bluuebunny/crossref_metadata_2025 huggingface dataset:
BASIC EQUALITY AND THE SITE OF EGALITARIAN JUSTICE
Authors: Carter Ian
Published: April 2013

The nature of basic equality (what it is that makes us all equals) can have implications not only for the question of the currency of egalitarian justice but also for that of its ‘site’. The latter question is raised by G. A. Cohen in his critique of John Rawls's theory of justice. In this paper I argue that Rawlsian liberals might provide an answer to Cohen's critique by establishing two distinct kinds of basic equality, thus providing a ‘twofold account’ of basic equality. A first kind of basic equality gains moral relevance in the context of respectful relations between individuals, and establishes egalitarian duties between them. A second kind of basic equality gains moral relevance in the context of respectful relations between the state and individual citizens, and establishes egalitarian duties of the state toward citizens. The strength of Cohen's critique depends, in part, on the fact that Rawls identified only one kind of basic equality while at the same time wishing to defend a dualist account of individual and state duties.
NATIONAL GUIDELINES FOR HIGH-COST DRUGS IN BRAZIL: ACHIEVEMENTS AND CONSTRAINTS OF AN INNOVATIVE NATIONAL EVIDENCE-BASED PUBLIC HEALTH POLICY
Authors: Picon Paulo D. , Beltrame Alberto , Banta David
Published: April 2013

Introduction: The translation of best evidence into practice has become an important purpose of policy making in health care. In Brazil, a country of continental dimensions with widespread regional and social inequalities, the dissemination and use of the best-evidence in policy making is a critical issue for the healthcare system.

Objectives: The main purpose of this study is to describe an evidence-based public health policy with special emphasis on guidelines creation for high-cost medicines. We also describe how that strategy was diffused to the judiciary system and to other parts of the healthcare system.

Results: We present an 11-year follow-up of a national project for creating and updating guidelines for high-cost medicines in Brazil. A total of 109 national guidelines were published (new or updated versions) for 66 selected diseases, the first such effort in Brazilian history. The project influenced the Brazilian legislature, which has recently established a Federal Law requiring national guidelines for any new technology listed for payment by the Brazilian public healthcare system.

Conclusion: We were able to involve many different stakeholders in a partnership between academia and policy makers, which made possible the widespread dissemination of the clinical practice guidelines. Problems and constraints were also encountered. This evolving public health strategy might be useful for other developing countries.
ASSESSING THE INTERNATIONAL USE OF HEALTH TECHNOLOGY ASSESSMENTS: EXPLORING THE MERITS OF DIFFERENT METHODS WHEN APPLIED TO THE NATIONAL INSTITUTE OF HEALTH RESEARCH HEALTH TECHNOLOGY ASSESSMENT (NIHR HTA) PROGRAMME
Authors: Wright David , Milne Ruairidh , Price Alison , Tose Nicola
Published: April 2013

Objectives: This study presents findings from a study that explores the merits of different methods for assessing the international use of UK funded research by the National Institute of Health Research Health Technology Assessment (NIHR HTA) Programme.

Methods: The study adopted an exploratory approach and used three core methods: (i) Academic use was explored through bibliometric and citation analysis of the top ten most cited health technology assessment (HTA) reports. (ii) Internet use was assessed using Webtrends software to identify the proportion of international visits of the top ten most downloaded HTA reports from January 1, 2004 to June 30, 2010. (iii) International HTA use was assessed by searching the Center for Reviews and Dissemination (CRD) HTA database to explore the citation of NIHR HTA reports in reports by non-UK HTA agencies.

Results: Bibliometric analysis identified published output and international citations with 41 percent of the 549 journals citing NIHR HTA reports being based in the United States. Nine of ten most downloaded reports from the NIHR HTA Web site (www.hta.ac.uk) had in excess of 50 percent of visits outside the United Kingdom. Four of five selected NIHR HTA reports were cited in twenty-eight other HTA reports, eighteen of these outside the United Kingdom.

Conclusions: Assessing international use is important when exploring the uptake of research evidence. Methods used in identifying research impact, such as bibliometrics and Webtrends, are helpful in generating evidence of international use. HTA agencies should consider these techniques and international use when assessing the uptake of findings from research they undertake and/or commission.
COST-EFFECTIVENESS ANALYSIS OF CARDIAC RESYNCHRONIZATION THERAPY IN PATIENTS WITH NYHA I AND NYHA II HEART FAILURE IN SPAIN
Authors: Almenar Luis , Díaz Beatriz , Quesada Aurelio , Crespo Carlos , Martí Belén , Mealing Stuart , Linde Cecilia , Daubert Claude
Published: April 2013

Objectives: The aim of the study was to combine clinical results from the European Cohort of the REVERSE study and costs associated with the addition of cardiac resynchronization therapy (CRT) to optimal medical therapy (OMT) in patients with mild symptomatic (NYHA I-II) or asymptomatic left ventricular dysfunction and markers of cardiac dyssynchrony in Spain.

Methods: A Markov model was developed with CRT + OMT (CRT-ON) versus OMT only (CRT-OFF) based on a retrospective cost-effectiveness analysis. Raw data was derived from literature and expert opinion, reflecting clinical and economic consequences of patient's management in Spain. Time horizon was 10 years. Both costs (euro 2010) and effects were discounted at 3 percent per annum.

