bluuebunny/crossref_metadata_2025 huggingface dataset:
Fine needle aspiration cytology of insular carcinoma of thyroid
Authors: Barwad Adarsh , Dey Pranab , Nahar Saikia Uma , Gupta Nalini , Rajwanshi Arvind , Nijhawan Raje , Srinivasan Radhika
Published: February 2011

Poorly differentiated (insular) thyroid carcinoma is defined as a thyroglobulin‐producing non‐follicular non‐papillary thyroid carcinoma, having an intermediate behavior between well‐differentiated and anaplastic carcinomas. FNAC is widely used as aid for workup of thyroid gland lesion. However, scant information is available in the literature about cytologic findings of this rare entity.

Ten cases of surgically resected insular carcinoma with a corresponding cytology were selected. The cytologic smears and histological sections were reviewed for presence of cytomorphologic features including cellularity, predominant cytoarchitectural pattern, additional cytologic co‐patters pattern, cell size, cell shape, nuclear pleomorphism, nuclear/cytoplasmic (N/C) ratio, chromatin pattern, amount of cytoplasm, mitotic figures, colloid, background debris, nuclear grooves, and intranuclear pseudoinclusions.

In all the cases, the cells were arranged predominantly in solid clusters. Focal microfollicular pattern was identified in five cases of which three cases showed presence of inspissated colloid within the follicles. Singly scattered malignant cells and bare nuclei were seen in all cases. Cells were monomorphic, round with high N/C ratio, finely granular chromatin and inconspicuous nucleoli. Background showed presence of cellular debris in two cases. Mitotic figures were obvious and atypical mitosis was also identified.

Cellular smears composed of monomorphic population of small cells arranged in large clusters and sheets with high N/C ratio and high mitosis suggest the possibility of insular carcinoma. Background cellular debris/necrosis also supports the diagnosis. Cell block preparation in these cases may be of additional help in accurate diagnosis. © Diagn. Cytopathol. 2012;40:E43–E47. © 2011 Wiley Periodicals, Inc.
Episodic memory in 3‐ and 4‐year‐old children
Authors: Hayne Harlene , Imuta Kana
Published: February 2011

There is considerable debate about the phylogenic and ontogenic origins of episodic memory. In the present experiment, we examined episodic memory in 3‐ and 4‐year‐old children. To do this, we developed a hide‐and‐seek task that allowed us to assess children's recall of thewhat‐where‐when (www)of the hiding event. In this task, the experimenter and the child hid three plush toys in three separate locations around the house. After a brief retention interval, children were asked to verbally recall, in order (i.e.,when),whattoy was hidingwhere. Following this verbal test, children were given the opportunity to find the toys. On the verbal recall test, 4‐year‐olds reported more information than 3‐year‐olds. On the behavioral recall test, 3‐year‐olds performed equivalently to 4‐year‐olds on thewherecomponents of the test, however, their performance on thewhencomponent remained inferior to that of 4‐year‐olds. We conclude that, by the age of 3, children exhibit rudimentary episodic memory skills, and that strict reliance on verbal recall may underestimate their episodic memory ability. © 2011 Wiley Periodicals, Inc. Dev Psychobiol 53:317–322, 2011.
Three methodologies for measuring the acoustic startle response in early infancy
Authors: Agnoli Sergio , Franchin Laura , Dondi Marco
Published: February 2011

The present study investigated whether three methodologies currently used in animal as well as human adult startle research could be adapted for measuring the startle response in 5‐month‐old infants. The three methods performed: an automated and computerized recording of the infants' whole‐body motor reactions (Automated Infant Motor Movement Startle Seat, AIMMSS); a coding of the infants' facial muscular contractions involved in the startle response (FACS, Baby FACS); an analysis of the infants' eyeblink intensity in response to the startle probes (Eye‐Blink Strength scale). The results showed that these methods accurately registered the latency and intensity parameters of the reactions to acoustic startle stimuli. A correlational analysis showed, also, that the three methods registered the same motor reaction measuring the infant acoustic startle response in a consistent way. © 2011 Wiley Periodicals, Inc. Dev Psychobiol 53:323–329, 2011.
The “enduring mission” of Zing‐Yang Kuo to eliminate the nature–nurture dichotomy in psychology
Authors: Honeycutt Hunter
Published: February 2011

