bluuebunny/crossref_metadata_2025 huggingface dataset:
‘Proterosuchia’: the origin and early history of Archosauriformes
Authors: Ezcurra Martín D. , Butler Richard J. , Gower David J.
Published: April 2013

The earliest history of Archosauriformes is mainly represented by members of Proterosuchidae and Erythrosuchidae, which are known worldwide from latest Permian to Middle Triassic beds. These two groups were historically combined within ‘Proterosuchia’, with approximately 30 nominal species. Two morphotypes have been recognized among proterosuchians: proterosuchids with a generally more sprawling gait and elongated and low skulls with an overhanging premaxilla, and the more heavily built erythrosuchids, with a probably less sprawling gait and large, presumably hypercarnivorous, skulls. The systematics of ‘Proterosuchia’ was relatively chaotic throughout most of the twentieth century, but currently there exists consensus regarding the non-monophyly of proterosuchians and their phylogenetic position outside all other archosauriforms. In contrast, the delimitation and taxonomic content of Proterosuchidae and Erythrosuchidae remain unstable. Few studies of proterosuchian palaeobiology have been carried out. Current lines of evidence favour a predominantly terrestrial lifestyle for proterosuchians. Limb bone histology indicates rapid continuous growth rates in
Proterosuchus
and
Erythrosuchus
before reaching sexual maturity. A better knowledge of proterosuchian anatomy, systematics, evolution and ecology is important for advancing understanding of the origin and early radiation of Archosauriformes and the patterns of biotic recovery following the Permo-Triassic mass extinction event. There remains much research to be carried out in proterosuchian palaeobiology.
Prorotodactylus
and
Rotodactylus
tracks: an ichnological record of dinosauromorphs from the Early–Middle Triassic of Poland
Authors: Niedźwiedzki Grzegorz , Brusatte Stephen L. , Butler Richard J.
Published: April 2013

We present the first comprehensive description of
Prorotodactylus
and
Rotodactylus
dinosauromorph tracks from the Early and Middle Triassic of the Holy Cross Mountains, Poland. We describe and comprehensively figure tracks that have been mentioned briefly in previous accounts as well as new, recently discovered material, and analyse the variation and stratigraphic distribution of these specimens. Tracks have been recorded from four sites – Koszary, Stryczowice, Wióry and Baranów – which span the early Olenekian–early Anisian (
c.
250–246 Ma). These tracks therefore represent an ichnological record of the evolutionary succession of early dinosauromorphs during the earliest part of their evolutionary history. Recognized track types include cf.
Prorotodactylus
isp
.
,
Prorotodactylus
isp.,
Prorotodactylus mirus
,
Rotodactylus cursorius
,
Rotodactylus
isp. and cf.
Rotodactylus
isp. At least three distinct Early and early Middle Triassic early dinosauromorph ichnofaunas can be recognized. The oldest, which is early Olenekian in age, is characterized by the presence of
Prorotodactylus
isp., cf.
Prorotodactylus
isp
.
and non-archosaurian archosauromorph or archosaur tracks (e.g.
Synaptichnium
isp.,
Protochirotherium
isp.), recorded at the Stryczowice and Koszary sites. The following assemblage, recorded at the late Olenekian Wióry site, displays the highest ichnodiversity of dinosauromorphs, with four track types present (
Prorotodactylus
isp.,
Prorotodactylus mirus
,
Rotodactylus cursorius
and cf.
Rotodactylus
isp.). The youngest site, Baranów, includes
Rotodactylus
isp., as well as other larger dinosauromorph tracks. The first body fossil evidence of dinosauromorphs is a few million years younger than the youngest Polish tracks, so
Prorotodactylus
and
Rotodactylus
tracks currently provide the oldest record of dinosauromorph morphology, biology and evolution.
Leptin-sensitive sensory nerves innervate white fat
Authors: Murphy Keegan T. , Schwartz Gary J. , Nguyen Ngoc Ly T. , Mendez Jennifer M. , Ryu Vitaly , Bartness Timothy J.
Published: April 2013

Leptin, the primary white adipose tissue (WAT) adipokine, is thought to convey lipid reserve information to the brain via the circulation. Because WAT responds to environmental/internal signals in a fat pad-specific (FPS) manner, systemic signals such as leptin would fail to communicate such distinctive information. Saturation of brain leptin transport systems also would fail to convey increased lipid levels beyond that point. WAT possesses sensory innervation exemplified by proven sensory-associated peptides in nerves within the tissue and by viral sensory nerve-specific transneuronal tract tracer, H129 strain of herpes simplex virus 1 labeling of dorsal root ganglia (DRG) pseudounipolar neurons, spinal cord and central sensory circuits. Leptin as a paracrine factor activating WAT sensory innervation could supply the brain with FPS information. Therefore, we tested for and found the presence of the long form of the leptin receptor (Ob-Rb) on DRG pseudounipolar neurons immunohistochemically labeled after injections of Fluorogold, a retrograde tract tracer, into inguinal WAT (IWAT). Intra-IWAT leptin injections (300 ng) significantly elevated IWAT nerve spike rate within 5 min and persisted for at least 30 min. Intra-IWAT leptin injections also induced significant c-Fos immunoreactivity (ir), indicating neural activation across DRG pseudounipolar sensory neurons labeled with Fluorogold IWAT injections. Intraperitoneal leptin injection did not increase c-Fos-ir in DRG or the arcuate nucleus, nor did it increase arcuate signal transducer and activator of transcription 3 phosphorylation-ir. Collectively, these results strongly suggest that endogenous leptin secreted from white adipocytes functions as a paracrine factor to activate spinal sensory nerves innervating the tissue.
High-fat diet changes the temporal profile of GLP-1 receptor-mediated hypophagia in rats
Authors: Mul Joram D. , Begg Denovan P. , Barrera Jason G. , Li Bailing , Matter Emily K. , D'Alessio David A. , Woods Stephen C. , Seeley Randy J. , Sandoval Darleen A.
Published: April 2013

