bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery of β-Arrestin–Biased Dopamine D
2
Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy
Authors: Allen John A. , Yost Julianne M. , Setola Vincent , Chen Xin , Sassano Maria F. , Chen Meng , Peterson Sean , Yadav Prem N. , Huang Xi-ping , Feng Bo , Jensen Niels H. , Che Xin , Bai Xu , Frye Stephen V. , Wetsel William C. , Caron Marc G. , Javitch Jonathan A. , Roth Bryan L. , Jin Jian
Published: October 2011

Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D
2
receptor (D
2
R) signaling via β-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D
2
R agonists that display signaling bias via β-arrestin–ergic signaling. Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D
2
R ligands. These compounds also represent unprecedented β-arrestin–biased ligands for a G
i
-coupled G protein–coupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of G
i
-regulated cAMP production and partial agonists for D
2
R/β-arrestin-2 interactions. Importantly, UNC9975 displayed potent antipsychotic-like activity without inducing motoric side effects in inbred C57BL/6 mice in vivo. Genetic deletion of β-arrestin-2 simultaneously attenuated the antipsychotic actions of UNC9975 and transformed it into a typical antipsychotic drug with a high propensity to induce catalepsy. Similarly, the antipsychotic-like activity displayed by UNC9994, an extremely β-arrestin–biased D
2
R agonist, in wild-type mice was completely abolished in β-arrestin-2 knockout mice. Taken together, our results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, β-arrestin–biased D
2
R ligands represent valuable chemical probes for further investigations of D
2
R signaling in health and disease.
The main auxin biosynthesis pathway in
Arabidopsis
Authors: Mashiguchi Kiyoshi , Tanaka Keita , Sakai Tatsuya , Sugawara Satoko , Kawaide Hiroshi , Natsume Masahiro , Hanada Atsushi , Yaeno Takashi , Shirasu Ken , Yao Hong , McSteen Paula , Zhao Yunde , Hayashi Ken-ichiro , Kamiya Yuji , Kasahara Hiroyuki
Published: October 2011

The phytohormone auxin plays critical roles in the regulation of plant growth and development. Indole-3-acetic acid (IAA) has been recognized as the major auxin for more than 70 y. Although several pathways have been proposed, how auxin is synthesized in plants is still unclear. Previous genetic and enzymatic studies demonstrated that both TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS (TAA) and YUCCA (YUC) flavin monooxygenase-like proteins are required for biosynthesis of IAA during plant development, but these enzymes were placed in two independent pathways. In this article, we demonstrate that the TAA family produces indole-3-pyruvic acid (IPA) and the YUC family functions in the conversion of IPA to IAA in
Arabidopsis
(
Arabidopsis thaliana
) by a quantification method of IPA using liquid chromatography–electrospray ionization–tandem MS. We further show that YUC protein expressed in
Escherichia coli
directly converts IPA to IAA. Indole-3-acetaldehyde is probably not a precursor of IAA in the IPA pathway. Our results indicate that YUC proteins catalyze a rate-limiting step of the IPA pathway, which is the main IAA biosynthesis pathway in
Arabidopsis
.
Nitrogen economics of root foraging: Transitive closure of the nitrate–cytokinin relay and distinct systemic signaling for N supply vs. demand
Authors: Ruffel Sandrine , Krouk Gabriel , Ristova Daniela , Shasha Dennis , Birnbaum Kenneth D. , Coruzzi Gloria M.
Published: October 2011

As sessile organisms, root plasticity enables plants to forage for and acquire nutrients in a fluctuating underground environment. Here, we use genetic and genomic approaches in a “split-root” framework—in which physically isolated root systems of the same plant are challenged with different nitrogen (N) environments—to investigate how systemic signaling affects genome-wide reprogramming and root development. The integration of transcriptome and root phenotypes enables us to identify distinct mechanisms underlying “N economy” (i.e., N supply and demand) of plants as a system. Under nitrate-limited conditions, plant roots adopt an “active-foraging strategy”, characterized by lateral root outgrowth and a shared pattern of transcriptome reprogramming, in response to either local or distal nitrate deprivation. By contrast, in nitrate-replete conditions, plant roots adopt a “dormant strategy”, characterized by a repression of lateral root outgrowth and a shared pattern of transcriptome reprogramming, in response to either local or distal nitrate supply. Sentinel genes responding to systemic N signaling identified by genome-wide comparisons of heterogeneous vs. homogeneous split-root N treatments were used to probe systemic N responses in
Arabidopsis
mutants impaired in nitrate reduction and hormone synthesis and also in decapitated plants. This combined analysis identified genetically distinct systemic signaling underlying plant N economy: (
i
) N supply, corresponding to a long-distance systemic signaling triggered by nitrate sensing; and (
ii
) N demand, experimental support for the transitive closure of a previously inferred nitrate–cytokinin shoot–root relay system that reports the nitrate demand of the whole plant, promoting a compensatory root growth in nitrate-rich patches of heterogeneous soil.
Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa
Authors: Martineau Adrian R. , Nhamoyebonde Shepherd , Oni Tolu , Rangaka Molebogeng X. , Marais Suzaan , Bangani Nonzwakazi , Tsekela Relebohile , Bashe Lizl , de Azevedo Virginia , Caldwell Judy , Venton Timothy R. , Timms Peter M. , Wilkinson Katalin A. , Wilkinson Robert J.
Published: October 2011