Results: CRT-ON showed higher total costs than CRT-OFF; however, CRT reduced the length of hospitalization in ICU by 94 percent (0.006 versus 0.091 days) and general ward in by 34 percent (0.705 versus 1.076 days). Surviving CRT-ON patients (88.2 percent versus 77.5 percent) remained in better functional class longer, and they achieved an improvement of 0.9 life years (LYGs) and 0.77 years quality-adjusted life years (QALYs). CRT-ON proved to be cost-effective after 6 years, except for the 7th year due to battery depletion. At 10 years, the results were €18,431 per LYG and €21,500 per QALY gained. Probabilistic sensitivity analysis showed CRT-ON was cost-effective in 75.4 percent of the cases at 10 years.

Conclusions: The use of CRT added to OMT represents an efficient use of resources in patients suffering from heart failure in NYHA functional classes I and II.
Time-reversal algorithms in viscoelastic media
Authors: AMMARI HABIB , BRETIN ELIE , GARNIER JOSSELIN , WAHAB ABDUL
Published: April 2013

In this paper we consider the problem of reconstructing sources in a homogeneous viscoelastic medium from wavefield measurements. We first present a modified time-reversal imaging algorithm based on a weighted Helmholtz decomposition and justify mathematically that it provides a better approximation than by simply time reversing the displacement field, where artifacts appear due to the coupling between the pressure and shear waves. Then we investigate the source inverse problem in an elastic attenuating medium. We provide a regularized time-reversal imaging which corrects the attenuation effect at the first order. The results of this paper yield the fundamental tools for solving imaging problems in elastic media using cross-correlation techniques.
A review of brief cognitive assessment tests
Authors: Slater Helen , Young John
Published: April 2013

There is a rising prevalence of dementia in line with the continuing demographic transition. More timely diagnosis of dementia is recommended. Brief cognitive tests are useful as they provide a rapid assessment that can indicate the possibility of dementia and identify people for detailed cognitive assessment. Many brief cognitive tests have been developed and practitioners need information in order to select a test that performs well, is acceptable to patients, and is suitable for the relevant care setting. In a structured review, we identified twelve brief cognitive impairment tests, of which six have been sufficiently studied and can be recommended for use in routine care.
Conservation of Iberian Black Storks Ciconia nigra outside breeding areas: distribution, movements and mortality
Authors: CANO LUIS SANTIAGO , FRANCO CLÁUDIA , DOVAL GUILLERMO , TORÉS ALEJANDRO , CARBONELL ISIDORO , TELLERÍA JOSÉ LUIS
Published: April 2013

Seven out of ten Black Stork chicks fitted with satellite tags successfully made the journey from Iberia to the Sahel. Four died there during their first winter and one additional bird in the second winter. Our results show that 30% of the tagged fledglings died in Iberia and 50% (5/10) in the Sahel. In the Sahel, Black Storks occupy areas of seasonal rivers and small bodies of water in these sub-Saharan savannas, where they track suitable sites according to the progressive drying of the Sahel after the summer monsoon. This behaviour may make them more susceptible to coming into contact with humans and, consequently, current and future action plans for conserving the Iberian Black Stork population should link efforts with AEWA's Strategic Plan and other international initiatives to promote the global use of water resources for humans and wildlife in the Sahel.
Social Competence at 6 Months Following Childhood Traumatic Brain Injury
Authors: Anderson Vicki , Beauchamp Miriam H. , Yeates Keith Owen , Crossley Louise , Hearps Stephen J.C. , Catroppa Cathy
Published: April 2013

Children with traumatic brain injury (TBI) are at risk for social impairment. This study aimed to examine social function at 6 months post-TBI and to explore the contribution of injury, cognitive, and environmental influences. The sample included 136 children, 93 survivors of TBI, and 43 healthy controls. TBI participants were recruited on admission and underwent magnetic resonance imaging scan within 8 weeks of injury and behavioral assessment at 6 months post-injury. Healthy controls underwent magnetic resonance imaging scansand behavioral assessment on recruitment. Assessment included parent and child questionnaires tapping social outcome and child-direct testing of cognitive abilities important for social competence (communication, attention/executive function, social cognition). Injury characteristics and environmental measures were collected. At 6-months post-injury, social problems were evident, but not global. Social participation appeared most vulnerable, with more severe injuries leading to greater problems. Greater injury severity and poorer communication skills were associated with poorer social adjustment and social participation, with the impact of family function also significant. Processing speed, younger age, and male gender also contributed to social outcomes. Further follow-up is required to track the recovery of social skills and the changing influences of cognition, brain, and environment over time. (JINS, 2013,19, 1–12)
Are Empirically-Derived Subtypes of Mild Cognitive Impairment Consistent with Conventional Subtypes?
Authors: Clark Lindsay R. , Delano-Wood Lisa , Libon David J. , McDonald Carrie R. , Nation Daniel A. , Bangen Katherine J. , Jak Amy J. , Au Rhoda , Salmon David P. , Bondi Mark W.
Published: April 2013