This paper reviews the arguments against the instinct concept and the nature–nurture dichotomy put forward by Zing‐Yang Kuo (1898–1970) during the 1920s. Kuo insisted that nativism represented a kind of finished psychology, and that the labels of nature and nurture reflected and promoted one's ignorance of the development of a trait. Also discussed are his lesser known lines of research on the origins of the so‐called rat‐killing instinct in cats and his analysis on the determinants of animal fighting. His research illustrated the shortcomings of a nature–nurture framework and highlighted the necessity of his developmentally grounded alternative to studying behavior. Reasons for why Kuo's work has been marginalized in modern histories of psychology are also discussed. © 2011 Wiley Periodicals, Inc. Dev Psychobiol 53:331–342, 2011.
Effects of physical exercise on ADHD‐like behavior in male and female adolescent spontaneously hypertensive rats
Authors: Robinson Andrea M. , Hopkins Michael E. , Bucci David J.
Published: February 2011

The present study examined the effects of exercising (voluntary wheel running) during adolescence on attentional function in male and female spontaneously hypertensive rats (SHRs), a commonly used animal model of attention‐deficit/hyperactivity disorder (ADHD). Once rats reached adulthood, they received one session in which a light was presented 12 times but not reinforced, followed by training sessions in which the light was paired with a food reward. Male and female SHRs that had access to running wheels exhibited levels of unconditioned orienting behavior that were similar to Wistar–Kyoto rats (normo‐active control) while SHRs that did not have access to running wheels exhibited higher levels of unconditioned orienting behavior. When the light was later paired with food there were no differences between the groups of male rats, but exercising female SHRs exhibited a decrease in conditioned food cup behavior. Consistent with their established phenotype, SHR rats exhibited more locomotor activity during an open field exploration session than WKY rats, but there was no relationship between orienting behavior and locomotor activity. Together these data suggest that physical exercise during adolescence can benefit attentional capabilities. © 2011 Wiley Periodicals, Inc. Dev Psychobiol 53:383–390, 2011.
The cytoskeletal and signaling mechanisms of axon collateral branching
Authors: Gallo Gianluca
Published: February 2011

During development, axons are guided to their appropriate targets by a variety of guidance factors. On arriving at their synaptic targets, or while en route, axons form branches. Branches generated de novo from the main axon are termed collateral branches. The generation of axon collateral branches allows individual neurons to make contacts with multiple neurons within a target and with multiple targets. In the adult nervous system, the formation of axon collateral branches is associated with injury and disease states and may contribute to normally occurring plasticity. Collateral branches are initiated by actin filament–based axonal protrusions that subsequently become invaded by microtubules, thereby allowing the branch to mature and continue extending. This article reviews the current knowledge of the cellular mechanisms of the formation of axon collateral branches. The major conclusions of this review are (1) the mechanisms of axon extension and branching are not identical; (2) active suppression of protrusive activity along the axon negatively regulates branching; (3) the earliest steps in the formation of axon branches involve focal activation of signaling pathways within axons, which in turn drive the formation of actin‐based protrusions; and (4) regulation of the microtubule array by microtubule‐associated and severing proteins underlies the development of branches. Linking the activation of signaling pathways to specific proteins that directly regulate the axonal cytoskeleton underlying the formation of collateral branches remains a frontier in the field. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 71: 201–220, 2011.
Phytochemical and biological investigation of the extracts of Nigella sativa L. seed waste
Authors: Michel Camilia G. , El‐Sayed Nesrine S. , Moustafa Sherifa F. , Ezzat Shahira M. , Nesseem Demiana I. , El‐Alfy Taha S.
Published: February 2011