Vitamin D deficiency is associated with susceptibility to tuberculosis (TB) in HIV-uninfected people in Europe, but it is not known whether such an association exists among HIV-infected people in subtropical Africa. We conducted a cross-sectional study to determine whether vitamin D deficiency was associated with susceptibility to active TB in HIV-uninfected (
n
= 196) and HIV-infected (
n
= 174) black Africans in Cape Town, South Africa. We also investigated whether there was evidence of seasonal variation in vitamin D status and TB notifications in this setting over an 8-y period. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) was present in 232 (62.7%) of 370 participants and was associated with active TB in both HIV-uninfected (odds ratio = 5.2, 95% confidence interval: 2.8–9.7;
P
< 0.001) and HIV-infected (odds ratio = 5.6, 95% confidence interval: 2.7–11.6;
P
< 0.001) people. Vitamin D status varied according to season: The mean serum 25(OH)D concentration was highest in January through March and lowest in July through September (56.8 vs. 30.7 nmol/L, respectively;
P
< 0.001). Reciprocal seasonal variation in TB notifications was observed: The mean number of TB notifications per quarter for Cape Town in 2003 to 2010 was lowest in April through June and highest in October through December (4,222 vs. 5,080;
P
< 0.001). Vitamin D deficiency is highly prevalent among black Africans in Cape Town and is associated with susceptibility to active TB both in the presence and absence of HIV infection. Reciprocal seasonal variation in serum 25(OH)D concentration and TB notifications suggests that seasonal variations in vitamin D status and TB incidence in this setting are causally related.
The major central endocannabinoid directly acts at GABA
A
receptors
Authors: Sigel Erwin , Baur Roland , Rácz Ildiko , Marazzi Janine , Smart Trevor G. , Zimmer Andreas , Gertsch Jürg
Published: October 2011

GABA
A
receptors are the major ionotropic inhibitory neurotransmitter receptors. The endocannabinoid system is a lipid signaling network that modulates different brain functions. Here we show a direct molecular interaction between the two systems. The endocannabinoid 2-arachidonoyl glycerol (2-AG) potentiates GABA
A
receptors at low concentrations of GABA. Two residues of the receptor located in the transmembrane segment M4 of β
2
confer 2-AG binding. 2-AG acts in a superadditive fashion with the neurosteroid 3α, 21-dihydroxy-5α-pregnan-20-one (THDOC) and modulates δ-subunit–containing receptors, known to be located extrasynaptically and to respond to neurosteroids. 2-AG inhibits motility in CB
1
/CB
2
cannabinoid receptor double-KO, whereas β
2
-KO mice show hypermotility. The identification of a functional binding site for 2-AG in the GABA
A
receptor may have far-reaching consequences for the study of locomotion and sedation.
Self-amplifying autocrine actions of BDNF in axon development
Authors: Cheng Pei-Lin , Song Ai-Hong , Wong Yu-Hui , Wang Sheng , Zhang Xiang , Poo Mu-Ming
Published: October 2011

A critical step in neuronal development is the formation of axon/dendrite polarity, a process involving symmetry breaking in the newborn neuron. Local self-amplifying processes could enhance and stabilize the initial asymmetry in the distribution of axon/dendrite determinants, but the identity of these processes remains elusive. We here report that BDNF, a secreted neurotrophin essential for the survival and differentiation of many neuronal populations, serves as a self-amplifying autocrine factor in promoting axon formation in embryonic hippocampal neurons by triggering two nested positive-feedback mechanisms. First, BDNF elevates cytoplasmic cAMP and protein kinase A activity, which triggers further secretion of BDNF and membrane insertion of its receptor TrkB. Second, BDNF/TrkB signaling activates PI3-kinase that promotes anterograde transport of TrkB in the putative axon, further enhancing local BDNF/TrkB signaling. Together, these self-amplifying BDNF actions ensure stable elevation of local cAMP/protein kinase A activity that is critical for axon differentiation and growth.
Whichever way you Choose to Categorize, Working Memory Helps you Learn
Authors: Craig Stewart , Lewandowsky Stephan
Published: October 2011

There has been growing interest in the relationship between the capacity of a person's working memory and their ability to learn to categorize stimuli. While there is evidence that working memory capacity (WMC) is related to the speed of category learning, it is unknown whether WMC predicts which strategies people use when there are multiple possible solutions to a categorization problem. To explore the relationship between WMC, category learning, and categorization strategy use, 173 participants completed two categorization tasks and a battery of WMC tasks. WMC predicted the speed of category learning, but it did not predict which strategies participants chose to perform categorization. Thus, WMC does not predict which categorization strategies people use but it predicts how well they will use the strategy they select.
Reading strategy modulates parafoveal-on-foveal effects in sentence reading
Authors: Wotschack Christiane , Kliegl Reinhold
Published: October 2011

Task demands and individual differences have been linked reliably to word skipping during reading. Such differences in fixation probability may imply a selection effect for multivariate analyses of eye-movement corpora if selection effects correlate with word properties of skipped words. For example, with fewer fixations on short and highly frequent words the power to detect parafoveal-on-foveal effects is reduced. We demonstrate that increasing the fixation probability on function words with a manipulation of the expected difficulty and frequency of questions reduces an age difference in skipping probability (i.e., old adults become comparable to young adults) and helps to uncover significant parafoveal-on-foveal effects in this group of old adults. We discuss implications for the comparison of results of eye-movement research based on multivariate analysis of corpus data with those from display-contingent manipulations of target words.
Class III PI-3-kinase activates phospholipase D in an amino acid–sensing mTORC1 pathway
Authors: Yoon Mee-Sup , Du Guangwei , Backer Jonathan M. , Frohman Michael A. , Chen Jie
Published: October 2011

