bluuebunny/crossref_metadata_2025 huggingface dataset:
Social network analysis and agent-based modeling in social epidemiology
Authors: El-Sayed Abdulrahman M , Scarborough Peter , Seemann Lars , Galea Sandro
Published: February 2012

The past five years have seen a growth in the interest in systems approaches in epidemiologic research. These approaches may be particularly appropriate for social epidemiology. Social network analysis and agent-based models (ABMs) are two approaches that have been used in the epidemiologic literature. Social network analysis involves the characterization of social networks to yield inference about how network structures may influence risk exposures among those in the network. ABMs can promote population-level inference from explicitly programmed, micro-level rules in simulated populations over time and space. In this paper, we discuss the implementation of these models in social epidemiologic research, highlighting the strengths and weaknesses of each approach. Network analysis may be ideal for understanding social contagion, as well as the influences of social interaction on population health. However, network analysis requires network data, which may sacrifice generalizability, and causal inference from current network analytic methods is limited. ABMs are uniquely suited for the assessment of health determinants at multiple levels of influence that may couple with social interaction to produce population health. ABMs allow for the exploration of feedback and reciprocity between exposures and outcomes in the etiology of complex diseases. They may also provide the opportunity for counterfactual simulation. However, appropriate implementation of ABMs requires a balance between mechanistic rigor and model parsimony, and the precision of output from complex models is limited. Social network and agent-based approaches are promising in social epidemiology, but continued development of each approach is needed.
Combination antiretroviral therapy and chronic HIV infection affect serum retinoid concentrations: longitudinal and cross-sectional assessments
Authors: Loignon Maude , Brodeur Hélène , Deschênes Sonia , Phaneuf Denis , Bhat Pangala V , Toma Emil
Published: February 2012

Background

Several lines of evidence suggest that retinoids (retinol-ROL or vitamin A, and its active metabolites, retinoic acids-RAs) play important pathogenic roles in HIV infection and combination antiretroviral therapy (cART)-related events. We previously reported that antiretrovirals alter RAs synthesis in vitro. We hypothesised that in vivo serum retinoid concentrations are affected by both cART and HIV infection. This might explain several clinical and laboratory abnormalities reported in HIV-infected patients receiving cART.

Methods

The effects of optimal cART and chronic HIV on serum retinoids were firstly assessed longitudinally in 10 HIV-infected adults (group1 = G1): twice while on optimal cART (first, during long-term and second, during short term cART) and twice during 2 cART interruptions when HIV viral load (VL) was detectable. Retinoid concentrations during optimal long term cART in G1 were compared with cross-sectional results from 12 patients (G2) with suboptimal cART (detectable VL) and from 28 healthy adults (G3). Serum retinoids were measured by HPLC with ultraviolet detection. Retinoid concentrations were correlated with VL, CD4+ T- cell count and percentages, CD8+38+ fluorescence, triglycerides, cholesterol and C-peptide serum levels.

Results

During optimal cART, G1 participants had drastically reduced RAs (0.5 ± 0.3 μg/dL; P < 0.01) but the highest ROL (82 ± 3.0 μg/dL) concentrations. During cART interruptions in these patients, RAs slightly increased whereas ROL levels diminished significantly (P < 0.05). G3 had the highest RAs levels (7.2 ± 1.1 μg/dL) and serum ROL comparable to values in North Americans. Serum ROL was decreased in G2 (37.7 ± 3.2 μg/dL; P < 0.01). No correlations were noted between RA and ROL levels or between retinoid concentrations and CD4+ T- cell count, CD8+38+ fluorescence, VL. ROL correlated with triglycerides and cholesterol in G1 (rs = 0.8; P = 0.01).

Conclusions

Serum RAs levels are significantly diminished by cART, whereas ROL concentrations significantly decreased during uncontrolled HIV infection but augmented with optimal cART. These alterations in retinoid concentrations may affect the expression of retinoid-responsive genes involved in metabolic, hormonal and immune processes and be responsible for some adverse events observed in HIV-infected persons treated with antiretrovirals. Further studies should assess concomitant serum and intracellular retinoid levels in different clinical situations in larger, homogenous populations.
Giant primary adrenal hydatid cyst presenting with arterial hypertension: a case report and review of the literature
Authors: Tazi Fadl , Ahsaini Mustapha , Khalouk Abdelhak , Mellas Soufiane , Stuurman-Wieringa Roos E , Elfassi Mohammed Jamal , Farih Moulay Hassan
Published: February 2012

Introduction

A primary hydatid cyst of the adrenal gland is still an exceptional localization. The adrenal gland is an uncommon site even in Morocco, where echinococcal disease is endemic.

Case presentation

We report the case of a 64-year-old Moroccan man who presented with the unusual symptom of arterial hypertension associated with left flank pain. Computed tomography showed a cystic mass of his left adrenal gland with daughter cysts filing the lesion (Type III). Despite his negative serology tests, the diagnosis of a hydatid cyst was confirmed on surgical examination. Our patient underwent surgical excision of his left adrenal gland with normalization of blood pressure. No recurrence has occurred after 36 months of follow-up.