Given the importance of identifying dementia prodromes for future treatment efforts, we examined two methods of diagnosing mild cognitive impairment (MCI) and determined whether empirically-derived MCI subtypes of these diagnostic methods were consistent with one another as well as with conventional MCI subtypes (i.e., amnestic, non-amnestic, single-domain, multi-domain). Participants were diagnosed with MCI using either conventional Petersen/Winblad criteria (n = 134; >1.5 SDs below normal on one test within a cognitive domain) or comprehensive neuropsychological criteria developed by Jak et al. (2009) (n = 80; >1 SD below normal on two tests within a domain), and the resulting samples were examined via hierarchical cluster and discriminant function analyses. Results showed that neuropsychological profiles varied depending on the criteria used to define MCI. Both criteria revealed an Amnestic subtype, consistent with prodromal Alzheimer's disease (AD), and a Mixed subtype that may capture individuals in advanced stages of MCI. The comprehensive criteria uniquely yielded Dysexecutive and Visuospatial subtypes, whereas the conventional criteria produced a subtype that performed within normal limits, suggesting its susceptibility to false positive diagnostic errors. Whether these empirically-derived MCI subtypes correspond to dissociable neuropathologic substrates and represent reliable prodromes of dementia will require additional follow-up. (JINS, 2013, 19, 1–11)
Science Friction: Phenomenology, Naturalism and Cognitive Science
Authors: Wheeler Michael
Published: April 2013

Recent years have seen growing evidence of a fruitful engagement between phenomenology and cognitive science. This paper confronts an in-principle problem that stands in the way of this (perhaps unlikely) intellectual coalition, namely the fact that a tension exists between the transcendentalism that characterizes phenomenology and the naturalism that accompanies cognitive science. After articulating the general shape of this tension, I respond as follows. First, I argue that, if we view things through a kind of neo-McDowellian lens, we can open up a conceptual space in which phenomenology and cognitive science may exert productive constraints on each other. Second, I describe some examples of phenomenological cognitive science that illustrate such constraints in action. Third, I use the mutually constraining relationship at work here as the platform from which to bring to light a domesticated version of the transcendental and a minimal form of naturalism that are compatible with each other.
Naturalism, Objectivism and Everyday Life
Authors: Dorfman Eran
Published: April 2013

In this paper I analyse the role of naturalism and objectivism in everyday life according to Husserl and Merleau-Ponty. Whereas Husserl attributes the naturalistic attitude mainly to science, he defines the objectivist attitude as a naiveté which equally applies to the natural attitude of everyday life. I analyse the relationship between the natural attitude and lived experience and show Husserl's hesitation regarding the task of phenomenology in describing the lived experience of everyday life, since he considers this experience to be too objectivistic. I use Merleau-Ponty's work to argue that objectivism is an essential characteristic of lived experience and that phenomenology should therefore find ways to integrate it into its descriptions while simultaneously suggesting ways to overcome its rigidity in order to renew perception. I finally propose that the project of the naturalisation of phenomenology could be one of the ways to connect lived experience to the objectivism of everyday life.
Naturalistic and Phenomenological Theories of Health: Distinctions and Connections
Authors: Svenaeus Fredrik
Published: April 2013

In this paper I present and compare the ideas behind naturalistic theories of health on the one hand and phenomenological theories of health on the other. The basic difference between the two sets of theories is no doubt that whereas naturalistic theories claim to rest on value neutral concepts, such as normal biological function, the phenomenological suggestions for theories of health take their starting point in what is often named intentionality: meaningful stances taken by the embodied person in experiencing and understanding her situation and taking action in the world.

Although naturalism and phenomenology are fundamentally different in their approach to health, they are not necessarily opposed when it comes to understanding the predicament of ill persons. The starting point of medical investigations is what the patient feels and says about her illness and the phenomenological investigation should include the way diagnoses of different diseases are interpreted by the person experiencing the diseases as an embodied being. Furthermore, the two theories display similarities in their emphasis of embodiment as the central element of health theory and in their stress on the alien nature of the body displayed in illness. Theories of biology and phenomenology are, indeed, compatible and in many cases also mutually supportive in the realm of health and illness.
LABOR MARKET VOLATILITY, SKILLS, AND FINANCIAL GLOBALIZATION
Authors: Buch Claudia M. , Pierdzioch Christian
Published: April 2013

We analyze the impact of financial globalization on volatilities of hours worked and wages of high-skilled and low-skilled workers. Using cross-country, industry-level data for the years 1970–2004, we establish stylized facts that document how volatilities of hours worked and wages of workers with different skill levels have changed over time. We then document that the volatility of hours worked by low-skilled workers has increased the most in response to the increase in financial globalization. We develop a dynamic stochastic general equilibrium model of a small open economy that is consistent with the empirical results. The model predicts that greater financial globalization increases the volatility of hours worked, and this effect is strongest for low-skilled workers.
PERSISTENT CATASTROPHIC SHOCKS AND EQUITY PREMIUMS: A NOTE
Authors: Saito Makoto , Suzuki Shiba
Published: April 2013

This note demonstrates analytically that a persistent catastrophic shock on endowment growth, even if moderate, yields negative equity premiums when a representative agent is relatively prudent. In particular, it derives the minimum persistence necessary to have zero equity premiums.
TASTE SHOCKS, ENDOGENOUS LABOR SUPPLY, AND EQUITY HOME BIAS
Authors: Feng Ling
Published: April 2013