The rapamycin-sensitive mammalian target of rapamycin (mTOR) complex, mTORC1, regulates cell growth in response to mitogenic signals and amino acid availability. Phospholipase D (PLD) and its product, phosphatidic acid, have been established as mediators of mitogenic activation of mTORC1. In this study, we identify a novel role for PLD1 in an amino acid–sensing pathway. We find that amino acids activate PLD1 and that PLD1 is indispensable for amino acid activation of mTORC1. Activation of PLD1 by amino acids requires the class III phosphatidylinositol 3-kinase hVps34, which stimulates PLD1 activity through a functional interaction between phosphatidylinositol 3-phosphate and the Phox homology (PX) domain of PLD1. Furthermore, amino acids stimulate PLD1 translocation to the lysosomal region where mTORC1 activation occurs in an hVps34-dependent manner, and this translocation is necessary for mTORC1 activation. The PX domain is required for PLD1 translocation, mTORC1 activation, and cell size regulation. Finally, we show that the hVps34-PLD1 pathway acts independently of, and in parallel to, the Rag pathway in regulating amino acid activation of mTORC1.
Fraudulent Democracy? An Analysis of Argentina'sInfamous DecadeUsing Supervised Machine Learning
Authors: Cantú Francisco , Saiegh Sebastián M.
Published: October 2011

In this paper, we introduce an innovative method to diagnose electoral fraud using vote counts. Specifically, we use synthetic data to develop and train a fraud detection prototype. We employ a naive Bayes classifier as our learning algorithm and rely on digital analysis to identify the features that are most informative about class distinctions. To evaluate the detection capability of the classifier, we use authentic data drawn from a novel data set of district-level vote counts in the province of Buenos Aires (Argentina) between 1931 and 1941, a period with a checkered history of fraud. Our results corroborate the validity of our approach: The elections considered to be irregular (legitimate) by most historical accounts are unambiguously classified as fraudulent (clean) by thelearner. More generally, our findings demonstrate the feasibility of generating and using synthetic data for training and testing an electoral fraud detection system.
Beyond Fat Mass: Exploring the Role of Adipokines in Rheumatic Diseases
Authors: Scotece Morena , Conde Javier , Gómez Rodolfo , López Veronica , Lago Francisca , Gómez-Reino Juan Jesus , Gualillo Oreste
Published: October 2011

The cloning of leptin in 1994 by Zhang et al. introduced a novel concept about white adipose tissue (WAT) as a very dynamic organ that releases a plethora of immune and inflammatory mediators, such as adipokines and cytokines, which are involved in multiple diseases. Actually, adipokines exert potent modulatory actions on target tissues involved in rheumatic diseases including cartilage, synovial, bone and immune cells. The goal of this paper is to elucidate the recent findings concerning the involvement of adipokines in rheumatic diseases, such as rheumatoid arthritis (RA), osteoarthritis (OA), and systemic lupus erythematosus (SLE).
Scheduling of newly emerging drugs: a critical review of decisions over 40 years
Authors: Coulson Carolyn , Caulkins Jonathan P.
Published: October 2011

Aims  Decisions on whether and how to ‘schedule’ drugs (i.e. to determine their legal status and penalties to be applied for sale or possession) are often heavily criticized. We sought to assess more comprehensively the results of such decisions for newly emerging drugs.

Methods  Through analysis of legislation and secondary sources, we identified 63 substances that have emerged since 1971, including all that have been added to the most restrictive schedule by the United Nations, United States, United Kingdom, Canada, Australia and/or New Zealand.

Measurements  For each jurisdiction we recorded whether, when, and how the substance was scheduled and note what decisions engendered substantial criticism or controversy within the international treaties' framework of balancing medical benefits with risk of abuse.

Findings  (i) The rate of emergence of new drugs has been fairly steady. (ii) There is broad cross‐national agreement on what should be scheduled. (iii) The United States often acts first. (iv) Temporary bans that delay final decisions by 12–18 months can sometimes allow final decisions to be grounded on a substantially expanded research base. (v) It appears that no more than seven of the decisions reached by the United States with respect to the 63 substances are candidates for being considered errors, and arguably the United States has committed at most one serious Type I and one serious Type II error. Results for other countries are broadly similar.

Conclusions  The process for determining the legal status of new psychoactive substances appears to function reasonably well, within the framework of international treaty obligations. Most criticisms relate to one or a few substances (e.g. 3,4‐methylenedioxymethamphetamine) and/or complaints that the decisions discount benefits that are not recognized by the treaties (e.g. recreational or religious use).
IL‐12 and IL‐10 Production are Differentially Regulated by Phosphatidylinositol 3‐Kinase in Mast Cells
Authors: Song C. , Zhang Q. , Liu X. , Shan Y.
Published: October 2011