Conclusion

There are two remarkable characteristics of this case report; the first is the unusual location of the cyst, the second is the association of an adrenal hydatid cyst with arterial hypertension, which has rarely been reported in the literature.
Reproducibility and intraindividual variation over days in buccal cell DNA methylation of two asthma genes, interferon γ (IFNγ) and inducible nitric oxide synthase (iNOS)
Authors: Torrone DZ , Kuriakose JS , Moors K , Jiang H , Niedzwiecki MM , Perera FF , Miller RL
Published: February 2012

The biological mechanisms responsible for the onset and exacerbation of asthma symptoms in children may involve the epigenetic regulation of inflammatory genes after environmental exposures. Using buccal cells, we hypothesized that DNA methylation in promoter regions of two asthma genes, inducible nitric oxide synthase (iNOS) and interferon γ (IFNγ), can vary over several days. Repeat buccal samples were collected 4 to 7 days apart from 34 children participating in the Columbia Center for Children's Environmental Health (CCCEH) birth cohort study. Several field duplicates (sequential collection of two samples in the field) and replicates (one sample pyrosequenced twice) also were collected to ensure consistency with collection and laboratory procedures. DNA methylation was assessed by pyrosequencing a PCR of bisulfite-treated DNA. We found that replicate and field duplicate samples were correlated strongly (r = 0.86 to 0.99, P < 0.05), while repeat samples demonstrated low within-subject correlations (r = 0.19 to 0.56, P = 0.06 to 0.30). Our data reveal DNA methylation as a dynamic epigenetic mechanism that can be accessed safely and reproducibly in an inner city pediatric cohort using non-invasive buccal swabs and pyrosequencing technology.
Synthesis and anti-HSV-1 evaluation of new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines
Authors: Bernardino Alice MR , Azevedo Alexandre R , Pinheiro Luiz CS , Borges Júlio C , Paixão Izabel CP , Mesquita Milene , Souza Thiago ML , dos Santos Maurício S
Published: February 2012

Background

Herpes simplex virus type-1 (HSV-1) is the primary cause of facial lesions (mouth, lips, and eyes) in humans. The widespread use of acyclovir and nucleoside analogues has led to emergence of HSV strains that are resistant to these drugs. Recently, non-nucleoside anti-HSV compounds have received considerable attention. 1,6-Naphthyridines are a class of heterocyclic compounds that exhibit a broad spectrum of biological activities such as inhibitor of HIV-1 integrase, HCMV, FGF receptor-1 tyrosine kinase, and the enzyme acetylcholinesterase. We previously reported the synthesis, SAR studies, and evaluation anti-HSV-1 activity of 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines. In the course of our search for new 1,6-naphthyridines derivatives with potential activity against HSV-1, we have synthesized and evaluated new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines(1a-k)and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines(2a-c).

Results

A known synthetic approach was used for preparing new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines(1a-k)and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines(2a-c), starting from ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(7). All compounds were identified by FTIR,1H NMR, and mass spectrometry. The antiviral effect on HSV-1 virus replication was determined.

Conclusions

The compounds1d,1f,1g, and1hexhibited the highest anti-HSV-1 activity. In general, 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines were more effective inhibitors than their corresponding 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines. The compound1hreduced the virus yield in 91% at 50 μM and exhibited a low cytotoxicity (CC50600 μM).
Mobile communication for intellectually challenged people: a proposed set of requirements for interface design on touch screen devices
Authors: de Urturi Breton Zelai Saenz , Hernández Fernando Jorge , Zorrilla Amaia Méndez , Zapirain Begoña García
Published: February 2012

The use of certain applications for touch-based mobile devices can prove to be difficult for intellectually challenged people. By performing tests and gathering user feedback, great difficulty has been detected in the use of various applications due to their complicated interfaces.

The authors propose a set of guidelines, aimed at developers, to help design more accessible interfaces when developing applications for intellectually challenged, so this might increase the overall ease of use of mobile devices.
Emerging roles of pulmonary macrophages in driving the development of severe asthma
Authors: Yang Ming , Kumar Rakesh K , Hansbro Philip M , Foster Paul S
Published: February 2012

Asthma is recognized as a heterogeneous disorder, although in most patients, the clinical manifestations are effectively managed with established combination therapies. However, 5–10% of asthmatics have severe asthma, which does not respond to treatment, and these patients account for >50% of asthma-related healthcare costs. New investigations into the pathogenesis of glucocorticoid resistance in severe asthma indicate that pulmonary macrophages may play central roles in promoting airway inflammation, particularly in asthma that is resistant to steroid therapy. Importantly, factors that are linked to the activation of pulmonary macrophages may contribute to glucocorticoid resistance and severe asthma. Here, we review recent advances in understanding the roles of pulmonary macrophages in the mechanisms of glucocorticoid resistance and the pathogenesis of severe asthma. We discuss the role of macrophage phenotype, infection, IFN-γ, LPS, associated signaling pathways, TNF-α, MIF, and other macrophage-associated factors. Understanding the pathogenesis of steroid-resistant severe asthma will contribute to the identification of optimal therapeutic strategies for the effective management of the disease.
Model-based fluid factor for controlled source electromagnetic data
Authors: Kolbjørnsen Odd , Hauge Ragnar , Drange-Espeland Maren , Buland Arild
Published: February 2012

