary-adrenal (HPA) responses to emotional stress via influences on neuroendocrine effector mechanisms housed in the paraventricular hypothalamic nucleus (PVH). Previous work also suggests an involvement of the locus ceruleus (LC) in behavioral and neuroendocrine responses to a variety of acute stressors. The LC issues a widespread set of noradrenergic projections, and its innervation of the prefrontal cortex plays an important role in the modulation of working memory and attention. Because these operations are likely to be critical for stimulus selection, evaluation, and comparison with past experience in mounting adaptive responses to emotional stress, it follows that the LC-to-mPFC pathway might also be involved in regulating HPA activity under such conditions. Therefore, in the present study, we assessed the effects of selectively ablating noradrenergic inputs into the mPFC, using the axonally transported catecholamine immunotoxin, saporin-conjugated antiserum to dopamine-β-hydroxylase, on acute restraint stress-induced activation of HPA output. Immunotoxin injections in the dorsal mPFC (centered in the prelimbic cortex) attenuated increments in restraint-induced Fos and corticotropin-releasing factor mRNA expression in the neurosecretory region of PVH, as well as HPA secretory responses. Stress-induced Fos expression in dorsal mPFC was enhanced after noradrenergic deafferentation and was negatively correlated with stress-induced PVH activation, independent of lesion status. These findings identify the LC as an upstream component of a circuitry providing for dorsal mPFC modulation of emotional stress-induced HPA activation.
Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence
Authors: Roberto Marisa , Gilpin Nicholas W. , O'Dell Laura E. , Cruz Maureen T. , Morse Andrew C. , Siggins George R. , Koob George F.
Published: May 2008

Gabapentin is a structural analog of GABA that has anticonvulsant properties. Despite the therapeutic efficacy of gabapentin, its molecular and cellular mechanisms of action are unclear. The GABAergic system in the central nucleus of the amygdala (CeA) plays an important role in regulating voluntary ethanol intake. Here, we investigated the effect of gabapentin on GABAergic transmission in CeA slices, on ethanol intake, and on an anxiety measure using animal models of ethanol dependence. Gabapentin increased the amplitudes of evoked GABA receptor-mediated IPSCs (GABA-IPSCs) in CeA neurons from nondependent rats, but decreased their amplitudes in CeA of ethanol-dependent rats. Gabapentin effects were blocked in the presence of a specific GABABreceptor antagonist. The sensitivity of the GABA-IPSCs to a GABABreceptor antagonist and an agonist was decreased after chronic ethanol, suggesting that ethanol-induced neuroadaptations of GABABreceptors associated with ethanol dependence may account for the differential effects of gabapentin after chronic ethanol. Systemic gabapentin reduced ethanol intake in dependent, but not in nondependent, rats and reversed the anxiogenic-like effects of ethanol abstinence using an acute dependence model. Gabapentin infused directly into the CeA also blocked dependence-induced elevation in operant ethanol responding. Collectively, these findings show that gabapentin reverses behavioral measures of ethanol dependence and, in turn, dependence reverses the effects of gabapentin on CeA neurons, and suggest that gabapentin represents a potential medication for treatment of alcoholism.
Organization of the Arp2/3 Complex in Hippocampal Spines
Authors: Rácz Bence , Weinberg Richard J.
Published: May 2008

Changes in the morphology of a dendritic spine require remodeling of its actin-based cytoskeleton. Biochemical mechanisms underlying actin remodeling have been studied extensively, but little is known about the physical organization of the actin-binding proteins that mediate remodeling in spines. Long-term potentiation-inducing stimuli trigger expansion of the spine head, suggesting local extension and branching of actin filaments. Because filament branching requires the Arp2/3 complex, we used quantitative immunoelectron microscopy to elucidate the organization of ARPC-2 (Arp2/3 complex subunit 2), an essential component of the complex. Our data from CA1 hippocampus indicate that Arp2/3 concentrates within spines in a previously unrecognized torroidal domain, apparently specialized to mediate actin filament branching.
The h Channel Mediates Location Dependence and Plasticity of Intrinsic Phase Response in Rat Hippocampal Neurons
Authors: Narayanan Rishikesh , Johnston Daniel
Published: May 2008