The puzzling bias of equity portfolios toward domestic assets (equity home bias) remains substantial. This paper proposes a dynamic stochastic general equilibrium model and demonstrates that shocks to consumption tastes (taste shocks) are an effective explanation for the equity home bias puzzle. In the model, home assets provide insurance for home agents to hedge against domestic taste fluctuations, whereas such insurance cannot be offered by foreign assets. The empirical evidence shows that, in explaining equity home bias, hedging against consumption taste risks is more relevant than hedging against labor income risks or real exchange rate risks.
Augmentation of antipsychotic drug action by azapirone 5-HT1A receptor partial agonists: a meta-analysis
Authors: Kishi Taro , Meltzer Herbert Y. , Iwata Nakao
Published: April 2013

The aim of the study was to evaluate the evidence that serotonin1A (5-HT1A) receptor partial agonists of the azapirone class, which are not antipsychotic, have benefits for adjunctive treatment of overall psychopathology, positive and negative symptoms for patients with schizophrenia. We carried out a systematic review of the literature available through PubMed, Cochrane Library, PsycINFO and Google Scholar during September 2012, followed by a meta-analysis of randomized placebo-controlled trials. Risk ratio (RR), 95% confidence intervals (CI) and standardized mean difference (s.m.d.) were calculated. Four studies, involving 163 patients with schizophrenia, met inclusion criteria: buspirone: three trials and 137 patients; tandospirone: one trial and 26 patients. As adjunctive therapy, 5-HT1A partial agonists were significantly superior to placebo for overall improvement in psychopathology (s.m.d. = −0.46, CI = −0.79 to −0.13, p = 0.006, N = 4, n = 149) and marginally more effective to improve positive symptoms (s.m.d. = −0.31, CI = −0.64 to 0.01, p = 0.06, N = 4, n = 149). However, 5-HT1A partial agonists were not more efficacious than placebo as adjunctive therapy for improving negative symptoms (s.m.d. = −0.09, CI = −0.60 to 0.42, p = 0.72, N = 4, n = 149). In addition, there was no significant difference in discontinuation rates between 5-HT1A partial agonists and placebo (all cause: RR = 0.98, CI = 0.49–1.98, p = 0.96, N = 4, n = 153, side-effects: RR = 1.96, CI = 0.54–7.19, p = 0.31, N = 4, n = 153). 5-HT1A partial agonists as adjunctive therapy improved overall psychopathology with a trend to improve positive symptoms in patients with schizophrenia. Because the number of studies was small, additional controlled clinical trials with larger numbers of patients are indicated.
3D imaging by fast deconvolution algorithm in short-range UWB radar for concealed weapon detection
Authors: Savelyev Timofey , Yarovoy Alexander
Published: April 2013

A fast imaging algorithm for real-time use in short-range (ultra-wideband) radar with synthetic or real-array aperture is proposed. The reflected field is presented here as a convolution of the target reflectivity and point spread function (PSF) of the imaging system. To obtain a focused 3D image, the proposed algorithm deconvolves the PSF out from the acquired data volume with high speed due to fast Fourier transform and implementation in frequency-wavenumber domain. Then the result is tested against two numerical criteria for efficiency, namely error and instability, whose optimal values can be obtained iteratively. Since the PSF differs with distance, the algorithm suits mainly applications with relatively small objects such as concealed weapon detection. Using several PSFs allows us to image a certain range of interest by their successive deconvolution from the same data. Performance of the algorithm has been evaluated experimentally and compared with that of Kirchhoff migration. Measurements were carried out by a 5–25 GHz synthetic aperture radar in the lab, and scenarios included a gun and a ceramic knife in free space, on a large metal plate, and a gun concealed on a dummy under a thick raincoat. The results demonstrate sufficient image quality obtained in a fraction of time.
Association of Adiponectin Gene Polymorphism With Birth Weight in Korean Neonates
Authors: Kong Kyoung Ae , Suh Young Ju , Cho Su Jin , Park Eun Ae , Park Mi Hye , Kim Young Ju
Published: April 2013

Adiponectin has been associated with insulin resistance and type 2 diabetes mellitus and possibly fetal growth. Our aim was to assess the association between the single nucleotide polymorphisms (SNPs) of the adiponectin gene (ADIPOQ) and the birth sizes. We investigated four SNPs of ADIPOQ (rs182052, rs2241766, rs1501299, and rs266729) and birth height and weight in 237 healthy full-term neonates. The neonates with the rs182052 G allele had a greater birth weight (p = .043 in the dominant model) and a higher ponderal index (p = .028 in the additive model). The rs2241766 G allele was associated with a greater birth weight (p = .016 in the recessive model). In a logistic regression analysis, the homozygotes for the rs182052 G allele and those for the rs2241766 G allele showed a significant association with a greater birth weight above 90 percentile (OR 2.75, 95% CI 1.13–6.70 and OR 5.15, 95% CI 1.66–15.99, respectively). In conclusion, we found an association between rs182052 and rs2241766 and birth weight and ponderal index among healthy neonates and suggested that adiponectin might have some roles in fetal growth.
The Musical Stroop Effect
Authors: Grégoire Laurent , Perruchet Pierre , Poulin-Charronnat Bénédicte
Published: April 2013