The cellular mechanisms that directly regulate the production of pro‐ and anti‐inflammatory cytokines after lipopolysaccharide (LPS) stimulation in mast cells are currently unresolved. The aim of this study was to clarify the role of phosphatidylinositol 3‐kinase (PI3K) in the production of IL‐12 and IL‐10 in mouse bone marrow‐derived mast cells (BMMCs), stimulated with Escherichia coli‐derived LPS. LPS activates the PI3K signalling pathway; analysis of cytokine production following LPS stimulation of BMMCs revealed that inhibition of the PI3K pathway differentially regulated IL‐10 and IL‐12 syntheses. IL‐12 production was enhanced, whereas IL‐10 levels were suppressed. Inhibition of LPS‐mediated activation of the PI3K pathway resulted in a pronounced reduction of NF‐κB activity that was dependent on IκBα phosphorylation. These findings demonstrate a regulatory function for PI3K in modulating IL‐10 and IL‐12 production in mast cells and provide insight into how engagement of the PI3K pathway affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of early inflammation.
Environmental heterogeneity influences the reliability of secondary sexual traits as condition indicators
Authors: VERGARA P. , MARTINEZ‐PADILLA J. , MOUGEOT F. , LECKIE F. , REDPATH S. M.
Published: October 2011

Numerous studies have shown positive associations between ornaments and condition, as predicted by indicator models of sexual selection. However, this idea is continuously challenged by opposite results, which reveal our lack of full understanding of how sexual selection works. Environmental heterogeneity may explain such inconsistencies, but valid field tests of this idea are currently lacking. We first analysed the relationship between condition and ornament expression from nine populations over 7 years in a wild bird, the red grouse Lagopus lagopus scoticus. We then manipulated male aggressiveness at the population level by means of testosterone implants in a replicated field experiment. We found that the relationship between condition and ornamentation varied greatly between environments and became stronger when environmental conditions (ECs) were worse or when aggressiveness in the population was experimentally increased. Some ornaments may therefore reliably advertise a better condition only in adverse ECs. Considering environmental heterogeneity can help reconcile conflicting findings regarding the reliability of ornaments as indicators of condition and will help our understanding of sexual selection processes.
The SNP Genotypes of Growth Hormone Gene Associated with Reproductive Traits in Tsaiya Ducks
Authors: Chang Mu‐Tzu , Cheng Yu‐Shin , Huang Mu‐Chiou
Published: October 2011

Contents

Our previous cDNA microarray study showed that the growth hormone (GH) gene may involve in the duck egg formation process. The purpose of this study was to investigate the relationship between GH genotypes of single nucleotide polymorphisms (SNPs) and reproductive traits of Tsaiya ducks. Primer pairs for the coding region in the GH were designed based on the duck genomic sequence. Polymorphisms were detected by polymerase chain reaction (PCR)‐single strand polymorphism (SSCP) and were verified by DNA sequencing. Nineteen SNPs were identified in the duck GH gene, of which three coding SNPs (C3169T, C3700T and C5058G) were genotyped to investigate the associations with reproductive traits. The results showed that each SNP was associated with at least one duck fertility‐related trait (p < 0.05). Haplotypes constructed on these three SNPs were associated with fertility rate (FR) and maximum duration of fertility (MDF) (p < 0.05). In particular, diplotype H1H1 was dominant for FR and MDF. This suggested that GH gene polymorphisms are associated with duck fertility‐related traits. The SNPs in this gene may be used as potential markers for marker‐assisted selection.
Relationship Between Apoptosis and Proliferation in Granulosa and Theca Cells of Cystic Follicles in Sows
Authors: Sun Y‐L , Zhang J , Ping Z‐G , Wang C‐Q , Sun Y‐F , Chen L , Li X‐Y , Li C‐J , Zhu X‐L , Liu Z , Zhang W , Zhou X
Published: October 2011

Contents

To investigate the causes of the occurrence and persistence of porcine cystic follicles, we evaluated the apoptosis and proliferation of follicular cells in these cysts. Apoptotic frequencies were examined by TUNEL assay and the expression of apoptosis regulators (XIAP, bax, bc1‐2 and caspase‐3) by immunohistochemistry, Western blotting and real‐time quantitative PCR; cell proliferation activity was evaluated by PCNA immunohistochemistry and proliferation of in vitro cultured granulosa and theca cells. The low apoptotic frequency and weak proliferative activity were found in cystic follicles. Low frequency of apoptosis might be associated with decreased amounts of apoptotic‐related factors (bax and caspase‐3) and increased amounts of anti‐apoptotic factors (XIAP and bcl‐2) in cystic follicles. Significantly lower proliferation activity was detected in granulosa and theca cells from cystic follicles, and lesser PCNA‐positive cells were found in cystic follicles. Our results indicate that the programmed cell death and cell proliferation system were altered in cystic follicles. The disorder between apoptosis and proliferation was responsible for maintaining a static condition without degeneration, which leads to the long‐term persistence of follicles. These findings provide important novel insights into the pathogenesis of follicular cysts in sows.
PERFORMING SUCCESS AND FAILURE IN GOVERNANCE: DUTCH PLANNING EXPERIENCES
Authors: VAN ASSCHE KRISTOF , BEUNEN RAOUL , DUINEVELD MARTIJN
Published: October 2011

We present an analytical framework for analyzing the functions of failure and success ascriptions in public administration. The framework incorporates concepts and insights from Michel Foucault, Mieke Bal, and other discourse theorists, enriched with notions derived from Niklas Luhmann's theory of social systems. The Dutch system of spatial planning serves as a context to investigate the rhetorical functions, performance, discursive configurations, and consequences of success and failure. Two cases nested in the Dutch context are used to elaborate on the performance and performativity of success and failure. We discuss the performance of success and failure in terms of productive competition between discourses and organizations, and emphasize the self‐reinforcing nature of success and failure ascriptions in the creation of developmental pathways of the governance system.
Trends in numbers of petrels attracted to artificial lights suggest population declines in Tenerife, Canary Islands
Authors: RODRÍGUEZ AIRAM , RODRÍGUEZ BENEHARO , LUCAS MATTHEW P.
Published: October 2011