Overconsumption of a high-fat diet promotes weight gain that can result in obesity and associated comorbidities, including Type 2 diabetes mellitus. Consumption of a high-fat diet also alters gut-brain communication. Glucagon-like peptide 1 (GLP-1) is an important gastrointestinal signal that modulates both short- and long-term energy balance and is integral in maintenance of glucose homeostasis. In the current study, we investigated whether high-fat diets (40% or 81% kcal from fat) modulated the ability of the GLP-1 receptor (GLP-1r) agonists exendin-4 (Ex4) and liraglutide to reduce food intake and body weight. We observed that rats maintained on high-fat diets had a delayed acute anorexic response to peripheral administration of Ex4 or liraglutide compared with low-fat diet-fed rats (17% kcal from fat). However, once suppression of food intake in response to Ex4 or liraglutide started, the effect persisted for a longer time in the high-fat diet-fed rats compared with low-fat diet-fed rats. In contrast, centrally administered Ex4 suppressed food intake similarly between high-fat diet-fed and low-fat diet-fed rats. Chronic consumption of a high-fat diet did not change the pharmacokinetics of Ex4 but increased intestinal Glp1r expression and decreased hindbrain Glp1r expression. Taken together, these findings demonstrate that dietary composition alters the temporal profile of the anorectic response to exogenous GLP-1r agonists.
Compressive spatial summation in human visual cortex
Authors: Kay Kendrick N. , Winawer Jonathan , Mezer Aviv , Wandell Brian A.
Published: April 2013

Neurons within a small (a few cubic millimeters) region of visual cortex respond to stimuli within a restricted region of the visual field. Previous studies have characterized the population response of such neurons using a model that sums contrast linearly across the visual field. In this study, we tested linear spatial summation of population responses using blood oxygenation level-dependent (BOLD) functional MRI. We measured BOLD responses to a systematic set of contrast patterns and discovered systematic deviation from linearity: the data are more accurately explained by a model in which a compressive static nonlinearity is applied after linear spatial summation. We found that the nonlinearity is present in early visual areas (e.g., V1, V2) and grows more pronounced in relatively anterior extrastriate areas (e.g., LO-2, VO-2). We then analyzed the effect of compressive spatial summation in terms of changes in the position and size of a viewed object. Compressive spatial summation is consistent with tolerance to changes in position and size, an important characteristic of object representation.
Vascular reactivity and ACE activity response to exercise training are modulated by the +9/−9 bradykinin B2receptor gene functional polymorphism
Authors: Alves Cléber Rene , Alves Guilherme Barreto , Pereira Alexandre Costa , Trombetta Ivani Credidio , Dias Rodrigo Gonçalves , Mota Glória F. A. , Fernandes Tiago , Krieger José Eduardo , Negrão Carlos Eduardo , Oliveira Edilamar Menezes
Published: April 2013

The bradykinin receptor B2( BDKRB2) gene +9/−9 polymorphism has been associated with higher gene transcriptional activity, and characteristics of cardiovascular phenotypes and physical performance. We hypothesized that vasodilation and ACE activity response to exercise training is modulated by BDKRB2gene. We genotyped 71 healthy volunteers were genotyped for the BDKRB2gene polymorphism. Heart rate (HR), mean blood pressure (MBP), and forearm blood flow (FBF) were evaluated. Angiotensin-I converting enzyme (ACE) activity was measured by fluorescence. Aerobic training was performed for 16 wk. All variables were reassessed after completion of the training period. In pretraining period, HR, MBP, FBF, and forearm vascular conductance (FVC) were similar among all genotypes. After physical training, the FBF and the FVC response during handgrip exercise such as area under the curve were higher in −9/−9 carriers than the other two groups. However, there were no changes in HR and MBP for all three groups. In addition, in posttraining period the decrease in ACE activity was higher in the −9/−9 group than the other two groups. These results suggest that reflex muscle vasodilation and ACE activity in response to exercise training are modulated by BDKRB2gene +9/−9 polymorphism in healthy individuals.
Optical Properties of One-Dimensional Structured GaN:Mn Fabricated by a Chemical Vapor Deposition Method
Authors: Ui Sang-Wook , Choi In-Seok , Choi Sung-Churl
Published: April 2013

Group III nitride semiconductors with direct band gaps have recently become increasingly important in optoelectronics and microelectronics applications due to their direct band gaps, which cover the whole visible spectrum and a large part of the UV range. Major developments in wide band gap III–V nitride semiconductors have recently led to the commercial production of high-temperature, high-power electronic devices, light-emitting diodes (LEDs), and laser diodes (LDs). In this study, GaN nanowires were grown on horizontal reactors by chemical vapor deposition (CVD) employing a vapor-solid mechanism. Many studies have described how to control the diameters of wires in the liquid phase catalytic process, but one-dimensional nanostructures, which are grown using a noncatalytic process, are relatively unexplored due to the challenge of producing high-quality synthetic materials of controlled size. However, vapor-solid mechanisms to make synthesized nanowires are simple to implement. We obtained results from GaN nanostructures that were a preferentialc-axis orientation from the substrate. The morphology and crystallinity of the GaN nanowires were characterized by field-emission scanning electron microscopy and X-ray diffraction. The chemical compositions of GaN with Mn were analyzed by energy dispersive X-ray spectroscopy. Optical properties were investigated using photo luminescence and cathode-luminescence measurements.
Evaluation of EEG Features in Decoding Individual Finger Movements from One Hand
Authors: Xiao Ran , Ding Lei
Published: April 2013