Different extracts of Nigella sativa L. seed waste; aqueous (AE) 200 mg/kg, ethanol 70% (EE) 250 mg/kg and hexane (HE) 10 mg/kg, were evaluated for their hepatoprotective activities. They were administered orally, once daily, for 5 consecutive days. On day 5, liver injury was induced in animals by a single i.p. injection of carbon tetrachloride (10 mg/kg b. w. of 0.25% (v/v). Hepatoxicity produced, was evaluated by both biochemical and histopathological investigations. The aqueous extract attenuated the CCl4‐induced liver damage likely due to the decrease of proinflammatory cytokines and T‐cell proliferation. This was noticed by a significant decrease in both serum and tissue cytokines; tumor necrosis factor‐alpha (TNF‐α), interferon‐gamma (INF‐γ) and interlukin‐beta (IL‐1β), in the markers of liver functions; bilirubin and glutamic pyruvic transaminase (GPT) and in the oxidative stress markers; malondialdehyde (MDA) and glutathione content (GSH). Fractionation of this extract was performed and its component, protein, saponin, and polyphenol fractions were evaluated by appropriate analytical procedures. The crude protein of the seed waste reached 36.85% while protein fingerprint showed four bands ranging from 91.97 KD and 29.00 KD. The saponin content was evaluated through the determination of the haemolytic index and reached 15.56 mg/g dry powder. Finally, Folin Ciocalteu method was used for the determination of the total polyphenols. The same biochemical and histopathological studies were again performed on the different fractions of the aqueous extract; protein fraction (PF) 10 mg/kg, saponin fraction (SF) 5 mg/kg and polyphenol fraction (FF) 10 mg/kg. The biochemical changes were improved only by the protein fraction (PF) of the seed waste of Nigella sativa. This was manifested by a significant reduction in both serum and tissue cytokines in the liver markers and in the oxidative stress markers. Moreover, liver histopathology showed that (PF) reduced the incidence of liver lesions including hepatic cells cloudy swelling, lymphocytes infiltration, hepatic necrosis and fibrous connective tissue proliferation induced by CCl4 in mice. From this study, it is concluded that the protein fraction of the aqueous extract of Nigella sativa seed waste exhibited a promising hepatoprotective effect in the management of different liver disorders. Copyright © 2011 John Wiley & Sons, Ltd.
Simultaneous estimation of atorvastatin and its two metabolites from human plasma by ESI‐LC‐MS/MS
Authors: Ghosh Chinmoy , Jain Ina , Gaur Shashank , Patel Niraj , Upadhyay Anita , Chakraborty Bhaswat S.
Published: February 2011

A selective, sensitive, and fast high performance liquid chromatography (HPLC) method with mass spectrometric (MS) detection mode has been developed and validated completely in human plasma. Atorvastatin (ATO), p‐hydroxy atorvastatin (p‐HATO), o‐hydroxy atorvastatin (o‐HATO) and internal standard (IS) are extracted from human plasma via solid phase extraction (SPE) technique. After elution, the solution is evaporated, then reconstituted with 250 µL of Mobile Phase and analyzed using HPLC/MS/MS system. An isocratic mode is used to separate interference peaks using a Symmetry C‐18, 75 × 4.6 mm ID, 3.5 µ, column. The m/z of ATO, o‐HATO and p‐HATO are 559.2/440.2, 575.3/440.4 and 575.0/440.4 respectively. Linearity ranges are 0.05 to 252.92 ng/mL for ATO, p‐HATO and o‐HATO respectively. Calibration functions, lower limit of quantitation (LLOQ), stability, intra‐ and inter‐day reproducibility, accuracy, and recovery are estimated. This method is free from matrix effects and any abnormal ionization. This method was successfully applied to a single dose 80 mg tablet bioequivalence (BE) study of Atorvastatin. Copyright © 2011 John Wiley & Sons, Ltd.
Voltammetric determination of isoproterenol using multiwall carbon nanotubes‐ionic liquid paste electrode
Authors: Ensafi Ali A. , Karimi‐Maleh H.
Published: February 2011

A sensitive and selective electrochemical method for the determination of isoproterenol (ISPT) was developed using multiwall carbon nanotubes and a room temperature ionic liquid (i.e. 1‐butyl‐3‐methylimidazolium hexafluoro phosphate, ([C4mim]‐[PF6])). This multiwall carbon nanotubes ionic liquid electrode (MWCNTILEE) is a very good alternative to previously described electrodes because the electrocatalytic effect is achieved without any electrode modification. The oxidation peak potentials in cyclic voltammogram of ISPT on MWCNTILEE was occurred around 470 mV vs Ag/AgCl (at pH 6.0) while this peak potential at carbon paste electrode was appeared around 605 mV at the same scan rate of 100 mV s−1. The electrochemical parameters such as diffusion coefficient and charge transfer resistance were determined using cyclic voltammetry and electrochemical impedance spectroscopy. Under the optimized conditions, the peak current was linear to ISPT concentration over the concentration range of 1.0 to 520 µmol L−1 using differential pulse voltammetry. The detection limit was 0.85 µmol L−1. The proposed method was successfully applied to the determination of ISPT in both ampoules and urine samples. Copyright © 2011 John Wiley & Sons, Ltd.
The planar cell polarity pathway in vertebrate development
Authors: Wansleeben Carolien , Meijlink Frits
Published: February 2011