The secretive breeding behaviour of petrels makes monitoring their breeding populations challenging. To assess population trends of Cory’s Shearwater Calonectris diomedea, Bulwer’s Petrel Bulweria bulwerii and Macaronesian Shearwater Puffinus baroli in Tenerife from 1990 to 2010, we used data from rescue campaigns that aim to reduce the mortality of fledgling petrels attracted to artificial lights as proxies for trends in breeding population size. Despite increases in human population size and light pollution, the number of rescued fledglings of Cory’s Shearwater and Bulwer’s Petrel increased and remained stable, respectively, whereas numbers of rescued Macaronesian Shearwaters sharply declined. In the absence of more accurate population estimates, these results suggest a worrying decline in the Macaronesian Shearwater’s breeding population.
Male Golden‐collared Manakins Manacus vitellinus do not adapt their courtship display to spatial alteration of their court
Authors: COCCON FRANCESCA , SCHLINGER BARNEY A. , FUSANI LEONIDA
Published: October 2011

Male Golden‐collared Manakins Manacus vitellinus perform an elaborate courtship display composed of acrobatic jumps between saplings delimiting a court on the forest floor. Males rehearse their displays for hours until they are executed with amazing precision and speed. Here we investigated the plasticity of the display by examining whether males modify their choreography in response to a disturbance, such as when a small branch is placed against one of the saplings. Male Manakins performed displays that were longer and lacked a key element that invites females to copulate, supporting the hypothesis that males learn a specific sequence of moves to build their choreography.
The RANKL‐OPG system in clinical periodontology
Authors: Belibasakis Georgios N. , Bostanci Nagihan
Published: October 2011

Background and Objectives

The receptor activator of NF‐κB ligand‐osteoprotegerin (RANKL‐OPG) bi‐molecular system is the “bottle‐neck” regulator of osteoclastogenesis and bone resorption, both in physiological and pathological conditions. This review aims to elaborate the current knowledge on RANKL and OPG in periodontal disease, and to evaluate their diagnostic and prognostic potential as biomarkers of the disease.

Materials and Methods

To pursue this aim, electronic and manual searches were performed for identifying clinical and in vivo studies on RANKL and OPG in gingival tissue, gingival crevicular fluid, saliva and blood. Smoking and diabetes mellitus were also considered for their potential effects.

Results

Papers fulfilling the inclusion criteria demonstrate that RANKL is up‐regulated, whereas OPG is down‐regulated in periodontitis, compared to periodontal health, resulting in an increased RANKL/OPG ratio. This ratio is further up‐regulated in smokers and diabetics, and is not affected by conventional periodontal treatment.

Conclusions

The increased RANKL/OPG ratio may serve as a biomarker that denotes the occurrence of periodontitis, but may not necessarily predict on‐going disease activity. Its steadily elevated levels post treatment may indicate that the molecular mechanisms of bone resorption are still active, holding an imminent risk for relapse of the disease. Additional adjunct treatment modalities that would “switch‐off” the RANKL/OPG ratio may therefore be required.
Price Ceilings on Milk Production Quota Values: Future or Folly?
Authors: Cairns Alex , Meilke Karl
Published: October 2011

Since the inception of supply management in Canada during the 1970s, milk production quota has been used to regulate output and participation in the dairy industry. In recent years, milk quota values have increased dramatically, almost tripling in value since the mid 1980s. This led to the Dairy Farmers of Ontario intervening on the milk production quota exchange on two occasions: first, in November 2006 with a progressive transfer assessment and then in July 2009, replacing the former policy with a firm price ceiling—fixing the unit price of quota at $25,000. These policies represent a significant redistribution of economic benefits from milk producers selling their quota to those remaining in the industry. The objective of this study is to first explore the reasons for the increase in production quota values; and second, to assess the welfare and distributional effects of each of the two quota policy schemes. Our results suggest that the increase in quota values were driven by basic economic factors and that the efficiency losses from intervention in the quota exchange are nontrivial. We conclude by suggesting there are several alternative policy options that could minimize efficiency losses while moderating the escalation in quota values.

Depuis la mise en place du système de gestion de l’offre au Canada dans les années 1970, les quotas laitiers sont utilisés pour régulariser la production et la participation dans l’industrie laitière. Au cours des dernières années, la valeur des quotas laitiers a fait un bond considérable et a pratiquement triplé depuis le milieu des années 1980. Cette situation a amené la Dairy Farmers of Ontario à intervenir à deux reprises dans le système d’échange de quotas laitiers : en novembre 2006, en imposant l’établissement d’un transfert progressif et en juillet 2009, en remplaçant la politique précédente par l’établissement d’un prix plafond ferme fixéà 25 000 $. Ces politiques permettent une importante redistribution des avantages économiques lorsque des producteurs de lait vendent leurs quotas à des producteurs qui demeurent dans le secteur. La présente étude visait d’abord à examiner les raisons qui sous‐tendent l’augmentation de la valeur des quotas de production et ensuite àévaluer le bien‐être et les effets distributifs de chaque plan de quotas. Les résultats de notre étude autorisent à penser que l’augmentation de la valeur des quotas a été motivée par des facteurs économiques fondamentaux et que les pertes d’efficacité découlant de l’intervention dans les échanges de quotas n’étaient pas sans importance. En conclusion, nous estimons qu’il existe plusieurs politiques de rechange qui pourraient minimiser les pertes d’efficacité tout en modérant l’escalade de la valeur des quotas.
Shaping a new Ca2+ conductance to suppress early afterdepolarizations in cardiac myocytes
Authors: Madhvani Roshni V. , Xie Yuanfang , Pantazis Antonios , Garfinkel Alan , Qu Zhilin , Weiss James N. , Olcese Riccardo
Published: October 2011