With the advancements in modern signal processing techniques, the field of brain-computer interface (BCI) is progressing fast towards noninvasiveness. One challenge still impeding these developments is the limited number of features, especially movement-related features, available to generate control signals for noninvasive BCIs. A few recent studies investigated several movement-related features, such as spectral features in electrocorticography (ECoG) data obtained through a spectral principal component analysis (PCA) and direct use of EEG temporal data, and demonstrated the decoding of individual fingers. The present paper evaluated multiple movement-related features under the same task, that is, discriminating individual fingers from one hand using noninvasive EEG. The present results demonstrate the existence of a broadband feature in EEG to discriminate individual fingers, which has only been identified previously in ECoG. It further shows that multiple spectral features obtained from the spectral PCA yield an average decoding accuracy of 45.2%, which is significantly higher than the guess level (P<0.05) and other features investigated (P<0.05), including EEG spectral power changes in alpha and beta bands and EEG temporal data. The decoding of individual fingers using noninvasive EEG is promising to improve number of features for control, which can facilitate the development of noninvasive BCI applications with rich complexity.
Second-Order Multiagent Systems with Event-Driven Consensus Control
Authors: Hu Jiangping , Zhou Yulong , Lin Yunsong
Published: April 2013

Event-driven control scheduling strategies for multiagent systems play a key role in future use of embedded microprocessors of limited resources that gather information and actuate the agent control updates. In this paper, a distributed event-driven consensus problem is considered for a multi-agent system with second-order dynamics. Firstly, two kinds of event-driven control laws are, respectively, designed for both leaderless and leader-follower systems. Then, the input-to-state stability of the closed-loop multi-agent system with the proposed event-driven consensus control is analyzed and the bound of the inter-event times is ensured. Finally, some numerical examples are presented to validate the proposed event-driven consensus control.
Numerical Investigation of Thin Film Spreading Driven by Surfactant Using Upwind Schemes
Authors: Momoniat E. , Rashidi M. M. , Herbst R. S.
Published: April 2013

Numerical solutions of a coupled system of nonlinear partial differential equations modelling the effects of surfactant on the spreading of a thin film on a horizontal substrate are investigated. A CFL condition is obtained from a von Neumann stability analysis of a linearised system of equations. Numerical solutions obtained from a Roe upwind scheme with a third-order TVD Runge-Kutta approximation to the time derivative are compared to solutions obtained with a Roe-Sweby scheme coupled to a minmod limiter and a TVD approximation to the time derivative. Results from both of these schemes are compared to a Roe upwind scheme and a BDF approximation to the time derivative. In all three cases high-order approximations to the spatial derivatives are employed on the interior points of the spatial domain. The Roe-BDF scheme is shown to be an efficient numerical scheme for capturing sharp changes in gradient in the free surface profile and surfactant concentration. Numerical simulations of an initial exponential free surface profile coupled with initial surfactant concentrations for both exogenous and endogenous surfactants are considered.
Quality of Cosmetic Argan Oil Extracted by Supercritical Fluid Extraction from Argania spinosa L.
Authors: Taribak Chouaa , Casas Lourdes , Mantell Casimiro , Elfadli Zoubaida , Metni Rédouane E. , Martínez de la Ossa Enrique J.
Published: April 2013

Argan oil has been extracted using supercritical CO2. The influence of the variables pressure (100, 200, 300, and 400 bar) and temperature (35, 45, 55°C) was investigated. The best extraction yields were achieved at a temperature of 45°C and a pressure of 400 bar. The argan oil extracts were characterized in terms of acid, peroxide and iodine values, total tocopherol, carotene, and fatty acids content. Significant compositional differences were not observed between the oil samples obtained using different pressures and temperatures. The antioxidant capacity of the argan oil samples was high in comparison to those of walnut, almond, hazelnut, and peanut oils and comparable to that of pistachio oil. The physicochemical parameters of the extracted oils obtained by SFE, Soxhlet, and traditional methods are comparable. The technique used for oil processing does not therefore markedly alter the quality of argan oil.
Multimodal Imaging of Acquired Vitelliform Lesion Diagnosed at Pseudohypopyon Stage
Authors: Gonçalves Nuno Moreira , Carneiro Ângela M. , Brandão Elisete , Falcão-Reis Fernando M.
Published: April 2013

Purpose. To present a case study of a monocular acquired vitelliform lesion, studied with multimodal fundus imaging (spectral-domain-optical coherence tomography, fundus autofluorescence, and fluorescein angiography) with a followup of three years.Case Report. An asymptomatic macular lesion was detected on a 64-year-old man. Fundus exam revealed a macular lesion with an apparent horizontal level associated with multiple round small whitish lesions, suggestive of cuticular drusen. He was studied with autofluorescence of the fundus (FAF), fluorescein angiography (FA), spectral domain-optical coherence tomography (SD-OCT), and electrooculogram. The findings were compatible with the diagnosis of acquired vitelliform lesion, associated with cuticular drusen. After one year, the visual acuity decreased to 20/50, without identifiable alterations of the FAF, FA, or SD-OCT. Three years later, fundoscopy and imaging showed an evolution to a state similar to vitelli disruptive phase of Best disease with an improvement of visual acuity to 20/25. We report the results of FAF, FA, and SD-OCT at this stage.Conclusion. Acquired vitelliform lesions associated with cuticular drusen can present as a pseudohypopyon lesion, and the evolution to the atrophic phase can be associated with an improvement of visual acuity.
Multimodal Imaging in Hereditary Retinal Diseases
Authors: Pichi Francesco , Morara Mariachiara , Veronese Chiara , Nucci Paolo , Ciardella Antonio P.
Published: April 2013