The presence of phenomenological inductances in neuronal membrane has been known for more than one-half a century. Despite this, the dramatic contributions of such inductive elements to the amplitude and, especially, phase of neuronal impedance, and their roles in modulating temporal dynamics of neuronal responses have surprisingly remained unexplored. In this study, we demonstrate that the h channel contributes a location-dependent and plastic phenomenological inductive component to the input impedance of CA1 pyramidal neurons. Specifically, we show that the h channels introduce an apparent negative delay in the local voltage response of these neurons with respect to the injected current within the theta frequency range. The frequency range and the extent of this lead expand with increases in h current either through hyperpolarization, or with increasing distance of dendritic location from the soma. We also demonstrate that a spatially widespread increase in this inductive phase component accompanies long-term potentiation. Finally, using impedance analysis, we show that both location and activity dependence of intrinsic phase response are attributable not to changes in a capacitive or a leak component, but to changes in h-channel properties. Our results suggest that certain voltage-gated ion channels can differentially regulate internal time delays within neurons, thus providing them with an independent control mechanism in temporal coding of neuronal information. Our analyses and results also establish impedance as a powerful measure of intrinsic dynamics and excitability, given that it quantifies temporal relationships among signals and excitability as functions of input frequency.
GPR56 Regulates Pial Basement Membrane Integrity and Cortical Lamination
Authors: Li Shihong , Jin Zhaohui , Koirala Samir , Bu Lihong , Xu Lei , Hynes Richard O. , Walsh Christopher A. , Corfas Gabriel , Piao Xianhua
Published: May 2008

GPR56 is a member of the family of adhesion G-protein-coupled receptors that have a large extracellular region containing a GPS (G-protein proteolytic site) domain. Loss-of-function mutations in theGPR56gene cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). BFPP is a radiological diagnosis and its histopathology remains unclear. This study demonstrates that loss of the mouseGpr56gene leads to neuronal ectopia in the cerebral cortex, a cobblestone-like cortical malformation. There are four crucial events in the development of cobblestone cortex, namely defective pial basement membrane (BM), abnormal anchorage of radial glial endfeet, mislocalized Cajal–Retzius cells, and neuronal overmigration. By detailed time course analysis, we reveal that the leading causal events are likely the breaches in the pial BM. We show further that GPR56 is present in abundance in radial glial endfeet. Furthermore, a putative ligand of GPR56 is localized in the marginal zone or overlying extracellular matrix. These observations provide compelling evidence that GPR56 functions in regulating pial BM integrity during cortical development.
Zinc Triggers Microglial Activation
Authors: Kauppinen Tiina M. , Higashi Youichirou , Suh Sang Won , Escartin Carole , Nagasawa Kazuki , Swanson Raymond A.
Published: May 2008