We have developed a new Bayesian methodology for use of controlled source electromagnetic (CSEM) data in prospect risking. The methodology modifies the probability for hydrocarbon presence based on the information in the CSEM data. This is done by identifying the linear combination of the data where the weighted sum provides the optimal separation of cases with and without hydrocarbons. The weighted sum of the CSEM data is a model-based parallel to the well-known fluid factor used in seismic amplitude analysis. The optimal weighting is constructed based on forward modeling of models with and without hydrocarbons. We further compute the statistical distributions of the fluid factor with and without hydrocarbon presence, and use these distributions to compute the value of CSEM data and update the probability for hydrocarbon presence. The method does not involve inversion for the complete resistivity model but computes the chance of hydrocarbon presence directly. The method was tested on data from Troll, where it provided evidence for hydrocarbon presence, and on another data set, where it provided evidence against hydrocarbons. These real case examples showed the importance of rock physical knowledge. Improved control on the rock properties leads to stronger conclusions and higher value of the CSEM data. The proposed model-based approach is fast and robust.
Understanding imaging methods for potential field data
Authors: Fedi Maurizio , Pilkington Mark
Published: February 2012

Several noniterative, imaging methods for potential field data have been proposed that provide an estimate of the 3D magnetization/density distribution within the subsurface or that produce images of quantities related or proportional to such distributions. They have been derived in various ways, using generalized linear inversion, Wiener filtering, wavelet and depth from extreme points (DEXP) transformations, crosscorrelation, and migration. We demonstrated that the resulting images from each of these approaches are equivalent to an upward continuation of the data, weighted by a (possibly) depth-dependent function. Source distributions or related quantities imaged by all of these methods are smeared, diffuse versions of the true distributions; but owing to the stability of upward continuation, resolution may be substantially increased by coupling derivative and upward continuation operators. These imaging techniques appeared most effective in the case of isolated, compact, and depth-limited sources. Because all the approaches were noniterative, computationally fast, and in some cases, produced a fit to the data, they did provide a quick, but approximate picture of physical property distributions. We have found that inherent or explicit depth-weighting is necessary to image sources at their correct depths, and that the best scaling law or weighting function has to be physically based, for instance, using the theory of homogeneous fields. A major advantage of these techniques was their speed, efficiently providing a basis for further detailed, follow-up modelling.
Hyperbolic estimation of sparse models from erratic data
Authors: Li Yunyue , Zhang Yang , Claerbout Jon
Published: February 2012

We have developed a hyperbolic penalty function for image estimation. The center of a hyperbola is parabolic like that of an [Formula: see text] norm fitting. Its asymptotes are similar to [Formula: see text] norm fitting. A transition threshold must be chosen for regression equations of data fitting and another threshold for model regularization. We combined two methods: Newton’s and a variant of conjugate gradient method to solve this problem in a manner we call the hyperbolic conjugate direction (HYCD) method. We tested examples of (1) velocity transform with strong noise (2) migration of aliased data, and (3) blocky interval velocity estimation. For the linear experiments we performed in this study, nonlinearity is introduced by the hyperbolic objective function, but the convexity of the sum of the hyperbolas assures the convergence of gradient methods. Because of the sufficiently reliable performance obtained on the three mainstream geophysical applications, we expect the HYCD solver method to become our default method.
Moderating role of the MAOA genotype in antisocial behaviour
Authors: Fergusson David M. , Boden Joseph M. , Horwood L. John , Miller Allison , Kennedy Martin A.
Published: February 2012

Background

Recent studies have examined gene×environment (G×E) interactions involving the monoamine oxidase A (MAOA) gene in moderating the associations between exposure to adversity and antisocial behaviour. The present study examined a novel method for assessing interactions between a single gene and multiple risk factors related to environmental and personal adversity.

Aims

To test the hypothesis that the presence of the low-activity MAOA genotype was associated with an increased response to a series of risk factors.

Method

Participants were 399 males from the Christchurch Health and Development Study who had complete data on: (a) MAOA promoter region variable number tandem repeat genotype; (b) antisocial behaviour (criminal offending) to age 30 and convictions to age 21; and (c) maternal smoking during pregnancy, IQ, childhood maltreatment and school failure.

Results

Poisson regression models were fitted to three antisocial behaviour outcomes (property/violent offending ages 15–30; and convictions ages 17–21), using measures of exposure to adverse childhood circumstances. The analyses revealed consistent evidence of G x E interactions, such that those with the low-activity MAOA variant who were exposed to adversity in childhood were significantly more likely to report offending in late adolescence and early adulthood.