Non‐technical summary  Diseases, genetic defects, or ionic imbalances can alter the normal electrical activity of cardiac myocytes causing an anomalous heart rhythm, which can degenerate to ventricular fibrillation (VF) and sudden cardiac death. Well‐recognized triggers for VF are aberrations of the cardiac action potential, known as early afterdepolarizations (EADs). In this study, combining mathematical modelling and experimental electrophysiology in real‐time (dynamic clamp), we investigated the dependence of EADs on the biophysical properties of the L‐type Ca2+ current (ICa,L) and identified modifications of ICa,L properties which effectively suppress EAD. We found that minimal changes in the voltage dependence of activation or inactivation of ICa,L can dramatically reduce the occurrence of EADs in cardiac myocytes exposed to different EAD‐inducing conditions. This work assigns a critical role to the L‐type Ca2+ channel biophysical properties for EADs formation and identifies the L‐type Ca2+ channel as a promising therapeutic target to suppress EADs and their arrhythmogenic effects.
Exosomal transmission of functional aquaporin 2 in kidney cortical collecting duct cells
Authors: Street Jonathan M. , Birkhoff Willem , Menzies Robert I. , Webb David J. , Bailey Matthew A. , Dear James W.
Published: October 2011

Non‐technical summary  Like most cells, those of the kidney release protein and RNA in structures called exosomes. It is possible that the contents of exosomes released into the urine from one part of the kidney can alter the function of downstream cells. We have used a cell model to test whether exosomes act as cell‐to‐cell messengers within the kidney. First, cells were exposed to a hormone that regulates the body's retention of water. This increased the levels of water channels within the cells and also within their exosomes. Next, these exosomes were placed onto a separate batch of cells, which responded by increasing their transport of water. This study shows that exosomes are a new mechanism for the transfer of physiological information within the kidney.
Resilience-Driven System Design of Complex Engineered Systems
Authors: Youn Byeng D. , Hu Chao , Wang Pingfeng
Published: October 2011

Most engineered systems are designed with a passive and fixed design capacity and, therefore, may become unreliable in the presence of adverse events. Currently, most engineered systems are designed with system redundancies to ensure required system reliability under adverse events. However, a high level of system redundancy increases a system’s life-cycle cost (LCC). Recently, proactive maintenance decisions have been enabled through the development of prognostics and health management (PHM) methods that detect, diagnose, and predict the effects of adverse events. Capitalizing on PHM technology at an early design stage can transform passively reliable (or vulnerable) systems into adaptively reliable (or resilient) systems while considerably reducing their LCC. In this paper, we propose a resilience-driven system design (RDSD) framework with the goal of designing complex engineered systems with resilience characteristics. This design framework is composed of three hierarchical tasks: (i) the resilience allocation problem (RAP) as a top-level design problem to define a resilience measure as a function of reliability and PHM efficiency in an engineering context, (ii) the system reliability-based design optimization (RBDO) as the first bottom-level design problem for the detailed design of components, and (iii) the system PHM design as the second bottom-level design problem for the detailed design of PHM units. The proposed RDSD framework is demonstrated using a simplified aircraft control actuator design problem resulting in a highly resilient actuator with optimized reliability, PHM efficiency and redundancy for the given parameter settings.
In Vitro
Resistance Profile of the Hepatitis C Virus NS3 Protease Inhibitor BI 201335
Authors: Lagacé Lisette , White Peter W. , Bousquet Christiane , Dansereau Nathalie , Dô Florence , Llinas-Brunet Montse , Marquis Martin , Massariol Marie-Josée , Maurice Roger , Spickler Catherine , Thibeault Diane , Triki Ibtissem , Zhao Songping , Kukolj George
Published: October 2011

The
in vitro
resistance profile of BI 201335 was evaluated through selection and characterization of variants in genotype 1a (GT 1a) and genotype 1b (GT 1b) replicons. NS3 R155K and D168V were the most frequently observed resistant variants. Phenotypic characterization of the mutants revealed shifts in sensitivity specific to BI 201335 that did not alter susceptibility to alpha interferon. In contrast to macrocyclic and covalent protease inhibitors, changes at V36, T54, F43, and Q80 did not confer resistance to BI 201335.
MmpL3 Is the Cellular Target of the Antitubercular Pyrrole Derivative BM212
Authors: La Rosa Valentina , Poce Giovanna , Canseco Julio Ortiz , Buroni Silvia , Pasca Maria Rosalia , Biava Mariangela , Raju Ravikiran M. , Porretta Giulio Cesare , Alfonso Salvatore , Battilocchio Claudio , Javid Babak , Sorrentino Flavia , Ioerger Thomas R. , Sacchettini James C. , Manetti Fabrizio , Botta Maurizio , De Logu Alessandro , Rubin Eric J. , De Rossi Edda
Published: October 2011