Microglia are resident immune cells of the CNS. When stimulated by infection, tissue injury, or other signals, microglia assume an activated, “ameboid” morphology and release matrix metalloproteinases, reactive oxygen species, and other proinflammatory factors. This innate immune response augments host defenses, but it can also contribute to neuronal death. Zinc is released by neurons under several conditions in which microglial activation occurs, and zinc chelators can reduce neuronal death in animal models of cerebral ischemia and neurodegenerative disorders. Here, we show that zinc directly triggers microglial activation. Microglia transfected with a nuclear factor-κB (NF-κB) reporter gene showed a severalfold increase in NF-κB activity in response to 30 μmzinc. Cultured mouse microglia exposed to 15–30 μmzinc increased nitric oxide production, increased F4/80 expression, altered cytokine expression, and assumed the activated morphology. Zinc-induced microglial activation was blocked by inhibiting NADPH oxidase, poly(ADP-ribose) polymerase-1 (PARP-1), or NF-κB activation. Zinc injected directly into mouse brain induced microglial activation in wild-type mice, but not in mice genetically lacking PARP-1 or NADPH oxidase activity. Endogenous zinc release, induced by cerebral ischemia–reperfusion, likewise induced a robust microglial reaction, and this reaction was suppressed by the zinc chelator CaEDTA. Together, these results suggest that extracellular zinc triggers microglial activation through the sequential activation of NADPH oxidase, PARP-1, and NF-κB. These findings identify a novel trigger for microglial activation and a previously unrecognized mechanism by which zinc may contribute to neurological disorders.
Postsynaptic Density-93 Clusters Kv1 Channels at Axon Initial Segments Independently of Caspr2
Authors: Ogawa Yasuhiro , Horresh Ido , Trimmer James S. , Bredt David S. , Peles Elior , Rasband Matthew N.
Published: May 2008

Postsynaptic density-93 (PSD-93)/Chapsyn-110 is a PDZ (PSD-95/Discs large/zona occludens-1) domain-containing membrane-associated guanylate kinase (MAGUK) that functions as a scaffold to assemble channels, receptors, and other signaling proteins at cell membranes. PSD-93 is highly enriched at synapses, but mice lacking this protein have no synaptic structural abnormalities, probably because of overlapping expression and redundancy with other MAGUKs. Consequently, the function of PSD-93 is not well understood. Here, we show that PSD-93, but not other MAGUKs, is enriched at the axon initial segment (AIS), where it colocalizes with Kv1.1, Kv1.2, Kv1.4, and Kvβ2 subunit-containing K+channels, Caspr2, and TAG-1 (transient axonal glycoprotein-1). When coexpressed with Kv1 channels in heterologous cells, PSD-93 induces formation of large cell-surface clusters. Knockdown of PSD-93 in cultured hippocampal neurons by RNA interference disrupted Kv1 channel localization at the AIS. Similarly, PSD-93−/− mice failed to cluster Kv1 channels at the AIS of cortical and hippocampal neurons. In contrast, Caspr2, which mediates Kv1 channel clustering at the juxtaparanode, is not required for localization of Kv1 channels at the AIS. These results show PSD-93 mediates AIS accumulation of Kv1 channels independently of Caspr2.
Neutron photocrystallography: simulation and experiment
Authors: Schefer Jürg , Schaniel Dominik , Petříček Václav , Woike Theo
Published: May 2008

The investigation of light-induced structural changes by diffractive methods has improved significantly in the last two decades. We present here the case of neutron photocrystallography for which we have built a special experimental setup at the single crystal neutron diffractometer TriCS at the Swiss Spallation Neutron Source SINQ. We illustrate the progress of the method on the example of the structural determination of photoinduced nitrosyl linkage-isomers in Na2[Fe(CN)5NO] · 2 H2O. The in-situ determination of the population of the light-induced linkage isomers by optical transmission measurements enhances the reliability of such structural investigations considerably. Additionally we present a new simulation tool within the program package JANA2006 which allows to plan a photocrystallographic experiment thoroughly since the required q-range, the minimally needed population of the photoinduced species, as well as the necessary counting statistics for a successful single crystal diffraction experiment can be evaluated in advance.
Static and time-resolved photocrystallographic studies in supramolecular solids
Authors: Coppens Philip , Zheng Shao-Liang , Gembicky Milan
Published: May 2008