Conclusions

The present findings add to the evidence suggesting that there is a stable G x E interaction involving MAOA, a range of adverse environmental and personal factors, and antisocial behaviour across the life course. These analyses also demonstrate the utility of using multiple environmental/personal exposures to test G×E interactions.
A Covalently Dimerized Recombinant Human Bone Morphogenetic Protein-15 Variant Identifies Bone Morphogenetic Protein Receptor Type 1B as a Key Cell Surface Receptor on Ovarian Granulosa Cells
Authors: Pulkki Minna M. , Mottershead David G. , Pasternack Arja H. , Muggalla Pranuthi , Ludlow Helen , van Dinther Maarten , Myllymaa Samu , Koli Katri , ten Dijke Peter , Laitinen Mika , Ritvos Olli
Published: February 2012

Genetic studies have identified bone morphogenetic protein-15 (BMP15) as an essential regulator of female fertility in humans and in sheep. Oocyte-derived BMP15 is a noncovalently linked dimeric growth factor mediating its effects to ovarian somatic cells in a paracrine manner. Although receptor ectodomains capable of binding BMP15 have previously been reported, no cell surface receptor complex involved in BMP15 signaling has previously been characterized. Here we have expressed and purified recombinant human BMP15 noncovalent and covalent dimer variants. The biological effects of these BMP15 variants were assessed in cultured human granulosa-luteal cells or COV434 granulosa cell tumor cells using BMP-responsive transcriptional reporter assays and an inhibin B ELISA. Biochemical characterization of ligand-receptor interactions was performed with affinity-labeling experiments using [125I]iodinated BMP15 variants. Both ligand variants were shown to form homodimers and to stimulate Smad1/5/8 signaling and inhibin B production in human granulosa cells in a similar manner. [125I]Iodination of both ligands was achieved, but only the covalent dimer variant retained receptor binding capacity. The [125I]BMP15S356C variant bound preferentially to endogenous BMP receptor 1B (BMPR1B) and BMPR2 receptors on COV434 cells. Binding experiments in COS cells with overexpression of these receptors confirmed that the [125I]BMP15S356C variant binds to BMPR1B and BMPR2 forming the BMP15 signaling complex. The results provide the first direct evidence in any species on the identification of specific cell surface receptors for a member of the GDF9/BMP15 subfamily of oocyte growth factors. The fact that BMP15 uses preferentially BMPR1B as its type I receptor suggests an important role for the BMPR1B receptor in human female fertility. The result is well in line with the demonstration of ovarian failure in a recently reported human subject with a homozygous BMPR1B loss-of-function mutant.
Excess DAX1 Leads to XY Ovotesticular Disorder of Sex Development (DSD) in Mice by Inhibiting Steroidogenic Factor-1 (SF1) Activation of the Testis Enhancer of SRY-box-9 (Sox9)
Authors: Ludbrook Louisa M. , Bernard Pascal , Bagheri-Fam Stefan , Ryan Janelle , Sekido Ryohei , Wilhelm Dagmar , Lovell-Badge Robin , Harley Vincent R.
Published: February 2012

Human DAX1 duplications cause dosage-sensitive sex reversal (DSS) whereby chromosomally XY individuals can develop as females due to gonadal dysgenesis. However, the mechanism of DSS-adrenal hypoplasia congenita on X, gene 1 (DAX1) action in the fetal testis is unknown. We show that in fetal testes from XY Dax1-overexpressing transgenic mice, the expression of the key testis-promoting gene sex-determining region on Y (SRY)-box-9 (Sox9) is reduced. Moreover, in XY Sox9 heterozygotes, in which testis development is usually normal, Dax1 overexpression results in ovotestes, suggesting a DAX1-SOX9 antagonism. The ovarian portion of the XY ovotestes was characterized by expression of the granulosa cell marker, Forkhead box-L2, with complete loss of the Sertoli cell markers, SOX9 and anti-Müllerian hormone, and the Leydig cell marker CYP17A1. However, the expression of SRY and steroidogenic factor-1 (SF1), two key transcriptional regulators of Sox9, was retained in the ovarian portion of the XY ovotestes. Using reporter mice, Dax1 overexpression reduced activation of TES, the testis enhancer of Sox9, indicating that DAX1 might repress Sox9 expression via TES. In cultured cells, increasing levels of DAX1 antagonized SF1-, SF1/SRY-, and SF1/SOX9-mediated activation of TES, due to reduced binding of SF1 to TES, providing a likely mechanism for DSS.
Rapid and Widespread Effects of 17β-Estradiol on Intracellular Signaling in the Male Songbird Brain: A Seasonal Comparison
Authors: Heimovics Sarah A. , Prior Nora H. , Maddison Chris J. , Soma Kiran K.
Published: February 2012