The 1,5-diarylpyrrole derivative BM212 was previously shown to be active against multidrug-resistant clinical isolates and
Mycobacterium tuberculosis
residing within macrophages as well as against
Mycobacterium avium
and other atypical mycobacteria. To determine its mechanism of action, we identified the cellular target. Spontaneous
Mycobacterium smegmatis
,
Mycobacterium bovis
BCG, and
M. tuberculosis
H37Rv mutants that were resistant to BM212 were isolated. By the screening of genomic libraries and by whole-genome sequencing, we found that all the characterized mutants showed mutations in the
mmpL3
gene, allowing us to conclude that resistance to BM212 maps to the MmpL3 protein, a member of the MmpL (
m
ycobacterial
m
embrane
p
rotein,
l
arge) family. Susceptibility was unaffected by the efflux pump inhibitors reserpine, carbonylcyanide
m
-chlorophenylhydrazone, and verapamil. Uptake/efflux experiments with [
14
C]BM212 demonstrated that resistance is not driven by the efflux of BM212. Together, these data strongly suggest that the MmpL3 protein is the cellular target of BM212.
Enterobacterial Common Antigen Mutants of Salmonella enterica Serovar Typhimurium Establish a Persistent Infection and Provide Protection against Subsequent Lethal Challenge
Authors: Gilbreath Jeremy J. , Colvocoresses Dodds Jennifer , Rick Paul D. , Soloski Mark J. , Merrell D. Scott , Metcalf Eleanor S.
Published: October 2011

Infection withSalmonellaspp. is a significant source of disease globally. A substantial proportion of these infections are caused bySalmonella entericaserovar Typhimurium. Here, we characterize the role of the enterobacterial common antigen (ECA), a surface glycolipid ubiquitous among enteric bacteria, inS.Typhimurium pathogenesis. Construction of a defined mutation in the UDP-N-acetylglucosamine-1-phosphate transferase gene,wecA, in two clinically relevant strains ofS.Typhimurium, TML and SL1344, resulted in strains that were unable to produce ECA. Loss of ECA did not affect the gross cell surface ultrastructure, production of lipopolysaccharide (LPS), flagella, or motility. However, thewecAmutant strains were attenuated in both oral and intraperitoneal mouse models of infection (P< 0.001 for both routes of infection; log rank test), and virulence could be restored by complementation of thewecAgene intrans. Despite the avirulence of the ECA-deficient strains, thewecAmutant strains were able to persistently colonize systemic sites (spleen and liver) at moderate levels for up to 70 days postinfection. Moreover, immunization with thewecAmutant strains provided protection against a subsequent lethal oral or intraperitoneal challenge with wild-typeS.Typhimurium. Thus,wecAmutant (ECA-negative) strains ofSalmonellamay be useful as live attenuated vaccine strains or as vehicles for heterologous antigen expression.
Role of Toll Interleukin-1 Receptor (IL-1R) 8, a Negative Regulator of IL-1R/Toll-Like Receptor Signaling, in Resistance to Acute Pseudomonas aeruginosa Lung Infection
Authors: Véliz Rodriguez Tania , Moalli Federica , Polentarutti Nadia , Paroni Moira , Bonavita Eduardo , Anselmo Achille , Nebuloni Manuela , Mantero Stefano , Jaillon Sébastien , Bragonzi Alessandra , Mantovani Alberto , Riva Federica , Garlanda Cecilia
Published: October 2011

Toll interleukin-1 receptor (IL-1R) 8 (TIR8), also known as single Ig IL-1 receptor (IL-R)-related molecule, or SIGIRR, is a member of the IL-1R-like family, primarily expressed by epithelial cells. Current evidence suggests that TIR8 plays a nonredundant role as a negative regulatorin vivounder different inflammatory conditions that are dependent on IL-R and Toll-like receptor (TLR) activation. In the present study, we examined the role of TIR8 in innate resistance to acute lung infections caused byPseudomonas aeruginosa, a Gram-negative pathogen responsible for life-threatening infections in immunocompromised individuals and cystic fibrosis patients. We show that Tir8 deficiency in mice was associated with increased susceptibility to acuteP. aeruginosainfection, in terms of mortality and bacterial load, and to exacerbated local and systemic production of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], IL-1β, and IL-6) and chemokines (CXCL1, CXCL2, and CCL2). It has been reported that host defense againstP. aeruginosaacute lung infection can be improved by blocking IL-1 since exaggerated IL-1β production may be harmful for the host in this infection. In agreement with these data, IL-1RI deficiency rescues the phenotype observed in Tir8-deficient mice: in Tir8−/−IL-1RI−/−double knockout mice we observed higher survival rates, enhanced bacterial clearance, and reduced levels of local and systemic cytokine and chemokine levels than in Tir8-deficient mice. These results suggest that TIR8 has a nonredundant effect in modulating the inflammation caused byP. aeruginosa, in particular, by negatively regulating IL-1RI signaling, which plays a major role in the pathogenesis of this infectious disease.
Two Zinc Uptake Systems Contribute to the Full Virulence of Listeria monocytogenes during Growth
In Vitro
and
In Vivo
Authors: Corbett David , Wang Jiahui , Schuler Stephanie , Lopez-Castejon Gloria , Glenn Sarah , Brough David , Andrew Peter W. , Cavet Jennifer S. , Roberts Ian S.
Published: October 2011