The supramolecular solid state is a medium par excellence for photochemical studies of molecules in a well-defined environment. If the photoactive molecule is embedded within a strong photochemically-inert framework, reactions can proceed without breakdown of the crystal lattice. A number of examples of trans-cis and cis-trans reactions are presented. A variable temperature study of Zn-coordinated tiglic acid shows that the reaction is energy-controlled with a small activation energy of approx. 2 kJ/mol, dependent on the size of the cavity in which the molecule is located. Time-resolved studies of the instantaneous dimer-formation of an organic and an inorganic species are presented. The Cu(I)(NH3)2 cation forms a dimeric species with a contracted Cu(I)—Cu(I) distance through promotion of an electron from an antibonding to a weakly bonding orbital, whereas xanthone forms an excimer with decrease interplanar spacing. The concept of the photodifference map is defined and used thoughout the article.
Theoretical study on the structure of the ground state and photo-induced metastable states of [M(CN)5NO]2− (M = Ru, Fe), and mechanism of the photo-rearrangement among them
Authors: Ishikawa Takeshi , Tanaka Kiyoshi
Published: May 2008

In this note, we reviewed theoretical investigations of the photo-induced metastable states and discussed possible photo-rearrangement paths in [M(CN)5NO]2− (M = Fe and Ru). Using calculated results of ab initio multi-reference single and double excitation configuration interaction calculations with Davidson type quadruple correction (MRSDCI + Q) and those of density fuctional theory (DFT), we showed that the two metastable states (MS1 and MS2) were local minima of the electronic ground state potential surface. The theoretical calculations supported the experimental observation of the structure of the three isomers (GS, MS1 and MS2), relative stability of MS1 and MS2. We discussed the character of the lower electronic excited states and excitation energies of the three isomers of both compounds. Based on these results and excited state adiabatic potential energy surfaces, possible mechanism of photo-rearrangement among GS, MS1, and MS2 were discussed with the aid of our results on [Mn(CN)5NO]3− of which no photo-rearrangement has been reported.
Recurrent Deletion and Gene Presence/Absence Polymorphism: Telomere Dynamics Dominate Evolution at the Tip of 3L inDrosophila melanogasterandD. simulans
Authors: Kern Andrew D , Begun David J
Published: May 2008

Although Drosophila melanogaster has been the subject of intensive analysis of polymorphism and divergence, little is known about the distribution of variation at the most distal regions of chromosomes arms. Here we report a survey of genetic variation on the tip of 3L in D. melanogaster and D. simulans. Levels of single nucleotide polymorphism in the most distal euchromatic sequence are approximately one order of magnitude less than that typically observed in genomic regions of normal crossing over, consistent with what might be expected under models of linked selection in regions of low crossing over. However, despite this reduced level of nucleotide variation, we found abundant deletion polymorphism. These deletions create at least three gene presence/absence polymorphisms within D. melanogaster: the putative G-protein coupled receptor mthl-8 (which is the most distal known or predicted gene on 3L) and the unannotated mRNAs AY060886 and BT006009. Strikingly, D. simulans is also segregating deletions that cause mthl8 presence/absence polymorphism. Breakpoint sequencing and tests of correlations with segregating SNPs in D. melanogaster suggest that each deletion is unique. Cloned breakpoint sequences revealed the presence of Het-A elements just distal to unique, canonical euchromatic sequences. This pattern suggests a model in which repeated telomeric deficiencies cause deletions of euchromatic sequence followed by subsequent “healing” by retrotranposition of Het-A elements. These data reveal the dominance of telomeric dynamics on the evolution of closely linked sequences in Drosophila.
Breeding Designs for Recombinant Inbred Advanced Intercross Lines
Authors: Rockman Matthew V , Kruglyak Leonid
Published: May 2008