Introduction. In this retrospective study we evaluated the multimodal visualization of retinal genetic diseases to better understand their natural course.Material and Methods. We reviewed the charts of 70 consecutive patients with different genetic retinal pathologies who had previously undergone multimodal imaging analyses. Genomic DNA was extracted from peripheral blood and genotyped at the known locus for the different diseases.Results. The medical records of 3 families of a 4-generation pedigree affected by North Carolina macular dystrophy were reviewed. A total of 8 patients with Stargardt disease were evaluated for their two main defining clinical characteristics, yellow subretinal flecks and central atrophy. Nine male patients with a previous diagnosis of choroideremia and eleven female carriers were evaluated. Fourteen patients with Best vitelliform macular dystrophy and 6 family members with autosomal recessive bestrophinopathy were included. Seven patients with enhanced s-cone syndrome were ascertained. Lastly, we included 3 unrelated patients with fundus albipunctatus.Conclusions. In hereditary retinal diseases, clinical examination is often not sufficient for evaluating the patient’s condition. Retinal imaging then becomes important in making the diagnosis, in monitoring the progression of disease, and as a surrogate outcome measure of the efficacy of an intervention.
Hydromagnetic Non-Darcian Free-Convective Flow of a Non-Newtonian Fluid with Temperature Jump
Authors: Salem Ahmed M. , Abd El-Aziz Mohamed
Published: April 2013

In the present study, the effect of viscous dissipation on magnetohydrodynamic (MHD) non-Darcian free-convection flow of a non-Newtonian power-law fluid past a vertical flat plate in a saturated porous medium with variable viscosity and temperature jump is considered. The fluid is permeated by a transverse magnetic field imposed perpendicularly to the plate on the assumption of a small magnetic Reynolds number. The fluid viscosity is assumed to vary as a reciprocal of linear function of temperature. The governing boundary layer equations and boundary conditions are cast into a dimensionless form and simplified by using a similarity transformation into a system of nonlinear ordinary differential equations and solved numerically. The effects of the governing parameters on the flow fields and heat transfer are shown in graphs and tabular form.
Late Adherent Human Bone Marrow Stromal Cells Form Bone and Restore the Hematopoietic MicroenvironmentIn Vivo
Authors: Vianna Verônica Fernandes , Bonfim Danielle Cabral , Cavalcanti Amanda dos Santos , Fernandes Marco Cury , Kahn Suzana Assad , Casado Priscila Ladeira , Lima Inayá Correa , Murray Samuel S. , Murray Elsa J. Brochmann , Duarte Maria Eugenia Leite
Published: April 2013

Bone marrow stromal cells (BMSCs) are a valuable resource for skeletal regenerative medicine because of their osteogenic potential. In spite of the very general term “stem cell,” this population of cells is far from homogeneous, and different BMSCs clones have greatly different phenotypic properties and, therefore, potentially different therapeutic potential. Adherence to a culture flask surface is a primary defining characteristic of BMSCs. We hypothesized that based on the adherence time we could obtain an enriched population of cells with a greater therapeutic potential. We characterized two populations of bone marrow-derived cells, those that adhered by three days (R-cells) and those that did not adhere by three days but did by six days (L-cells). Clones derived from L-cells could be induced into adipogenic, chondrogenic, and osteogenic differentiationin vitro. L-cells appeared to have greater proliferative capacity, as manifested by larger colony diameter and clones with higher CD146 expression. Only clones from L-cells developed bone marrow stromain vivo. We conclude that the use of late adherence of BMSCs is one parameter that can be used to enrich for cells that will constitute a superior final product for cell therapy in orthopedics.
Finite Unions ofD-Spaces and Applications of Nearly Good Relation
Authors: Zhang Xin , Guo Hongfeng , Xu Yuming
Published: April 2013

Some results are obtained on finite unions ofD-spaces. It is proved that if a space is the union of finitely many locally compactD-subspaces, then it is aD-space. It follows that a space is aD-space if it is the union of finitely many locally compact submetacompact subspaces. And a space is aD-space if it is the union of aD-subspace with a locally compactD-subspace. This partially answers one problem raised by Arhangel’skii. At last, some examples are given to exhibit the applications of nearly good relation to discoverD-classes.
Invariants for Weighted Digraphs under One-Sided State Splittings
Authors: Chen Sheng , Chen Xiaomei , Xia Chao
Published: April 2013

Using Matrix-Forest theorem and Matrix-Tree theorem, we present some invariants for weighted digraphs under state in-splittings or out-splittings.
Multiple Roles for the sRNA GcvB in the Regulation of Slp Levels inEscherichia coli
Authors: Stauffer Lorraine T. , Stauffer George V.
Published: April 2013