Directing the orientation of cells in three dimensions is a fundamental aspect of many of the processes underlying the generation of the appropriate shape and function of tissues and organs during embryonic development. In an epithelium, this requires not only the establishment of apicobasal polarity, but also cell arrangement in a specific direction in the plane of the cell sheet. The molecular pathway central to regulating this planar cell polarity (PCP) was originally discovered in the fruit fly Drosophila melanogaster and has more recently been shown to act in a highly analogous way in vertebrates, involving a strongly overlapping set of genes. Mutant studies and molecular analyses have led to insights into the role of ordered planar cell polarity in the development of a wide variety of organs and tissues. In this review, we give an overview of recent developments in the study of planar polarity signaling in vertebrates. Developmental Dynamics 240:616–626, 2011. © 2011 Wiley‐Liss, Inc.
Novel type II collagen reporter mice: New tool for assessing collagen 2α1 expression in vivo and in vitro
Authors: Tryfonidou Marianna A. , Lunstrum Gregory P. , Hendriks Kristyanne , Riemers Frank M. , Wubbolts Richard , Hazewinkel H.A.W. , Degnin Catherine R. , Horton William A.
Published: February 2011

We report the generation of a new mouse strain harboring a Col2‐pd2EGFP reporter transgene; pd2EGFP has a much shorter half‐life than EGFP, making it a near real‐time reporter for Col2α1 expression in vivo and in vitro. In the post‐natal growth plate, pd2EGFP fluorescence was expressed in almost all proliferative chondrocytes and in some hypertrophic chondrocytes based on localization with type X collagen. In articular cartilage, pd2EGFP fluorescence diminished over time, nicely illustrating the decrease of type II collagen synthesis in articular chondrocytes during growth. Monolayers of FACS‐sorted chondrocytes from P1‐2 mice showed faster loss of pd2EGFP compared to EGFP, reflecting rapid chondrocyte de‐differentiation. High‐density culture of FACS‐pd2EGFP‐ growth plate chondrocytes revealed the typical temporal expression pattern in which type II collagen preceded type X collagen matrix deposition. The Col2‐pd2EGFP reporter mouse will be a valuable tool for studies of growth plate chondrocyte biology. Developmental Dynamics 240:663–673, 2011. © 2011 Wiley‐Liss, Inc.
The emerging face of primary cilia
Authors: Zaghloul Norann A. , Brugmann Samantha A.
Published: February 2011

Primary cilia are microtubule‐based organelles that serve as hubs for the transduction of various developmental signaling pathways includingHedgehog, Wnt, FGF, and PDGF. Ciliary dysfunction contributes to a range of disorders, collectively known as the ciliopathies. Recently, interest has grown in these syndromes, particularly among craniofacial biologists, as many known and putative ciliopathies have severe craniofacial defects. Herein we discuss the current understanding of ciliary biology and craniofacial development in an attempt to gain insight into the molecular etiology for craniofacial ciliopathies, and uncover a characteristic ciliopathic craniofacial gestalt. genesis 49:231–246, 2011. © 2011 Wiley‐Liss, Inc.
Estrogen‐induced protection against experimental autoimmune encephalomyelitis is abrogated in the absence of B cells
Authors: Bodhankar Sheetal , Wang Chunhe , Vandenbark Arthur A. , Offner Halina
Published: February 2011