Recombinant inbred lines derived from an advanced intercross, in which multiple generations of mating have increased the density of recombination breakpoints, are powerful tools for mapping the loci underlying complex traits. We investigated the effects of intercross breeding designs on the utility of such lines for mapping. The simplest design, random pair mating with each pair contributing exactly two offspring to the next generation, performed as well as the most extreme inbreeding avoidance scheme at expanding the genetic map, increasing fine-mapping resolution, and controlling genetic drift. Circular mating designs offer negligible advantages for controlling drift and exhibit greatly reduced map expansion. Random-mating designs with variance in offspring number are also poor at increasing mapping resolution. Given equal contributions of each parent to the next generation, the constraint of monogamy has no impact on the qualities of the final population of inbred lines. We find that the easiest crosses to perform are well suited to the task of generating populations of highly recombinant inbred lines.
Inferring Causal Phenotype Networks From Segregating Populations
Authors: Chaibub Neto Elias , Ferrara Christine T , Attie Alan D , Yandell Brian S
Published: May 2008

A major goal in the study of complex traits is to decipher the causal interrelationships among correlated phenotypes. Current methods mostly yield undirected networks that connect phenotypes without causal orientation. Some of these connections may be spurious due to partial correlation that is not causal. We show how to build causal direction into an undirected network of phenotypes by including causal QTL for each phenotype. We evaluate causal direction for each edge connecting two phenotypes, using a LOD score. This new approach can be applied to many different population structures, including inbred and outbred crosses as well as natural populations, and can accommodate feedback loops. We assess its performance in simulation studies and show that our method recovers network edges and infers causal direction correctly at a high rate. Finally, we illustrate our method with an example involving gene expression and metabolite traits from experimental crosses.
A Mutation in the Putative MLH3 Endonuclease Domain Confers a Defect in Both Mismatch Repair and Meiosis inSaccharomyces cerevisiae
Authors: Nishant K T , Plys Aaron J , Alani Eric
Published: May 2008

Interference-dependent crossing over in yeast and mammalian meioses involves the mismatch repair protein homologs MSH4-MSH5 and MLH1-MLH3. The MLH3 protein contains a highly conserved metal-binding motif DQHA(X)2E(X)4E that is found in a subset of MLH proteins predicted to have endonuclease activities (Kadyrov  et al. 2006). Mutations within this motif in human PMS2 and Saccharomyces cerevisiae PMS1 disrupted the endonuclease and mismatch repair activities of MLH1-PMS2 and MLH1-PMS1, respectively (Kadyrov  et al. 2006, 2007; Erdeniz  et al. 2007). As a first step in determining whether such an activity is required during meiosis, we made mutations in the MLH3 putative endonuclease domain motif (-D523N, -E529K) and found that single and double mutations conferred mlh3-null-like defects with respect to meiotic spore viability and crossing over. Yeast two-hybrid and chromatography analyses showed that the interaction between MLH1 and mlh3-D523N was maintained, suggesting that the mlh3-D523N mutation did not disrupt the stability of MLH3. The mlh3-D523N mutant also displayed a mutator phenotype in vegetative growth that was similar to mlh3Δ. Overexpression of this allele conferred a dominant-negative phenotype with respect to mismatch repair. These studies suggest that the putative endonuclease domain of MLH3 plays an important role in facilitating mismatch repair and meiotic crossing over.
Levels of Selection on Threshold Characters
Authors: Moorad Jacob A , Linksvayer Timothy A
Published: May 2008

Threshold models are useful for understanding the evolution of dimorphic traits with polygenic bases. Selection for threshold characters on individuals is expected to be frequency dependent because of the peculiar way that selection views underlying genetic and environmental factors. Selection among individuals is inefficient because individual phenotypes fall into only two discrete categories that map imperfectly to the underlying genes. Incidence, however, can be continuously distributed among groups, making among-group selection relatively more efficient. Differently put, the group-mean phenotype can be a better predictor of an individual's genotype than that individual's own phenotype. Because evolution in group-structured populations is governed by the balance of selection within and between groups, we can expect threshold traits to evolve in fundamentally different ways when group mean fitness is a function of morph frequency. We extend the theory of selection on threshold traits to include group selection using contextual analysis. For the simple case of linear group-fitness functions, we show that the group-level component of selection, like the individual-level component, is frequency dependent. However, the conditions that determine which component dominates when levels of selection are in conflict (as described by Hamilton's rule) are not frequency dependent. Thus, enhanced group selection is not an inherent property of threshold characters. Nevertheless, we show that predicting the effects of multiple levels of selection on dimorphic traits requires special considerations of the threshold model.
Single-Nucleotide-Polymorphism-Based Association Mapping of Dog Stereotypes
Authors: Jones Paul , Chase Kevin , Martin Alan , Davern Pluis , Ostrander Elaine A , Lark Karl G
Published: May 2008