TheEscherichia coli gcvBgene encodes a small RNA that regulates many genes involved in the transport of dipeptides, oligopeptides, and amino acids (oppA,dppA,cycA, andsstT). A microarray analysis of RNA isolated from anE. coliwild-type and aΔgcvBstrain grown to midlog phase in Luria-Bertani broth indicated that genes not involved in transport are also regulated by GcvB. One gene identified wasslpthat encodes an outer membrane lipoprotein of unknown function induced when cells enter stationary phase. The aim of this study was to verify thatslpis a new target for GcvB-mediated regulation. In this study we used RT-PCR to show that GcvB regulatesslpmRNA levels. GcvB negatively controlsslp::lacZin cells grown in Luria-Bertani broth by preventing an Hfq-mediated activation mechanism forslp::lacZexpression. In contrast, in glucose minimal medium supplemented with glycine, GcvB is required for inhibition ofslp::lacZexpression, and Hfq prevents GcvB-mediated repression. Thus, GcvB regulatesslpin both LB and in glucose minimal + glycine media and likely by mechanisms different than how it regulatessstT,dppA,cycA,andoppA. Repression ofslpby GcvB results in an increase in resistance to chloramphenicol, and overexpression ofslpin aΔgcvBstrain results in an increase in sensitivity to chloramphenicol.
OntCheck: An Ontology-Driven Static Correctness Checking Tool for Component-Based Models
Authors: Lin Xi , Zhang Hehua , Gu Ming
Published: April 2013

Component-based models are widely used for embedded systems. The models consist of components with input and output ports linked to each other. However, mismatched links or assumptions among components may cause many failures, especially for large scale models. Binding semantic knowledge into models can enable domain-specific checking and help expose modeling errors in the early stage. Ontology is known as the formalization of semantic knowledge. In this paper we propose an ontology-driven tool for static correctness checking of domain-specific errors. two kinds of important static checking, semantic type and domain-restrcted rules, are fulfilled in a unified framework. We first propose a formal way to precisely describe the checking requirements by ontology and then separately check them by a lattice-based constraint solver and a description logic reasoner. Compared with other static checking methods, the ontology-based method we proposed is model-externally configurable and thus flexible and adaptable to the changes of requirements. The case study demonstrates the effectiveness of our method.
RXRα Inhibits the NRF2-ARE Signaling Pathway through a Direct Interaction with the Neh7 Domain of NRF2
Authors: Wang Hongyan , Liu Kaihua , Geng Miao , Gao Peng , Wu Xiaoyuan , Hai Yan , Li Yangxia , Li Yulong , Luo Lin , Hayes John D. , Wang Xiu Jun , Tang Xiuwen
Published: April 2013

The transcription factor NRF2 (NFE2L2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that limit the action of cytotoxic therapies in cancer. NRF2 acts by binding antioxidant response elements (ARE) in its target genes, but there is relatively limited knowledge about how it is negatively controlled. Here, we report that retinoic X receptor alpha (RXRα) is a hitherto unrecognized repressor of NRF2. RNAi-mediated knockdown of RXRα increased basal ARE-driven gene expression and induction of ARE-driven genes by the NRF2 activator tert-butylhydroquinone (tBHQ). Conversely, overexpression of RXRα decreased ARE-driven gene expression. Biochemical investigations showed that RXRα interacts physically with NRF2 in cancer cells and in murine small intestine and liver tissues. Furthermore, RXRα bound to ARE sequences in the promoters of NRF2-regulated genes. RXRα loading onto AREs was concomitant with the presence of NRF2, supporting the hypothesis that a direct interaction between the two proteins on gene promoters accounts for the antagonism of ARE-driven gene expression. Mutation analyses revealed that interaction between the two transcription factors involves the DNA-binding domain of RXRα and a region comprising amino acids 209-316 in human NRF2 that had not been defined functionally, but that we now designate as the NRF2-ECH homology (Neh) 7 domain. In non–small cell lung cancer cells where NRF2 levels are elevated, RXRα expression downregulated NRF2 and sensitized cells to the cytotoxic effects of therapeutic drugs. In summary, our findings show that RXRα diminishes cytoprotection by NRF2 by binding directly to the newly defined Neh7 domain in NRF2. Cancer Res; 73(10); 3097–108. ©2013 AACR.
Targeting the BRAF V600E Mutation in Multiple Myeloma
Authors: Andrulis Mindaugas , Lehners Nicola , Capper David , Penzel Roland , Heining Christoph , Huellein Jennifer , Zenz Thorsten , von Deimling Andreas , Schirmacher Peter , Ho Anthony D. , Goldschmidt Hartmut , Neben Kai , Raab Marc S.
Published: April 2013

In multiple myeloma, there has been little progress in the specific therapeutic targeting of oncogenic mutations. Whole-genome sequencing data have recently revealed that a subset of patients carry an activating mutation (V600E) in the BRAF kinase. To uncover the clinical relevance of this mutation in multiple myeloma, we correlated the mutation status in primary tumor samples from 379 patients with myeloma with disease outcome. We found a significantly higher incidence of extramedullary disease and a shorter overall survival in mutation carriers when compared with controls. Most importantly, we report on a patient with confirmed BRAF V600E mutation and relapsed myeloma with extensive extramedullary disease, refractory to all approved therapeutic options, who has rapidly and durably responded to low doses of the mutation-specific BRAF inhibitor vermurafenib. Collectively, we provide evidence for the development of the BRAF V600E mutation in the context of clonal evolution and describe the prognostic and therapeutic relevance of this targetable mutation.

Significance: This is the first evidence of the clinical and therapeutic relevance of BRAF V600E mutations in multiple myeloma, proving the principle of specific inhibition of driver mutations in this disease. Cancer Discov; 3(8); 862–9. ©2013 AACR.