Increased remissions in multiple sclerosis (MS) during pregnancy suggest that elevated levels of sex steroids exert immunoregulatory activity. Estrogen (E2=17β‐estradiol) protects against experimental autoimmune encephalomyelitis (EAE), but the cellular basis for E2‐induced protection remains unclear. Studies demonstrate that depletion of B cells prior to induction of EAE exacerbates disease severity, implicating regulatory B cells. We thus evaluated pathogenic and E2‐induced protective mechanisms in B‐cell‐deficient (μMT−/−) mice. EAE‐protective effects of E2 were abrogated in μMT−/− mice, with no reduction in disease severity, cellular infiltration or pro‐inflammatory factors in the central nervous system compared to untreated controls. E2 treatment of WT mice selectively upregulated expression of PD‐L1 on B cells and increased the percentage of IL‐10‐producing CD1dhighCD5+ regulatory B cells. Upregulation of PD‐L1 was critical for E2‐mediated protection since E2 did not inhibit EAE in PD‐L1−/− mice. Direct treatment of B cells with E2 significantly reduced proliferation of MOG35–55‐specific T cells that required estrogen receptor‐α (ERα). These results demonstrate, for the first time, a requirement for B cells in E2‐mediated protection against EAE involving direct E2 effects on regulatory B cells mediated through ERα and the PD‐1/PD‐L1 negative co‐stimulatory pathway. E2‐primed B cells may represent an important regulatory mechanism in MS and have strong implications for women receiving current MS therapies that cause B‐cell depletion.
Immune inhibitory receptors: Essential regulators of phagocyte function
Authors: Steevels Tessa A. M. , Meyaard Linde
Published: February 2011

Phagocytes, including neutrophils, monocytes, and macrophages, play a crucial role in host defense by recognition and elimination of invading pathogens. Phagocytic cells produce reactive oxygen species (ROS), inflammatory cytokines, and chemokines, leading to bacterial killing and to recruitment and activation of additional immune cells. However, inflammatory mediators are potentially harmful for the host and their production is therefore tightly controlled by multiple regulatory mechanisms. One such mechanism is immune suppression by immune inhibitory receptors, which are increasingly acknowledged as potent regulators of the immune response. So far, research has focused on the role of these receptors in the regulation of NK cells, B cells, and T cells. Importantly, an accumulating number of inhibitory receptors have been identified on phagocytes. Here, we review the role of inhibitory receptors in the regulation of phagocyte cytokine production, migration, apoptosis, ROS production, and phagocytosis. Furthermore, we discuss the intracellular mechanisms utilized by distinct inhibitory receptors to regulate specific phagocyte functions. We demonstrate that inhibitory receptors are important regulators of the immune response, which bacteria can use to their advantage.
The Hydrogenase Subcomplex of the NAD+‐Reducing [NiFe] Hydrogenase from Ralstonia eutropha – Insights into Catalysis and Redox Interconversions
Authors: Lauterbach Lars , Liu Juan , Horch Marius , Hummel Phillip , Schwarze Alexander , Haumann Michael , Vincent Kylie A. , Lenz Oliver , Zebger Ingo
Published: February 2011

The O2‐tolerant, NAD+‐reducing soluble [NiFe] hydrogenase (SH) from Ralstonia eutropha H16, HoxHYFUI2, is a complex enzyme, harboring multiple redox cofactors: a [NiFe] active site, an electron relay of iron‐sulfur clusters, and two noncovalently bound flavin mononucleotides (FMN). The interplay and functional role of these cofactors is so far not understood in detail. In the present study, the isolated HoxHY module was investigated, which represents the smallest active subcomplex of a [NiFe] hydrogenase. Direct electrochemical studies and solution assays showed that the as‐isolated HoxHY is initially catalytically inactive, but after reductive activation at low potentials, exhibits both H2 oxidation and H+ reduction, consistent with the role of the SH in bidirectional catalysis. The overpotential relative to E(2H+/H2) is minimal, facilitating coupling of the closely spaced 2H+/H2 and NAD+/NADH half reactions in the SH. Methyl viologen reduction assays revealed that H2 oxidation by HoxHY is enhanced on addition of excess FMN, in line with results from optical spectroscopy which indicate that FMN is present at substoichiometric levels in as‐isolated HoxHY. X‐ray absorption spectroscopy suggested one 4Fe4S cluster in addition to the active site in HoxHY. FTIR investigations confirmed that the active site iron atom has a “standard” ligation, i.e., one CO and two cyanide ligands. At least two novel oxidized states were detected by FTIR, both of which could be reductively activated by artificial electron donors, such as dithionite, and by the native electron donor H2 in the presence of additional FMN. The flavin cofactor also appears to stabilize the active site, providing further evidence for its importance in HoxHY. All reduced states of the [NiFe] site previously identified for standard [NiFe] hydrogenases and for the native SH within living cells were detected in FTIR spectra of HoxHY with the exception of the intermediate Nia‐C species. Electrochemical experiments show that incubation of active HoxHY with O2 at high potentials causes slow inactivation, but activity is recovered within seconds at potentials below –170 mV at 30 °C, even in the presence of 2 % O2. This behavior is consistent with the HoxHY moiety of the SH remaining active in the presence of O2 at the potential of the NAD+/NADH pool in vivo.
Mercury speciation and biomagnification in the food web of Caddo Lake, Texas and Louisiana, USA, a subtropical freshwater ecosystem
Authors: Chumchal Matthew M , Rainwater Thomas R , Osborn Steven C , Roberts Aaron P , Abel Michael T , Cobb George P , Smith Philip N , Bailey Frank C
Published: February 2011