Phenotypic stereotypes are traits, often polygenic, that have been stringently selected to conform to specific criteria. In dogs, Canis familiaris, stereotypes result from breed standards set for conformation, performance (behaviors), etc. As a consequence, phenotypic values measured on a few individuals are representative of the breed stereotype. We used DNA samples isolated from 148 dog breeds to associate SNP markers with breed stereotypes. Using size as a trait to test the method, we identified six significant quantitative trait loci (QTL) on five chromosomes that include candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Less well-documented data for behavioral stereotypes tentatively identified loci for herding, pointing, boldness, and trainability. Four significant loci were identified for longevity, a breed characteristic not under direct selection, but inversely correlated with breed size. The strengths and limitations of the approach are discussed as well as its potential to identify loci regulating the within-breed incidence of specific polygenic diseases.
The Frequency of Fitness Peak Shifts Is Increased at Expanding Range Margins Due to Mutation Surfing
Authors: Burton Olivia J , Travis Justin M J
Published: May 2008

Dynamic species' ranges, those that are either invasive or shifting in response to environmental change, are the focus of much recent interest in ecology, evolution, and genetics. Understanding how range expansions can shape evolutionary trajectories requires the consideration of nonneutral variability and genetic architecture, yet the majority of empirical and theoretical work to date has explored patterns of neutral variability. Here we use forward computer simulations of population growth, dispersal, and mutation to explore how range-shifting dynamics can influence evolution on rugged fitness landscapes. We employ a two-locus model, incorporating sign epistasis, and find that there is an increased likelihood of fitness peak shifts during a period of range expansion. Maladapted valley genotypes can accumulate at an expanding range front through a phenomenon called mutation surfing, which increases the likelihood that a mutation leading to a higher peak will occur. Our results indicate that most peak shifts occur close to the expanding front. We also demonstrate that periods of range shifting are especially important for peak shifting in species with narrow geographic distributions. Our results imply that trajectories on rugged fitness landscapes can be modified substantially when ranges are dynamic.
Trial of Computerized Screening for Adolescent Behavioral Concerns
Authors: Stevens Jack , Kelleher Kelly J. , Gardner William , Chisolm Deena , McGeehan Jennifer , Pajer Kathleen , Buchanan Lindsay
Published: June 2008

OBJECTIVE. Injury risk, depressive symptoms, and substance use are the leading causes of adolescent morbidity and death. The goal of this randomized, controlled trial was to determine whether computerized screening with real-time printing of results for pediatricians increased the identification of these adolescent behavioral concerns.

METHODS. A total of 878 primary care patients 11 to 20 years of age participated in computerized behavioral screening (the Health eTouch system) in waiting rooms of 9 urban clinics. These clinics all served predominantly low-income patients. The clinics were randomly assigned to have pediatricians receive screening results either just before face-to-face encounters with patients (immediate-results condition) or 2 to 3 business days later (delayed-results condition).

RESULTS. Fifty-nine percent of Health eTouch respondents had positive results for ≥1 of the following behavioral concerns: injury risk behaviors, significant depressive symptoms, or substance use. Sixty-eight percent of youths in the immediate-results condition who screened positive were identified as having a problem by their pediatrician. This was significantly higher than the recognition rate of 52% for youths in the delayed-results condition.

CONCLUSION. Immediate provision of an adolescent's self-report of behavioral concerns to a pediatrician increased recognition of those problems, compared with the delayed provision of results.