The usual color-word Stroop task, as well as most other Stroop-like paradigms, has provided invaluable information on the automaticity of word reading. However, investigating automaticity through reading alone has inherent limitations. This study explored whether a Stroop-like effect could be obtained by replacing word reading with note naming in musicians. Note naming shares with word reading the crucial advantage of being intensively practiced over years by musicians, hence allowing to investigate levels of automatism that are out of reach of laboratory settings. But the situation provides much greater flexibility in manipulating practice. For instance, even though training in musical notation is often conducted in parallel with the acquisition of literacy skills during childhood, many exceptions make that it can be easily decoupled from age. Supporting the possibility of exploiting note naming as a new tool for investigating automatisms, musicians asked to process note names written inside note pictures in incongruent positions on a staff were significantly slowed down in both a go/no-go task (Experiment 1) and a verbal task (Experiment 2) with regard to a condition in which note names were printed inside note pictures in congruent positions.
Memory for Words Representing Modal Concepts
Authors: Vermeulen Nicolas , Chang Betty , Mermillod Martial , Pleyers Gordy , Corneille Olivier
Published: April 2013

The recent grounded cognition literature suggests that modal perception and conceptual representations share common modal systems and modal resources. We sought to show that memory and memory of words predominantly related to a visual modality (e.g., Light) or to an auditory modality (e.g., Song) are hindered more by sensory interference from a related than an unrelated modality. This result cannot be explained by semantic interference, because the present study manipulated interference using meaningless stimuli. Rather, we suggest that people spontaneously access conceptual sensory attributes when detecting words and when trying to memorize words, and that this process comes with modality-specific costs. We discuss this finding in the broader context of grounded cognition and compare it to previous findings using closely related sensory-conceptual designs.
Ionic Transporter Activity in Astrocytes, Microglia, and Oligodendrocytes During Brain Ischemia
Authors: Annunziato Lucio , Boscia Francesca , Pignataro Giuseppe
Published: April 2013

Glial cells constitute a large percentage of cells in the nervous system. During recent years, a large number of studies have critically attributed to glia a new role which no longer reflects the long-held view that glia constitute solely a silent and passive supportive scaffolding for brain cells. Indeed, it has been hypothesized that glia, partnering neurons, have a much more actively participating role in brain function. Alteration of intraglial ionic homeostasis in response to ischemic injury has a crucial role in inducing and maintaining glial responses in the ischemic brain. Therefore, glial transporters as potential candidates in stroke intervention are becoming promising targets to enhance an effective and additional therapy for brain ischemia. In this review, we will describe in detail the role played by ionic transporters in influencing astrocyte, microglia, and oligodendrocyte activity and the implications that these transporters have in the progression of ischemic lesion.
Genetic Elimination of eNOS Reduces Secondary Complications of Experimental Subarachnoid Hemorrhage
Authors: Sabri Mohammed , Ai Jinglu , Lass Elliot , D'abbondanza Josephine , Macdonald R Loch
Published: April 2013

Delayed complications of subarachnoid hemorrhage (SAH) such as angiographic vasospasm, cortical spreading ischemia, microcirculatory dysfunction, and microthrombosis are reported in both patients and animal models of SAH. We demonstrated previously that SAH is associated with increased oxidative stress in the brain parenchyma, and that this correlates with dysfunction of endothelial nitric oxide synthase (eNOS) (homodimeric uncoupling). Uncoupling of eNOS exacerbated oxidative stress and enhanced nitric oxide (NO) depletion, and was associated with multiple secondary complications such as microthrombosis, neuronal apoptosis, and release of reactive oxygen species. Thus, we hypothesized that genetic abbrogation of eNOS would confer a beneficial effect on the brain after SAH. Using a prechiasmatic injection model of SAH, we show here that eNOS knockout (KO) significantly alleviates vasospasm of the middle cerebral artery and reduces superoxide production. Endothelial nitric oxide synthase KO also affected other nitric oxide synthase isoforms. It significantly increases neuron nitric oxide synthase expression but has no effect on inducible nitric oxide synthase. Endothelial nitric oxide synthase KO decreases Zn2+ release after SAH, reduces microthrombi formation, and prevent neuronal degeneration. This work is consistent with our findings where, after SAH, increased oxidative stress can uncouple eNOS via Zn2+ thiolate oxidation, or theoretically by depletion or oxidation of tetrahydrobiopterin, resulting in a paradoxical release of superoxide anion radical, further exacerbating oxidative stress and microvascular damage.
A Quantitative System Pharmacology Computer Model for Cognitive Deficits in Schizophrenia
Authors: Geerts H , Roberts P , Spiros A
Published: April 2013

Although the positive symptoms of schizophrenia are reasonably well‐controlled by current antipsychotics, cognitive impairment remains largely unaddressed. The Matrics initiative lays out a regulatory path forward and a number of targets have been tested in the clinic, so far without much success. To address this translational disconnect, we have developed a mechanism‐based humanized computer model of a relevant key cortical brain network with schizophrenia pathology involved with the maintenance aspect of working memory (WM). The model is calibrated using published clinical experiments on N‐back WM tests. We further simulate the opposite effect of γ‐aminobutyric acid (GABA) modulators lorazepam and flumazenil and of a published augmentation trial of clozapine with risperidone, illustrating the introduction of new targets and the capacity of predicting the effects of polypharmacy. This humanized approach allows for early prospective and quantitative assessment of cognitive outcome in a central nervous system (CNS) research and development project, thereby hopefully increasing the success rate of clinical trials.

CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e36; doi:10.1038/psp.2013.12; advance online publication 3 April 2013
The distribution and functional properties of Pelizaeus–Merzbacher-like disease-linked Cx47 mutations on Cx47/Cx47 homotypic and Cx47/Cx43 heterotypic gap junctions
Authors: Kim Mi Seong , Gloor Gregory B. , Bai Donglin
Published: April 2013

GJs (gap junctions) allow direct intercellular communication, and consist of Cxs (connexins). In the mammalian central nervous system, oligodendrocytes express Cx47, Cx32 and Cx29, whereas astrocytes express Cx43, Cx30 and Cx26. Homotypic Cx47/Cx47 GJs couple oligodendrocytes, and heterotypic Cx47/Cx43 channels are the primary GJs at oligodendrocyte/astrocyte junctions. Interestingly, autosomal recessive mutations in the gene GJC2 encoding Cx47 have been linked to a central hypomyelinating disease termed PMLD (Pelizaeus–Merzbacher-like disease). The aim of the present study was to determine the cellular distribution and functional properties of PMLD-associated Cx47 mutants (I46M, G149S, G236R, G236S, M286T and T398I). Expressing GFP (green fluorescent protein)-tagged mutant versions of Cx47 in gap-junction-deficient model cells revealed that these mutants were detected at the cell–cell interface similar to that observed for wild-type Cx47. Furthermore, four of the six mutants showed no electrical coupling in both Cx47/Cx47 and Cx47/Cx43 GJ channels. These results suggest that most of the PMLD-linked Cx47 mutants disrupt Cx47/Cx47 and Cx47/Cx43 GJ function in the glial network, which may play a role in leading to PMLD symptoms.
PFKFB3 activation in cancer cells by the p38/MK2 pathway in response to stress stimuli
Authors: Novellasdemunt Laura , Bultot Laurent , Manzano Anna , Ventura Francesc , Rosa Jose Luis , Vertommen Didier , Rider Mark H. , Navarro-Sabate Àurea , Bartrons Ramon
Published: April 2013

PFK-2/FBPase-2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) catalyses the synthesis and degradation of Fru-2,6-P2 (fructose 2,6-bisphosphate), a key modulator of glycolysis and gluconeogenesis. The PFKFB3 gene is involved in cell proliferation owing to its role in carbohydrate metabolism. In the present study we analysed the mechanism of regulation of PFKFB3 as an immediate early gene controlled by stress stimuli that activates the p38/MK2 [MAPK (mitogen-activated protein kinase)-activated protein kinase 2] pathway. We report that exposure of HeLa and T98G cells to different stress stimuli (NaCl, H2O2, UV radiation and anisomycin) leads to a rapid increase (15–30 min) in PFKFB3 mRNA levels. The use of specific inhibitors in combination with MK2-deficient cells implicate control by the protein kinase MK2. Transient transfection of HeLa cells with deleted gene promoter constructs allowed us to identify an SRE (serum-response element) to which SRF (serum-response factor) binds and thus transactivates PFKFB3 gene transcription. Direct binding of phospho-SRF to the SRE sequence (−918 nt) was confirmed by ChIP (chromatin immunoprecipiation) assays. Moreover, PFKFB3 isoenzyme phosphorylation at Ser461 by MK2 increases PFK-2 activity. Taken together, the results of the present study suggest a multimodal mechanism of stress stimuli affecting PFKFB3 transcriptional regulation and kinase activation by protein phosphorylation, resulting in an increase in Fru-2,6-P2 concentration and stimulation of glycolysis in cancer cells.
Structural model of a putrescine-cadaverine permease from Trypanosoma cruzi predicts residues vital for transport and ligand binding
Authors: Soysa Radika , Venselaar Hanka , Poston Jacqueline , Ullman Buddy , Hasne Marie-Pierre
Published: April 2013

The TcPOT1.1 gene from Trypanosoma cruzi encodes a high affinity putrescine-cadaverine transporter belonging to the APC (amino acid/polyamine/organocation) transporter superfamily. No experimental three-dimensional structure exists for any eukaryotic member of the APC family, and thus the structural determinants critical for function of these permeases are unknown. To elucidate the key residues involved in putrescine translocation and recognition by this APC family member, a homology model of TcPOT1.1 was constructed on the basis of the atomic co-ordinates of the Escherichia coli AdiC arginine/agmatine antiporter crystal structure. The TcPOT1.1 homology model consisted of 12 transmembrane helices with the first ten helices organized in two V-shaped antiparallel domains with discontinuities in the helical structures of transmembrane spans 1 and 6. The model suggests that Trp241 and a Glu247–Arg403 salt bridge participate in a gating system and that Asn245, Tyr148 and Tyr400 contribute to the putrescine-binding pocket. To test the validity of the model, 26 site-directed mutants were created and tested for their ability to transport putrescine and to localize to the parasite cell surface. These results support the robustness of the TcPOT1.1 homology model and reveal the importance of specific aromatic residues in the TcPOT1.1 putrescine-binding pocket.
Bacterial protein-O-mannosylating enzyme is crucial for virulence ofMycobacterium tuberculosis
Authors: Liu Chia-Fang , Tonini Laure , Malaga Wladimir , Beau Mathilde , Stella Alexandre , Bouyssié David , Jackson Mary C. , Nigou Jérôme , Puzo Germain , Guilhot Christophe , Burlet-Schiltz Odile , Rivière Michel
Published: April 2013