We studied the biomagnification of total mercury and methylmercury in a subtropical freshwater lake, Caddo Lake, Texas and Louisiana, USA. The present study is unique in that it not only included invertebrates (seven species) and fish (six species) but also an amphibian (one species), reptiles (three species), and mammals (three species). Nonfish vertebrates such as those included in the present study are often not included in assessments of trophic transfer of Hg. Mean trophic position (determined using stable isotopes of nitrogen) ranged from 2.0 (indicative of a primary consumer) to 3.8 (indicative of a tertiary consumer). Mean total Hg concentrations ranged from 36 to 3,292 ng/g dry weight in muscle and whole body and from 150 to 30,171 ng/g dry weight in liver. Most of the Hg in muscle and whole-body tissue was found as methylmercury, and at least 50% of the Hg found in liver was in the inorganic form (with the exception of largemouth bass, Micropterus salmoides). Mercury concentrations were positively correlated with trophic position, indicating that biomagnification occurs in the food web of Caddo Lake. The food web magnification factors (FWMFs; slope of the relationship between mean Hg concentration and trophic position) for both total Hg and methylmercury were similar to those observed in other studies. Because most of the total Hg in consumers was methylmercury, the FWMF for methylmercury was not significantly different from the FWMF for total Hg. Some vertebrates examined in the present study had low Hg concentrations in their tissues similar to those observed in invertebrates, whereas others had concentrations of Hg in their tissues that in previous studies have been associated with negative health consequences in fish. Environ. Toxicol. Chem. 2011; 30:1153–1162. © 2011 SETAC
Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer
Authors: Vaughn Cecily P. , ZoBell Scott D. , Furtado Larissa V. , Baker Christine L. , Samowitz Wade S.
Published: February 2011

Mutational analysis of KRAS codons 12 and 13 is standard for patients with metastatic colorectal cancer since mutations in these codons predict lack of response to anti‐EGFR therapies. However, even among patients whose tumors are wildtype for KRAS codons 12 and 13, only a subset respond to therapy. Since additional activating mutations downstream of EGFR may also play a role in treatment resistance, we sought to establish the frequency of these mutations. We evaluated 2121 colorectal tumors for mutations in codons 12 and 13 of the KRAS gene. A subset of these samples, comprised of 513 samples wildtype for KRAS codons 12 and 13, were tested for mutations in codons 61 and 146 of KRAS, codon 600 of BRAF, and codons 12, 13, and 61 of NRAS. Mutation status was determined by targeted pyrosequencing. Mutations in KRAS codon 12 or 13 were identified in 900/2121 (42.4%) samples. Of the 513 wildtype samples tested for additional mutations, 78 samples were mutant for BRAF, 19 for KRAS codon 61, 17 for KRAS codon 146, and 26 for NRAS. In total, 140/513 (27.3%) tumors wildtype for KRAS codons 12 and 13 harbored a mutation in another of the RAS pathway genes. While further study is needed to determine the full therapeutic implications of mutations in these codons, mutational testing of these codons may be useful for identifying a significant proportion of patients who may also be resistant to anti‐EGFR therapies. © 2011 Wiley‐Liss, Inc.
Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non‐Hodgkin's lymphoma
Authors: Green Michael R. , Aya‐Bonilla Carlos , Gandhi Maher K. , Lea Rod A. , Wellwood Jeremy , Wood Peter , Marlton Paula , Griffiths Lyn R.
Published: February 2011