See related commentary by O'Donnell and Raje, p. 840

This article is highlighted in the In This Issue feature, p. 826
Symptom Dimensions in Obsessive-Compulsive Disorder: Phenomenology and Treatment Outcomes with Exposure and Ritual Prevention
Authors: Williams Monnica T. , Mugno Beth , Franklin Martin , Faber Sonya
Published: April 2013

Background: Obsessive-compulsive disorder (OCD) is a severe condition with varied symptom presentations. Currently, the cognitive-behavioral treatment with the most empirical support is exposure and ritual prevention (EX/RP); however, clinical impression and some empirical data suggest that certain OCD symptoms are more responsive to treatment than others. Methods: Prior work identifying symptom dimensions within OCD is discussed, including epidemiological findings, factor analytic studies, and biological findings. Symptom dimensions most reliably identified include contamination/cleaning, doubt about harm/checking, symmetry/ordering, and unacceptable thoughts/mental rituals. The phenomenology of each of these subtypes is described and research literature is summarized, emphasizing the differential effects of EX/RP and its variants on each of these primary symptom dimensions. Results: To date it appears that EX/RP is an effective treatment for the various OCD dimensions, although not all dimensions have been adequately studied (i.e. symmetry and ordering). Conclusions: Modifications to treatment may be warranted for some types of symptoms. Clinical implications and directions for future research are discussed.
Brain Size and Morphology of the Brood-Parasitic and Cerophagous Honeyguides (Aves: Piciformes)
Authors: Corfield Jeremy R. , Birkhead Tim R. , Spottiswoode Claire N. , Iwaniuk Andrew N. , Boogert Neeltje J. , Gutiérrez-Ibáñez Cristian , Overington Sarah E. , Wylie Douglas R. , Lefebvre Louis
Published: April 2013

Honeyguides (Indicatoridae, Piciformes) are unique among birds in several respects. All subsist primarily on wax, are obligatory brood parasites and one species engages in ‘guiding' behavior in which it leads human honey hunters to bees' nests. This unique life history has likely shaped the evolution of their brain size and morphology. Here, we test that hypothesis using comparative data on relative brain and brain region size of honeyguides and their relatives: woodpeckers, barbets and toucans. Honeyguides have significantly smaller relative brain volumes than all other piciform taxa. Volumetric measurements of the brain indicate that honeyguides have a significantly larger cerebellum and hippocampal formation (HF) than woodpeckers, the sister clade of the honeyguides, although the HF enlargement was not significant across all of our analyses. Cluster analyses also revealed that the overall composition of the brain and telencephalon differs greatly between honeyguides and woodpeckers. The relatively smaller brains of the honeyguides may be a consequence of brood parasitism and cerophagy (‘wax eating'), both of which place energetic constraints on brain development and maintenance. The inconclusive results of our analyses of relative HF volume highlight some of the problems associated with comparative studies of the HF that require further study.
Transitional Cell Carcinoma of the Ureteric Stump: A Systematic Review of the Literature
Authors: Bourdoumis Andreas , Syed Imran , Soosay Geraldine , Manzoor Ahmed , Barua Jayanta
Published: April 2013

Objective: To present a review of the literature using evidence-based criteria for diagnosis and treatment of malignant growths in the ureteric remnant following nephrectomy for non-malignant disease. Methods: A database search using the key search words was performed, producing a total of 16 articles published between 1952 and 2009. The Oxford Centre for Evidence-Based Medicine classification was used. Statistical significance was tested by Pearson correlation. Demographic data, reason for nephrectomy, symptoms, time to diagnosis since initial nephrectomy, imaging modality and treatment option chosen, as well as histology and overall survival were reviewed. Results: Analysis was possible for 33 out of 63 cases reported in the literature. There was a male predominance (82%). Visible, painless haematuria was the presenting symptom in 72% of cases. Open ureterectomy was performed in the majority of patients (85%), while none had laparoscopic surgery. Transitional cell carcinoma was found in 66% of cases. Mean follow-up was 2.7 years. Metastases were detected in 36% and correlated significantly with cancer-specific mortality (95% CI: p < 0.001). Tumour stage, grade and cell type did not correlate significantly with mortality. Conclusion: Gross, painless haematuria is a feature highly suggestive of neoplastic change. Diagnosis often involves multimodality imaging and endoscopy. Complete ureterectomy with removal of bladder cuff, previously resected endoscopically, is the treatment of choice. Metastases at diagnosis and follow-up carry a worse prognosis.
Reassessment of the Normal Fetal Cisterna Magna during Gestation and an Alternative Approach to the Definition of Cisterna Magna Dilatation
Authors: Brown Richard N.
Published: April 2013

Introduction: Cisterna magna (CM) measurement constitutes part of the sonographic assessment of the posterior fossa. CM enlargement (ECM) is defined as a measurement exceeding 10 mm, although it has previously been noted that the CM varies in size with gestation. Existing data do not appear to reflect observations regarding CM biometry within our population and this study was therefore undertaken in order to re-evaluate CM biometry. Materials and Methods: Data from 4,750 normal pregnancies between 15 and 32 weeks of gestation were collected and used to construct a reference range for the CM. Results: Regression analysis was used to model CM across gestational age and thereby define the upper limits for normal CM measurements across gestation. The CM increases with gestation. These data suggest that a 10-mm cut-off underestimates ECM, notably in the gestational age period below 24 weeks, whilst overestimating isolated ECM beyond this. Differences in CM measurements between genders were confirmed (p < 0.0001). Conclusions: Defining ECM based upon a cut-off of 10 mm across all gestations may be inappropriate given the variation observed with gestational age. More accurate identification of fetuses with, in particular, isolated ECM may facilitate more precise evaluation of the clinical significance of this finding.
CD300c is an Activating Receptor Expressed on Human Monocytes
Authors: Simhadri Venkateswara R. , Mariano John L. , Gil-Krzewska Aleksandra , Zhou Qing , Borrego Francisco
Published: April 2013