A posttranslational proteinO-mannosylation process resembling that found in fungi and animals has been reported in the major human pathogenMycobacterium tuberculosis(Mtb) and related actinobacteria. However, the role and incidence of this process, which is essential in eukaryotes, have never been explored in Mtb. We thus analyzed the impact of interruptingO-mannosylation in the nonpathogenic saprophyteMycobacterium smegmatisand in the human pathogen Mtb by inactivating the respective putative protein mannosyl transferase genesMsmeg_5447andRv1002c. Loss of proteinO-mannosylation in both mutant strains was unambiguously demonstrated by efficient mass spectrometry-based glycoproteomics analysis. Unexpectedly, although theM. smegmatisphenotype was unaffected by the lack of manno-proteins, the Mtb mutant had severely impacted growth in vitro and in cellulo associated with a strong attenuation of its pathogenicity in immunocompromised mice. These data are unique in providing evidence of the biological significance of proteinO-mannosylation in mycobacteria and demonstrate the crucial contribution of this protein posttranslational modification to Mtb virulence in the host.
Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles
Authors: Hikichi Takafusa , Matoba Ryo , Ikeda Takashi , Watanabe Akira , Yamamoto Takuya , Yoshitake Satoko , Tamura-Nakano Miwa , Kimura Takayuki , Kamon Masayoshi , Shimura Mari , Kawakami Koichi , Okuda Akihiko , Okochi Hitoshi , Inoue Takafumi , Suzuki Atsushi , Masui Shinji
Published: April 2013

Transcription factors (TFs) are able to regulate differentiation-related processes, including dedifferentiation and direct conversion, through the regulation of cell type-specific transcriptional profiles. However, the functional interactions between the TFs regulating different transcriptional profiles are not well understood. Here, we show that the TFs capable of inducing cell type-specific transcriptional profiles prevent the dedifferentiation induced by TFs for pluripotency. Of the large number of TFs expressed in a neural-lineage cell line, we identified a subset of TFs that, when overexpressed, strongly interfered with the dedifferentiation triggered by the procedure to generate induced pluripotent stem cells. This interference occurred through a maintenance mechanism of the cell type-specific transcriptional profile. Strikingly, the maintenance activity of the interfering TF set was strong enough to induce the cell line-specific transcriptional profile when overexpressed in a heterologous cell type. In addition, the TFs that interfered with dedifferentiation in hepatic-lineage cells involved TFs with known induction activity for hepatic-lineage cells. Our results suggest that dedifferentiation suppresses a cell type-specific transcriptional profile, which is primarily maintained by a small subset of TFs capable of inducing direct conversion. We anticipate that this functional correlation might be applicable in various cell types and might facilitate the identification of TFs with induction activity in efforts to understand differentiation.
Procollagen C-proteinase enhancer grasps the stalk of the C-propeptide trimer to boost collagen precursor maturation
Authors: Bourhis Jean-Marie , Vadon-Le Goff Sandrine , Afrache Hassnae , Mariano Natacha , Kronenberg Daniel , Thielens Nicole , Moali Catherine , Hulmes David J. S.
Published: April 2013

Tight regulation of collagen fibril deposition in the extracellular matrix is essential for normal tissue homeostasis and repair, defects in which are associated with several degenerative or fibrotic disorders. A key regulatory step in collagen fibril assembly is the C-terminal proteolytic processing of soluble procollagen precursors. This step, carried out mainly by bone morphogenetic protein-1/tolloid-like proteinases, is itself subject to regulation by procollagen C-proteinase enhancer proteins (PCPEs) which can dramatically increase bone morphogenetic protein-1/tolloid-like proteinase activity, in a substrate-specific manner. Although it is known that this enhancing activity requires binding of PCPE to the procollagen C-propeptide trimer, identification of the precise binding site has so far remained elusive. Here, use of small-angle X-ray scattering provides structural data on this protein complex indicating that PCPE binds to the stalk region of the procollagen C-propeptide trimer, where the three polypeptide chains associate together, at the junction with the base region. This is supported by site-directed mutagenesis, which identifies two highly conserved, surface-exposed lysine residues in this region of the trimer that are essential for binding, thus revealing structural parallels with the interactions of Complement C1r/C1s, Uegf, BMP-1 (CUB) domain-containing proteins in diverse biological systems such as complement activation, receptor signaling, and transport. Together with detailed kinetics and interaction analysis, these results provide insights into the mechanism of action of PCPEs and suggest clear strategies for the development of novel antifibrotic therapies.
RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators
Authors: Redfern Andrew D. , Colley Shane M. , Beveridge Dianne J. , Ikeda Naoya , Epis Michael R. , Li Xia , Foulds Charles E. , Stuart Lisa M. , Barker Andrew , Russell Victoria J. , Ramsay Kerry , Kobelke Simon J. , Li Xiaotao , Hatchell Esme C. , Payne Christine , Giles Keith M. , Messineo Adriana , Gatignol Anne , Lanz Rainer B. , O’Malley Bert W. , Leedman Peter J.
Published: April 2013