Recent developments in genomic technologies have resulted in increased understanding of pathogenic mechanisms and emphasized the importance of central survival pathways. Here, we use a novel bioinformatic based integrative genomic profiling approach to elucidate conserved mechanisms of lymphomagenesis in the three commonest non‐Hodgkin's lymphoma (NHL) entities: diffuse large B‐cell lymphoma, follicular lymphoma, and B‐cell chronic lymphocytic leukemia. By integrating genome‐wide DNA copy number analysis and transcriptome profiling of tumor cohorts, we identified genetic lesions present in each entity and highlighted their likely target genes. This revealed a significant enrichment of components of both the apoptosis pathway and the mitogen activated protein kinase pathway, including amplification of the MAP3K12 locus in all three entities, within the set of genes targeted by genetic alterations in these diseases. Furthermore, amplification of 12p13.33 was identified in all three entities and found to target the FOXM1 oncogene. Amplification of FOXM1 was subsequently found to be associated with an increased MYC oncogenic signaling signature, and siRNA‐mediated knock‐down of FOXM1 resulted in decreased MYC expression and induced G2 arrest. Together, these findings underscore genetic alteration of the MAPK and apoptosis pathways, and genetic amplification of FOXM1 as conserved mechanisms of lymphomagenesis in common NHL entities. Integrative genomic profiling identifies common central survival mechanisms and highlights them as attractive targets for directed therapy. © 2011 Wiley‐Liss, Inc.
Fusion gene microarray reveals cancer type‐specificity among fusion genes
Authors: Løvf Marthe , Thomassen Gard O. S. , Bakken Anne Cathrine , Celestino Ricardo , Fioretos Thoas , Lind Guro E. , Lothe Ragnhild A. , Skotheim Rolf I.
Published: February 2011

Detection of fusion genes for diagnostic purposes and as a guide to treatment is well‐established in hematological malignancies, and the prevalence of fusion genes in epithelial cancers is also increasingly appreciated. To study whether established fusion genes are present within additional cancer types, we have used an updated version of our fusion gene microarray in a systematic survey of reported fusion genes in multiple cancer types. We assembled a comprehensive database of published fusion genes, including those reported only in individual studies and samples, and fusion genes resulting from deep sequencing of cancer genomes and transcriptomes. From the total set of 548 fusion genes, we designed 599,839 oligonucleotides, targeting both chimeric transcript junctions as well as sequences internal to each of the fusion gene partners. We investigated the presence of fusion genes in a series of 67 cell lines representing 15 different cancer types. Data from ten leukemia cell lines with known fusion gene status were used to develop an automated scoring algorithm, and in five cell lines the correct fusion gene was the top scoring hit, and one came second. Two additional fusion genes, BCAS4‐BCAS3 in the MCF‐7 breast cancer cell line and CCDC6‐RET in the TPC‐1 thyroid cancer cell line were validated as true positive fusion transcripts. However, these fusion genes were not new to these cancer types, and none of 548 fusion genes were identified from a novel cancer type. We therefore find it unlikely that the assayed fusion genes are commonly present across multiple cancer types. © 2011 Wiley‐Liss, Inc.
Reconstructing landscape and vegetation through multiple proxy indicators: A geoarchaeological examination of the St. Louis site, Saskatchewan, Canada
Authors: Cyr Howard , McNamee Calla , Amundson Leslie , Freeman Andrea
Published: February 2011

The St. Louis site, located in the Plains–Parkland transition zone along the South Saskatchewan River, in Saskatchewan, Canada, is a multiple‐component site consisting of stratified floodplain alluvium with multiple, weakly developed soils. Human occupation at the site spans the Late Paleoindian to Middle Precontact periods (10,000–5,000 14C yr B.P.), a time poorly represented archaeologically on the Northern Plains. The dearth of early–middle Holocene‐age archaeological sites is often attributed to reduced inhabitability of the Northern Plains during the Hypsithermal, a period of maximum aridity and limited water availability. Stable isotope and phytolith data from the site indicate increased temperatures during the Hypsithermal and an expansion of Northern Plains grasslands into north‐central Saskatchewan. Although characterized by increased xeric conditions, human occupation at the St. Louis site, as well as the predominance of C3 grasses, attests to the habitability of Northern Plains river systems during this time period. © 2011 Wiley Periodicals, Inc.
Geoarchaeology of the Nehalem spit: Redistribution of beeswax galleon wreck debris by Cascadia earthquake and tsunami (∼A.D. 1700), Oregon, USA
Authors: Peterson Curt D. , Williams Scott S. , Cruikshank Kenneth M. , Dubè John R.
Published: February 2011