Human CD300 molecules comprise a family of receptors that regulate many immune cell processes. They are mostly expressed on myeloid cells, although expression of two members, CD300a and CD300c, has also been described on lymphocytes. However, due to the lack of specific antibodies that distinguish between these two receptors, it has been difficult to determine the expression pattern and function of CD300a and CD300c in primary cells. Here, we have identified a specific monoclonal antibody, clone TX45, that recognizes only CD300c and show that within freshly isolated blood leukocytes, monocytes are the only cells that express CD300c on the cell surface. In vitro differentiation experiments revealed that CD300c is differentially expressed on different monocyte-derived cells, including macrophages and dendritic cells. Furthermore, TLR ligands LPS and flagellin dynamically regulate the expression of CD300c. Cross-linking of this receptor with clone TX45 monoclonal antibody induced calcium mobilization, upregulation of the costimulatory molecule CD86 and the production of inflammatory cytokines. Importantly, LPS-mediated production of inflammatory cytokines by monocytes was further enhanced if CD300c was simultaneously engaged by the agonist antibody. Altogether, our results show that human CD300c is an activating receptor expressed on monocytes and that it has a potential role in inflammatory responses.
Update on Body Composition and Bone Density in Children with Prader-Willi Syndrome
Authors: Rubin Daniela A. , Cano-Sokoloff Natalia , Castner Diobel L. , Judelson Daniel A. , Wright Pamela , Duran Andrea , Haqq Andrea M.
Published: April 2013

Aim: To compare body composition in children with Prader-Willi syndrome (PWS) not naïve to growth hormone (GH) with obese and lean controls. Methods: Participants included 12 children with PWS, 12 children with obesity (body fat percentage >95th percentile for age and sex) and 12 lean children (body fat percentage <85th percentile for age and sex) matched by age and height. Fat mass, lean mass, bone mineral content (BMC), bone mineral density (BMD) and BMD z-score for total body, hips and lumbar spine were obtained through dual X-ray absorptiometry. Results: PWS had higher fat percentage in the legs (p = 0.04) but similar leg fat mass (p = 1.00) compared to obese. PWS exhibited lower lean mass in the body (p = 0.04) and legs (p = 0.02) than obese, but similar to lean (p = 1.00 and p = 0.89, respectively). PWS had lower hip BMC (p < 0.01), BMD (p < 0.01) and BMD z-score (p < 0.01) compared to obese but similar to lean. No other differences were found between PWS and obese (p > 0.05 for all). Conclusions: Children with PWS not naïve to GH present differences in fat and lean mass distribution compared to obese controls. BMC and BMD appear unaffected by PWS, except at the hips.
Follistatin Is an Early Player in Rainbow Trout Ovarian Differentiation and Is Both Colocalized with Aromatase and Regulated by the Wnt Pathway
Authors: Nicol B. , Yano A. , Jouanno E. , Guérin A. , Fostier A. , Guiguen Y.
Published: April 2013

In mammals, follistatin (FST) plays an important role in early ovarian differentiation, acting downstream of the Wnt pathway. In teleost fish, fst is implicated in folliculogenesis and oocyte maturation, and an early and specific expression during ovarian differentiation has been described in rainbow trout, Oncorhynchus mykiss. By in situ hybridization, we demonstrated that during rainbow trout gonadal differentiation, fst shares a similar expression pattern with cyp19a1a, the gene encoding ovarian aromatase, a key steroidogenic enzyme needed for ovarian differentiation in fish. Expression of fst and cyp19a1a was first detected in a few scattered cells in the embryonic ovary several days before hatching. Then, after histological differentiation, fst and cyp19a1a expression was localized in clusters of cells lining the future ovarian lamellae. As FST expression is known to be induced by the Wnt/β-catenin pathway in mammals, the Wnt pathway was inhibited in vivo with the IWR-1 molecule, and we analyzed by qPCR the effects of this treatment on fst expression. We found that IWR-1 decreased fst expression in female gonads, consistent with a regulation of fst expression by the Wnt pathway in rainbow trout. Furthermore, expression of cyp19a1a was also downregulated, suggesting an implication of the Wnt pathway in ovarian differentiation.
Pegylation of High-Density Lipoprotein Decreases Plasma Clearance and Enhances Antiatherogenic Activity
Authors: Murphy Andrew J. , Funt Samuel , Gorman Darren , Tall Alan R. , Wang Nan
Published: April 2013

Rationale:

Infusions of apolipoprotein AI (apoAI), mimetic peptides, or high-density lipoprotein (HDL) remain a promising approach for the treatment of atherosclerotic coronary disease. However, rapid clearance leads to a requirement for repeated administration of large amounts of material and limits effective plasma concentrations.

Objective:

Because pegylation of purified proteins is commonly used as a method to increase their half-life in the circulation, we determined whether pegylation of apoAI or HDL would increase its plasma half-life and in turn its antiatherogenic potential.

Methods and Results:

Initial pegylation attempts using lipid-poor apoAI showed a marked tendency to form multi-pegylated (PEG) species with reduced ability to promote cholesterol efflux from macrophage foam cells. However, pegylation of human holo-HDL or reconstituted phospholipid/apoAI particles (rHDL) led to selective N-terminal monopegylation of apoAI with full preservation of cholesterol efflux activity. The plasma clearance of PEG-rHDL was estimated after injection into hypercholesterolemic
Apoe

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mice; the half-life of pegylated PEG-apoAI after injection of PEG-rHDL was increased ≈7-fold compared with apoAI in nonpegylated rHDL. In comparison with nonpegylated rHDL, infusion of PEG-rHDL (40 mg/kg) into hypercholesterolemic
Apoe

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mice led to more pronounced suppression of bone marrow myeloid progenitor cell proliferation and monocytosis, as well as reduced atherosclerosis and a stable plaque phenotype.