Across vertebrate species, 17β-estradiol (E2) acts on the brain via both genomic and nongenomic mechanisms to influence neuronal physiology and behavior. Nongenomic E2 signaling is typically initiated by membrane-associated estrogen receptors that modulate intracellular signaling cascades, including rapid phosphorylation of ERK. Phosphorylated ERK (pERK) can, in turn, rapidly phosphorylate tyrosine hydroxylase (TH) and cAMP response element-binding protein (CREB). Recent data suggest that the rapid effects of E2 on mouse aggressive behavior are more prominent during short photoperiods (winter) and that acute aromatase inhibition reduces songbird aggression in winter only. To date, seasonal plasticity in the rapid effects of E2 on intracellular signaling has not been investigated. Here, we compared the effects of acute (15 min) E2 treatment on pERK, pTH, and pCREB immunoreactivity in male song sparrows (Melospiza melodia) pretreated with the aromatase inhibitor fadrozole during the breeding and nonbreeding seasons. We examined immunoreactivity in 14 brain regions including portions of the song control system, social behavior network, and the hippocampus (Hp). In both seasons, E2 significantly decreased pERK in nucleus taeniae of the amygdala, pTH in ventromedial hypothalamus, and pCREB in mesencephalic central gray, robust nucleus of the arcopallium, and caudomedial nidopallium. However, several effects were critically dependent upon season. E2 decreased pERK in caudomedial nidopallium in the breeding season only and decreased pCREB in the medial preoptic nucleus in the nonbreeding season only. Remarkably, E2 decreased pERK in Hp in the breeding season but increased pERK in Hp in the nonbreeding season. Together, these data demonstrate that E2 has rapid effects on intracellular signaling in multiple regions of the male brain and also demonstrate that rapid effects of E2 can be profoundly different across the seasons.
Impact of Oatp1c1 Deficiency on Thyroid Hormone Metabolism and Action in the Mouse Brain
Authors: Mayerl Steffen , Visser Theo J. , Darras Veerle M. , Horn Sigrun , Heuer Heike
Published: February 2012

Organic anion-transporting polypeptide 1c1 (Oatp1c1) (also known as Slco1c1 and Oatp14) belongs to the family of Oatp and has been shown to facilitate the transport of T4. In the rodent brain, Oatp1c1 is highly enriched in capillary endothelial cells and choroid plexus structures where it may mediate the entry of T4 into the central nervous system. Here, we describe the generation and first analysis of Oatp1c1-deficient mice. Oatp1c1 knockout (KO) mice were born with the expected frequency, were not growth retarded, and developed without any overt neurological abnormalities. Serum T3 and T4 concentrations as well as renal and hepatic deiodinase type 1 expression levels were indistinguishable between Oatp1c1 KO mice and control animals. Hypothalamic TRH and pituitary TSH mRNA levels were not affected, but brain T4 and T3 content was decreased in Oatp1c1-deficient animals. Moreover, increased type 2 and decreased type 3 deiodinase activities indicate a mild hypothyroid situation in the brain of Oatp1c1 KO mice. Consequently, mRNA expression levels of gene products positively regulated by T3 in the brain were down-regulated. This central nervous system-specific hypothyroidism is presumably caused by an impaired passage of T4 across the blood-brain barrier and indicates a unique function of Oatp1c1 in facilitating T4 transport despite the presence of other thyroid hormone transporters such as Mct8.
Evidence for Differential Regulation of GnRH Signaling via Heterodimerization among GnRH Receptor Paralogs in the Protochordate, Ciona intestinalis
Authors: Sakai Tsubasa , Aoyama Masato , Kawada Tsuyoshi , Kusakabe Takehiro , Tsuda Motoyuki , Satake Honoo
Published: February 2012

The endocrine and neuroendocrine systems for reproductive functions have diversified as a result of the generation of species-specific paralogs of peptide hormones and their receptors including GnRH and their receptors (GnRHR), which belong to the class A G protein-coupled receptor family. A protochordate, Ciona intestinalis, has been found to possess seven GnRH (tGnRH-3 to -8 and Ci-GnRH-X) and four GnRHR (Ci-GnRHR1 to -4). Moreover, Ci-GnRHR4 (R4) does not bind to any Ciona GnRH and activate any signaling pathways. Here we show novel functional diversification of GnRH signaling pathways via G protein-coupled receptor heterodimerization among Ciona GnRHR. R4 was shown to heterodimerize with R2 specifically in test cells of vitellogenic oocytes by coimmunoprecipitation. The R2-R4 heterodimerization in human embryonic kidney 293 cells cotransfected with R2 and R4 was also observed by coimmunoprecipitation and fluorescent energy transfer analyses. Of particular interest is that the R2-R4 heterodimer decreases the cAMP production in a nonligand-selective manner via shift of activation of Gs protein to Gi protein by R2, compared with R2 monomer/homodimer. Considering that the R1-R4 heterodimer elicits 10-fold more potent Ca2+ mobilization than R1 monomer/homodimer in a ligand-selective manner but does not affect cAMP production, these results indicate that R4 regulates differential GnRH signaling cascades via heterodimerization with R1 and R2 as an endogenous allosteric modulator. Collectively, the present study suggests that the heterodimerization among GnRHR paralogs, including the species-specific orphan receptor subtype, is involved in rigorous and diversified GnRHergic signaling of the protochordate, which lacks a hypothalamus-pituitary gonad axis.
Glucocorticoids Enhance Intestinal Glucose Uptake Via the Dimerized Glucocorticoid Receptor in Enterocytes
Authors: Reichardt Sybille D. , Föller Michael , Rexhepaj Rexhep , Pathare Ganesh , Minnich Kerstin , Tuckermann Jan P. , Lang Florian , Reichardt Holger M.
Published: February 2012