We report here the identification and characterization of two zinc uptake systems, ZurAM and ZinABC, in the intracellular pathogen
Listeria monocytogenes
. Transcription of both operons was zinc responsive and regulated by the zinc-sensing repressor Zur. Deletion of either
zurAM
or
zinA
had no detectable effect on growth in defined media, but a double
zurAM zinA
mutant was unable to grow in the absence of zinc supplementation. Deletion of
zinA
had no detectable effect on intracellular growth in HeLa epithelial cells. In contrast, growth of the
zurAM
mutant was significantly impaired in these cells, indicating the importance of the ZurAM system during intracellular growth. Notably, the deletion of both
zinA
and
zurAM
severely attenuated intracellular growth, with the double mutant being defective in actin-based motility and unable to spread from cell to cell. Deletion of either
zurAM
or
zinA
had a significant effect on virulence in an oral mouse model, indicating that both zinc uptake systems are important
in vivo
and establishing the importance of zinc acquisition during infection by
L. monocytogenes
. The presence of two zinc uptake systems may offer a mechanism by which
L. monocytogenes
can respond to zinc deficiency within a variety of environments and during different stages of infection, with each system making distinct contributions under different stress conditions.
Equity Ownership Determination in Foreign Direct Investments of Developing Economies: The Case of Korean Outward FDIs
Authors: Bae Sung C. , Ju Kyungwon , Kim Kyoo H. , Kwon Taek Ho
Published: October 2011

In this paper, we develop an international joint venture model and examine the equity ownership determination of Korean outward FDIs, one of the major developing economies (DEs), into both developed countries (DCs) and other DEs. We do this by explicitly considering the cost of technology leakage and the potential profits from FDI projects. Our results show that the relation between equity ownership and technology level depends on both the host country and industry sector. Regarding the host country, this relation is positive for FDIs into DEs but negative for FDIs into DCs. Regarding industry, this relation is positive and insignificant for the manufacturing sector but negative and significant for the nonmanufacturing sector. Combined together, these results indicate that Korean firms benefit most from competitive advantages through their FDIs into the manufacturing sector of DEs. In contrast, such competitive advantages of Korean firms diminish in their FDIs into DCs regardless of the industry sector.
New Insights on the Implied and Realized Volatility Relation
Authors: Blenman Lloyd P. , Wang Guan Jun
Published: October 2011

Existing studies on the informational content of at-the-money implied volatility (ATMIV) and past realized volatility (PRV) and the relation between the two have mainly focused on a single short forecast horizon and conclude that ATMIV outperforms PRV. We examine the relation between implied and realized volatility over both short and longer forecasting horizons to provide a forecasting competition. We analytically demonstrate the option maturity effect on the sensitivity of the implied volatility (IV) estimation. As time to maturity increases, vega increases but at a decreasing rate, up to [Formula: see text]. At shorter (longer) maturities, small pricing changes should have greater (smaller) corrective impact on IVs. We find that IV outperforms PRV over a one month forecast horizon. However, as the forecast horizon increases, PRV outperforms IV and subsumes the information contained in it. These mixed results may be attributed to the reduced efficiency of longer dated sections of the S&P 500 options index market we analyze.
Interactive surface modeling using modal analysis
Authors: Hildebrandt Klaus , Schulz Christian , Tycowicz Christoph Von , Polthier Konrad
Published: October 2011

We propose a framework for deformation-based surface modeling that is interactive, robust, and intuitive to use. The deformations are described by a nonlinear optimization problem that models static states of elastic shapes under external forces which implement the user input. Interactive response is achieved by a combination of model reduction, a robust energy approximation, and an efficient quasi-Newton solver. Motivated by the observation that a typical modeling session requires only a fraction of the full shape space of the underlying model, we use second and third derivatives of a deformation energy to construct a low-dimensional shape space that forms the feasible set for the optimization. Based on mesh coarsening, we propose an energy approximation scheme with adjustable approximation quality. The quasi-Newton solver guarantees superlinear convergence without the need of costly Hessian evaluations during modeling. We demonstrate the effectiveness of the approach on different examples including the test suite introduced in Sorkine [2008].
Efficient Search Engine Measurements
Authors: Bar-Yossef Ziv , Gurevich Maxim
Published: October 2011

We address the problem of externally measuring aggregate functions over documents indexed by search engines, like corpus size, index freshness, and density of duplicates in the corpus. State of the art estimators for such quantities [Bar-Yossef and Gurevich 2008b; Broder et al. 2006] are biased due to inaccurate approximation of the so called “document degrees”. In addition, the estimators in Bar-Yossef and Gurevich [2008b] are quite costly, due to their reliance on rejection sampling.

We present new estimators that are able to overcome the bias introduced by approximate degrees. Our estimators are based on a careful implementation of an approximate importance sampling procedure. Comprehensive theoretical and empirical analysis of the estimators demonstrates that they have essentially no bias even in situations where document degrees are poorly approximated.

By avoiding the costly rejection sampling approach, our new importance sampling estimators are significantly more efficient than the estimators proposed in Bar-Yossef and Gurevich [2008b]. Furthermore, building on an idea from Broder et al. [2006], we discuss
Rao-Blackwellization
as a generic method for reducing variance in search engine estimators. We show that Rao-Blackwellizing our estimators results in performance improvements, without compromising accuracy.