Conclusions:

We describe a novel method for effective monopegylation of apoAI in HDL particles, in which lipid binding seems to protect against pegylation of key functional residues. Pegylation of apoAI in rHDL markedly increases its plasma half-life and enhances antiatherogenic properties in vivo.
MiRNA-424 Protects Against Permanent Focal Cerebral Ischemia Injury in Mice Involving Suppressing Microglia Activation
Authors: Zhao Haiping , Wang Jun , Gao Li , Wang Rongliang , Liu Xiangrong , Gao Zhi , Tao Zhen , Xu Changmin , Song Juexian , Ji Xunming , Luo Yumin
Published: April 2013

Background and Purpose—

We observed that microRNA-424 (miR-424) significantly decreased in an miRNA profile of circulating lymphocytes of patients with ischemic stroke. The present study focused on the potential and mechanism of miR-424 in protecting ischemic brain injury in mice.

Methods—

Cerebral ischemia was induced by middle cerebral artery occlusion in C57/BL6 mice. Cerebral infarction volume, neuronal apoptosis, and microglia activation were determined by 2,3,5-triphenyltetrazolium chloride staining, immunofluorescence, and Western blot. BV2 microglial cell activity, cell cycle, mRNA, and protein levels of miR-424 targets were accessed by enzyme-linked immunosorbent assay, flow cytometry, real-time polymerase chain reaction, and Western blot, respectively.

Results—

MiR-424 levels were decreased in the plasma of patients with acute ischemic stroke, as well as in mouse plasma and ipsilateral brain tissue at 4, 8, and 24 hours after ischemia, likewise, in the cortex, hippocampus, and basal ganglia, respectively, after 8-hour ischemia. Interestingly, pre- and post-treatment with overexpression of miR-424 both decreased cerebral infarction size and brain edema after middle cerebral artery occlusion. Meanwhile, lentiviral overexpression of miR-424 inhibited neuronal apoptosis and microglia activation, including suppressing ionized calcium binding adaptor molecule-1 immunoreactivity and protein level, and reduced tumor necrosis factor-α production. In vitro study demonstrated that miR-424 mimics caused G1 phase cell-cycle arrest, inhibited BV2 microglia activity, and reduced the mRNA and protein levels of CDC25A, cyclin D1, and CDK6 in BV2 microglial cells, which were upregulated in brain of middle cerebral artery occlusion mice.

Conclusions—

MiR-424 overexpression lessened the ischemic brain injury through suppressing microglia activation by translational depression of key activators of G1/S transition, suggesting a novel miR-based intervention strategy for stroke.
Field Testing the Utility of Procalcitonin and the Acute Infantile Observation Score in Febrile Infants 6 to 36 Months Old Presenting to the Pediatric Emergency Department With No Obvious Focus of Infection
Authors: Freyne Bridget , Divilley Ray , Kissoon-Harrison Ghia , O’Neill Michael B.
Published: April 2013

Background. Serious bacterial illness (SBI) presents a diagnostic challenge in febrile infants. History, clinical signs, and laboratory information combined with experiential knowledge affects decisions to admit and treat. Aim. To assess the utility of serum procalcitonin and the Acute Infantile Observation Score (AIOS) performed at emergency department presentation in predicting (a) confirmed serious bacterial illness and (b) illness severity. Methods. Sensitivity, specificity, and likelihood ratios were calculated for C-reactive protein, white cell count, serum procalcitonin, and AIOS. Results. Forty-six infants were recruited. Seven had a diagnosis of SBI, 28 were moderately ill with length of stay >24 hours, and 12 were severely ill with length of stay >96 hours. The positive likelihood ratios for confirmed SBI were C-reactive protein = 5.3, procalcitonin = 0.43, white cell count = 1.9, and AIOS = 1.5. Conclusion. Procalcitonin and the AIOS do not modify the diagnostic uncertainty of the ED physician assessing the febrile infant with respect to admission or antibiotic treatment above standard laboratory investigations.
Predicting Anatomical Urological Abnormalities in Children Who Present With Their First Urinary Tract Infection
Authors: Zanetta Vitor C. , Rosman Brian M. , Rowe Courtney K. , Buonfiglio Helena B. , Passerotti Carlo C. , Yu Richard N. , Nguyen Hiep T.
Published: April 2013

Objectives. Classically, presence of fever ≥38.0°C is used to distinguish pyelonephritis from cystitis. We analyzed whether this is an appropriate marker to initiate further workup and whether temperature is correlated with urological abnormalities and further surgical or pharmacological intervention. Methods. Children who presented for their first workup of urinary tract infection between October 1, 2008, and September 30, 2009 were retrospectively selected from our institution. Demographics and clinical details were correlated with the diagnosis of urological abnormalities and requirement for intervention. Results. Age was the most important variable to predict urological abnormalities. The temperature value of 38.3°C maximized the balance between sensitivity (90%) and specificity (46%) for predicting the need to intervene and the presence of anatomical urological abnormalities. Conclusion. Young age (≤2 years) and temperature are the best factors to predict further intervention and urological abnormalities, with a temperature value of 38.3°C being a better predictive value than the currently used 38.0°C.