Glucocorticoid (GC) treatment of inflammatory disorders, such as inflammatory bowel disease, causes deranged metabolism, in part by enhanced intestinal resorption of glucose. However, the underlying molecular mechanism is poorly understood. Hence, we investigated transcriptional control of genes reported to be involved in glucose uptake in the small intestine after GC treatment and determined effects of GC on electrogenic glucose transport from transepithelial currents. GRvillinCre mice lacking the GC receptor (GR) in enterocytes served to identify the target cell of GC treatment and the requirement of the GR itself; GRdim mice impaired in dimerization and DNA binding of the GR were used to determine the underlying molecular mechanism. Our findings revealed that oral administration of dexamethasone to wild-type mice for 3 d increased mRNA expression of serum- and GC-inducible kinase 1, sodium-coupled glucose transporter 1, and Na+/H+ exchanger 3, as well as electrogenic glucose transport in the small intestine. In contrast, GRvillinCre mice did not respond to GC treatment, neither with regard to gene activation nor to glucose transport. GRdim mice were also refractory to GC, because dexamethasone treatment failed to increase both, gene expression and electrogenic glucose transport. In addition, the rise in blood glucose levels normally observed after GC administration was attenuated in both mutant mouse strains. We conclude that enhanced glucose transport in vivo primarily depends on gene regulation by the dimerized GR in enterocytes, and that this mechanism contributes to GC-induced hyperglycemia.
Minireview: Glucagon in Stress and Energy Homeostasis
Authors: Jones B. J. , Tan T. , Bloom S. R.
Published: February 2012

Glucagon is traditionally thought of as an antihypoglycemic hormone, for example in response to starvation. However, it actually increases energy expenditure and has other actions not in line with protection from hypoglycemia. Furthermore, it is often found to be elevated when glucose is also raised, for example in circumstances of psychological and metabolic stress. These findings seem more in keeping with glucagon having some role as a hormone enhancing the response to stress.
Observational Learning and Demand for Search Goods
Authors: Hendricks Kenneth , Sorensen Alan , Wiseman Thomas
Published: February 2012

We develop a model of herds in which consumers observe only the aggregate purchase history, not the complete ordered history of search actions. We show that the purchasing information changes the conditions under which herds can occur for both low- and high-quality products. Inferior products are certain to be ignored; high quality products may be ignored, but complete learning may also occur. We obtain closed form solutions for the probabilities of these events and conduct comparative statics. We test the model's predictions using data from an online music market created by Salganik, Dodds, and Watts (2006). (JEL D11, D12, L82)
Do Strikes Kill? Evidence from New York State
Authors: Gruber Jonathan , Kleiner Samuel A
Published: February 2012

Hospitals now represent one of the largest union sectors of the US economy, and there is particular concern about the impact of strikes on patient welfare. We analyze the effects of nurses' strikes in hospitals on patient outcomes in New York State. Controlling for hospital specific heterogeneity, the results show that nurses' strikes increase in-hospital mortality by 18.3 percent and 30-day readmission by 5.7 percent for patients admitted during a strike, with little change in patient demographics, disease severity or treatment intensity. The results suggest that hospitals functioning during nurses' strikes do so at a lower quality of patient care. (JEL H75, I11, I12, J52)
Income Taxes, Compensating Differentials, and Occupational Choice: How Taxes Distort the Wage-Amenity Decision
Authors: Powell David , Shan Hui
Published: February 2012

The link between taxes and occupational choices is central for understanding the welfare impacts of income taxes. Just as taxes distort the labor-leisure decision, they may also distort the wage-amenity decision. Yet, there have been few studies on the full response along this margin. When tax rates increase, workers favor jobs with lower wages and more amenities. We introduce a two-step methodology which uses compensating differentials to characterize the tax elasticity of occupational choice. We estimate a significant compensated elasticity of 0.03, implying that a 10 percent increase in the net-of-tax rate causes workers to change to a 0.3 percent higher wage job. (JEL H24, H31, J22, J24, J31)
Green Infrastructure: The Effects of Urban Rail Transit on Air Quality
Authors: Chen Yihsu , Whalley Alexander
Published: February 2012

The transportation sector is a major source of air pollution worldwide, yet little is known about the effects of transportation infrastructure on air quality. This paper quantifies the effects of one major type of transportation infrastructure—urban rail transit—on air quality using the sharp discontinuity in ridership on opening day of a new rail transit system in Taipei. We find that the opening of the Metro reduced air pollution from one key tailpipe pollutant, carbon monoxide, by 5 to 15 percent. Little evidence that the opening of the Metro affected ground level ozone pollution is found however. (JEL L92, Q53, R41, R53)
Sacred Cars? Cost-Effective Regulation of Stationary and Nonstationary Pollution Sources
Authors: Fowlie Meredith , Knittel Christopher R , Wolfram Catherine
Published: February 2012

For political and practical reasons, environmental regulations sometimes treat point-source polluters, such as power plants, differently from mobile-source polluters, such as vehicles. This paper measures the extent of this regulatory asymmetry in the case of nitrogen oxides (NOx), the most recalcitrant criteria air pollutant in the United States. We find significant differences in marginal abatement costs across source types: the marginal cost of reducing NOx from cars is less than half the marginal cost of reducing NOx from power plants. Our results measure the possible efficiency gains and distributional implications associated with increasing the sectoral scope of environmental regulations.(JEL Q53, Q58, R41)
Should registrars be reporting after-hours CT scans? A calculation of error rate and the influencing factors in South Africa
Authors: Terreblanche Owen D , Andronikou Savvas , Hlabangana Linda T , Brown Taryn , Boshoff Pieter E
Published: February 2012

Background

There is a heavy reliance on registrars for after-hours CT reporting with a resultant unavoidable error rate.