The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including protein kinase RNA activator (PACT), transactivation response RNA binding protein (TRBP), and Dicer, that process pre-microRNAs into mature microRNAs (miRNAs) that target specific mRNA species for regulation. There is increasing evidence for important functional interactions between the miRNA and nuclear receptor (NR) signaling networks, with recent data showing that estrogen, acting through the estrogen receptor, can modulate initial aspects of nuclear miRNA processing. Here, we show that the cytoplasmic RISC proteins PACT, TRBP, and Dicer are steroid receptor RNA activator (SRA) binding NR coregulators that target steroid-responsive promoters and regulate NR activity and downstream gene expression. Furthermore, each of the RISC proteins, together with Argonaute 2, associates with SRA and specific pre-microRNAs in both the nucleus and cytoplasm, providing evidence for links between NR-mediated transcription and some of the factors involved in miRNA processing.
The Social Stigma of Identity- and Status-Based Rejection Sensitivity
Authors: London Bonita , Rosenthal Lisa
Published: April 2013

Drawing on research and theory from the social identity, stereotyping, stress and coping, and personality literatures, we review research that uses a common theoretical framework (rejection sensitivity; RS) to explore the mechanisms through which stigmatization on the basis of race, gender, sexual orientation, and age affects and shapes the life experiences of targets of stigmatization. Rejection Sensitivity is conceptualized as a cognitive-affective processing dynamic borne out of past experiences of rejection and maltreatment, and leading to situationally activated anxious expectations of rejection in current contexts. Applied to the context of identity-based stigmatization, we present a review of empirical research aimed at exploring the underlying mechanism by which exposure to cues of identity-based marginalization activates the RS dynamic and leads to variations in perceptions and coping with threat among members of stigmatized groups. We review the RS literature applied to African Americans, Asian Americans, women, gay men, and the elderly.
Looking Back and Forward: Lessons Learned and Moving Ahead
Authors: DeWall C. Nathan
Published: April 2013

Over the past 15 years, psychologists embraced the importance social connections more than ever before. The chapters that included in the Oxford Handbook of Social Exclusion offer the most comprehensive and cutting-edge research on the impact of social exclusion ever assembled. In this concluding chapter, I provide an overview of the six basic lessons we learned and suggest avenues for future research.
Induction and Maintenance of Systemic Acquired Resistance by Acibenzolar-S-Methyl in Three Cultivated Tobacco Types
Authors: Parkunan V. , Johnson C. S. , Xu L. , Peng Y. , Tolin S. A. , Eisenback J. D.
Published: April 2013

Induction and maintenance of systemic acquired resistance (SAR) in ‘N’ gene containing burley, flue-cured, and oriental tobacco cultivars were assessed by monitoring decreases in the number of local lesions caused by Tobacco mosaic virus (TMV) following treatment with acibenzolar-S-methyl (ASM). Leaf samples were collected from lower, middle, and top positions on seedlings at 3-day intervals over 21 days following ASM treatment and subsequent inoculation with TMV under laboratory conditions. Local lesion number for each leaf was recorded 7 days postinoculation. Reductions in TMV local lesion numbers on ASM-treated versus nontreated tobacco varied over time, and differed for each tobacco type. Based on reduced local lesion numbers, SAR was induced in burley and flue-cured tobacco by 3 and 6 days postinoculation, respectively, while oriental tobacco responded by 9 days. SAR was maintained in burley tobacco from 3 to 9 days after ASM application, and from 9 to 15 days after application in oriental tobacco. ASM treatment reduced local lesion numbers in flue-cured tobacco significantly at 6, 12, and 21 days postapplication, but not at 15 and 18 days after treatment. The SAR response was similar among lower, middle, and top leaves with no effect of ASM on response by leaf position, although TMV local lesion numbers were greater on lower leaves than on middle and top leaves 6 days after treatment, but significantly less on lower leaves 18 days after treatment compared to middle and top leaves.
Cross Pathogenicity and Vegetative Compatibility of Fusarium oxysporum Isolated from Sugar Beet
Authors: Webb Kimberly M. , Case Austin J. , Brick Mark A. , Otto Kris , Schwartz Howard F.
Published: April 2013

Fusarium oxysporum f. sp. betae causes Fusarium yellows in sugar beet (Beta vulgaris). The F. oxysporum population from sugar beet can be highly variable in virulence and morphology and many isolates are nonpathogenic. Rapid and reliable methods to identify pathogenic isolates from nonpathogenic F. oxysporum generally are unavailable. Little is known about nonpathogenic isolates, including the role they may play in population diversity or virulence to sugar beet. Sugar beet is often grown in rotation with other crops, including dry edible bean (Phaseolus vulgaris) and onion (Allium cepa), with F. oxysporum able to cause disease on all three crops. Thirty-eight F. oxysporum isolates were collected from symptomatic sugar beet throughout the United States to investigate diversity of the F. oxysporum population and the influence of crop rotation on pathogenic variation. These isolates were characterized for pathogenicity to sugar beet, dry edible bean, and onion, as well as vegetative compatibility. Pathogenicity testing indicated that some F. oxysporum isolates from sugar beet may cause disease on onion and dry edible bean. Furthermore, vegetative compatibility testing supported previous reports that F. oxysporum f. sp. betae is polyphyletic and that pathogenic isolates cannot be differentiated from nonpathogenic F. oxysporum using vegetative compatibility.