Purpose

To determine the after-hours CT reporting error rate by radiology registrars and influencing factors on this error rate.

Material and Methods

A 2-month prospective study was undertaken at two tertiary, level 1 trauma centers in Johannesburg, South Africa. Provisional CT reports issued by the registrar on call were reviewed by a qualified radiologist the following morning and information relating to the number, time and type of reporting errors made as well as the body region scanned, indication for the scan, year of training of the registrar, and workload during the call were recorded and analyzed.

Results

A total of 1477 CT scans were performed with an overall error rate of 17.1% and a major error rate of 7.7%. The error rate for 2nd, 3rd, and 4th year registrars was 19.4%, 15.1%, and 14.5%, respectively. A significant difference was found between the error rate in reporting trauma scans (15.8%) compared to non-trauma scans (19.2%) although the difference between emergency scans (16.9%) and elective scans (22.6%) was found to be not significant, a finding likely due to the low number of elective scans performed. Abdominopelvic scans elicited the highest number of errors (33.9%) compared to the other body regions such as head (16.5%) and cervical, thoracic, or lumbar spine (11.7%). Increasing workload resulted in a significant increase in error rate when analyzed with a generalized linear model. There was also a significant difference noted in the time of scan groups which we attributed to a workload effect. Missed findings were the most frequent errors seen (57.3%).

Conclusion

We found an increasing error rate associated with increasing workload and marked increase in errors with the reporting of abdominopelvic scans. There was a decrease in the error rate when looking an increasing year of training although this there was only found to be significant difference between the 2nd and 3rd year registrars.
Microfluidic Amplification as a Tool for Massive Parallel Sequencing of the Familial Hypercholesterolemia Genes
Authors: Hollants Silke , Redeker Egbert J W , Matthijs Gert
Published: February 2012

BACKGROUND

Familial hypercholesterolemia (FH) is an autosomal dominant disorder that affects cholesterol metabolism and is an important risk factor for heart disease. Three different genes were causally linked to this disorder: LDLR (low density lipoprotein receptor), APOB [apolipoprotein B (including Ag(x) antigen)], and PCSK9 (proprotein convertase subtilisin/kexin type 9). We evaluated a new amplicon preparation tool for resequencing these genes on next generation sequencing (NGS) platforms.

METHODS

For the 3 genes, 38 primer pairs were designed and loaded on the Fluidigm Access Array, a microfluidic array in which a PCR was performed. We amplified 144 DNA samples (73 positive controls and 71 patient samples) and performed 3 sequencing runs on a GS FLX Titanium system from Roche 454, using pyrosequencing. Data were analyzed with the SeqNext module of the Sequence Pilot software.

RESULT

From the 38 amplicons, 37 were amplified successfully, without any further optimization. Sequencing resulted in a mean coverage of the individual amplicons of 71-fold, 74-fold, and 117-fold for the 3 runs, respectively. In the positive controls, all known mutations were identified. In 29% of the patient samples, a pathogenic point mutation or small deletion/insertion was found. Large rearrangements were not detectable with NGS, but were picked up by multiplex ligation-dependent probe amplification.

CONCLUSIONS

Combining a microfluidic amplification system with massive parallel sequencing is an effective method for mutation scanning in FH patients, which can be implemented in diagnostics. For data analysis, we propose a minimum variant frequency threshold of 20% and a minimum coverage of 25-fold.
Complexity Effects in Choice Experiment–Based Models
Authors: Dellaert Benedict G.C. , Donkers Bas , Van Soest Arthur
Published: February 2012

Many firms rely on choice experiment–based models to evaluate future marketing actions under various market conditions. This research investigates choice complexity (i.e., number of alternatives, number of attributes, and utility similarity between the most attractive alternatives) and individual differences in decision time as key factors that affect the predictive performance of models based on choice experiments, both within and between complexity conditions. The results show that complexity and individual decision time not only affect the error in consumer choice models but also consumers' decision strategy and systematic utilities. The authors introduce a complexity-adjusted mixed logit (CAM logit) model to capture the various influences of complexity in choice experiment–based models. They illustrate the consequences of complexity on choice behavior with market share predictions of the CAM logit model for different complexity conditions.
A TrkB Small Molecule Partial Agonist Rescues TrkB Phosphorylation Deficits and Improves Respiratory Function in a Mouse Model of Rett Syndrome
Authors: Schmid Danielle A. , Yang Tao , Ogier Michael , Adams Ian , Mirakhur Yatin , Wang Qifang , Massa Stephen M. , Longo Frank M. , Katz David M.
Published: February 2012

Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients andMecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits inMecp2mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous femaleMecp2mutant mice (Het), a model that recapitulates the somatic mosaicism for mutantMECP2found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.
Gene Coexpression Networks in Human Brain Identify Epigenetic Modifications in Alcohol Dependence
Authors: Ponomarev Igor , Wang Shi , Zhang Lingling , Harris R. Adron , Mayfield R. Dayne
Published: February 2012

Alcohol abuse causes widespread changes in gene expression in human brain, some of which contribute to alcohol dependence. Previous microarray studies identified individual genes as candidates for alcohol phenotypes, but efforts to generate an integrated view of molecular and cellular changes underlying alcohol addiction are lacking. Here, we applied a novel systems approach to transcriptome profiling in postmortem human brains and generated a systemic view of brain alterations associated with alcohol abuse. We identified critical cellular components and previously unrecognized epigenetic determinants of gene coexpression relationships and discovered novel markers of chromatin modifications in alcoholic brain. Higher expression levels of endogenous retroviruses and genes with high GC content in alcoholics were associated with DNA hypomethylation and increased histone H3K4 trimethylation, suggesting a critical role of epigenetic mechanisms in alcohol addiction. Analysis of cell-type-specific transcriptomes revealed remarkable consistency between molecular profiles and cellular abnormalities in alcoholic brain. Based on evidence from this study and others, we generated a systems hypothesis for the central role of chromatin modifications in alcohol dependence that integrates epigenetic regulation of gene expression with pathophysiological and neuroadaptive changes in alcoholic brain. Our results offer implications for epigenetic therapeutics in alcohol and drug addiction.
Mimicking Phosphorylation at Serine 87 Inhibits the Aggregation of Human α-Synuclein and Protects against Its Toxicity in a Rat Model of Parkinson's Disease
Authors: Oueslati Abid , Paleologou Katerina E. , Schneider Bernard L. , Aebischer Patrick , Lashuel Hilal A.
Published: February 2012

Several lines of evidence suggest that phosphorylation of α-synuclein (α-syn) at S87 or S129 may play an important role in regulating its aggregation, fibrillogenesis, Lewy body formation, and neurotoxicityin vivo. However, whether phosphorylation at these residues enhances or protects against α-syn toxicityin vivoremains unknown. In this study, we investigated the cellular and behavioral effect of overexpression of wild-type (WT), S87A, and S87E α-syn to block or to mimic S87 phosphorylation, respectively, in the substantia nigra of Wistar rats using recombinant adeno-associated vectors. Our results revealed that WT and S87A overexpression induced α-syn aggregation, loss of dopaminergic neurons, and fiber pathology. These neuropathological effects correlated well with the induction of hemi-parkinsonian motor symptoms. Strikingly, overexpression of the phosphomimic mutant S87E did not show any toxic effect on dopaminergic neurons and resulted in significantly less α-syn aggregates, dystrophic fibers, and motor impairment. Together, our data demonstrate, for the first time, that mimicking phosphorylation at S87 inhibits α-syn aggregation and protects against α-syn-induced toxicityin vivo, suggesting that phosphorylation at this residue would play an important role in controlling α-syn neuropathology. In addition, our results provide strong evidence for a direct correlation between α-syn-induced neurotoxicity, fiber pathology, and motor impairment and the extent of α-syn aggregationin vivo, suggesting that lowering α-syn levels and/or blocking its aggregation are viable therapeutic strategies for the treatment of Parkinson's disease and related synucleinopathies.
Neural Correlates of Humor Detection and Appreciation in Children
Authors: Neely Michelle N. , Walter Elizabeth , Black Jessica M. , Reiss Allan L.
Published: February 2012

Humor is a vital component of human well-being. Neuroimaging studies conducted with adults indicate that humor activates specific brain regions, including the temporo-occipito-parietal junction (TOPJ), involved in incongruity resolution, and mesolimbic regions, involved in reward processing. However, no study to date has used neuroimaging to examine humor in typically developing children. Here, we illuminate the neural network involved in the detection and appreciation of humor in childhood.

Fifteen typically developing children (ages, 6–12 years) were invited to watch and respond to video clips while neural activity was imaged with a 3T GE Discovery MR750 scanner. Before presentation during functional imaging, the clips were evaluated by age-matched controls and were representative of three categories: Funny, Positive (enjoyable but not funny), and Neutral (not intended to evoke any emotional response). We found TOPJ and mesolimbic activation in children's response to humor, suggesting these regions may form a humor-essential neural network already present in childhood. Furthermore, in a novel comparison of Funny to Positive stimuli, we found that bilateral TOPJ activation may be specific to humor processing and not part of a general constellation of neural activity in response to reward. Finally, we observed greater activation in the inferior frontal gyrus and nucleus accumbens in younger participants, indicating humor activation intensity changes during development.

By providing a crucial link in studying the neurodevelopment of humor processing across the lifespan, our findings contribute valuable information about the evolution of how children understand their world.