A coincidence of the Beeswax galleon shipwreck (ca. A.D. 1650–1700) and the last Cascadia earthquake tsunami and coastal subsidence at ∼A.D. 1700 redistributed and buried wreck artifacts on the Nehalem Bay spit, Oregon, USA. Ground‐penetrating radar profiles (∼7 km total distance), sand auger probes, trenches, cutbank exposures (29 in number), and surface cobble counts (49 sites) were collected from the Nehalem spit (∼5 km2 area). The field data demonstrate (1) the latest prehistoric integrity of the spit, (2) tsunami spit overtopping, and (3) coseismic beach retreat since the A.D. 1700 great earthquake in the Cascadia subduction zone. Wreck debris was (1) initially scattered along the spit ocean beaches, (2) washed over the spit by nearfield tsunami (6–8 m elevation), and (3) remobilized in beach strandlines by catastrophic beach retreat. Historic recovery of the spit (150 m beach progradation) and modern foredune accretion (>5 m depth) have buried both the retreat scarp strandlines and associated wreck artifacts. The recent onshore sand transport might re‐expose heavy ship remains in the offshore area if the wreck grounded in shallow water (<20 m water depth of closure). © 2011 Wiley Periodicals, Inc.
Relationship between genomic distance‐based regression and kernel machine regression for multi‐marker association testing
Authors: Pan Wei
Published: February 2011

To detect genetic association with common and complex diseases, two powerful yet quite different multimarker association tests have been proposed, genomic distance‐based regression (GDBR) (Wessel and Schork [2006] Am J Hum Genet 79:821–833) and kernel machine regression (KMR) (Kwee et al. [2008] Am J Hum Genet 82:386–397; Wu et al. [2010] Am J Hum Genet 86:929–942). GDBR is based on relating a multimarker similarity metric for a group of subjects to variation in their trait values, while KMR is based on nonparametric estimates of the effects of the multiple markers on the trait through a kernel function or kernel matrix. Since the two approaches are both powerful and general, but appear quite different, it is important to know their specific relationships. In this report, we show that, under the condition that there is no other covariate, there is a striking correspondence between the two approaches for a quantitative or a binary trait: if the same positive semi‐definite matrix is used as the centered similarity matrix in GDBR and as the kernel matrix in KMR, the F‐test statistic in GDBR and the score test statistic in KMR are equal (up to some ignorable constants). The result is based on the connections of both methods to linear or logistic (random‐effects) regression models. Genet. Epidemiol 35: 211‐216, 2011   © 2011 Wiley‐Liss, Inc.
Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants
Authors: Guey Lin T. , Kravic Jasmina , Melander Olle , Burtt Noël P. , Laramie Jason M. , Lyssenko Valeriya , Jonsson Anna , Lindholm Eero , Tuomi Tiinamaija , Isomaa Bo , Nilsson Peter , Almgren Peter , Kathiresan Sekar , Groop Leif , Seymour Albert B. , Altshuler David , Voight Benjamin F.
Published: February 2011

Next‐generation sequencing technologies are making it possible to study the role of rare variants in human disease. Many studies balance statistical power with cost‐effectiveness by (a) sampling from phenotypic extremes and (b) utilizing a two‐stage design. Two‐stage designs include a broad‐based discovery phase and selection of a subset of potential causal genes/variants to be further examined in independent samples. We evaluate three parameters: first, the gain in statistical power due to extreme sampling to discover causal variants; second, the informativeness of initial (Phase I) association statistics to select genes/variants for follow‐up; third, the impact of extreme and random sampling in (Phase 2) replication. We present a quantitative method to select individuals from the phenotypic extremes of a binary trait, and simulate disease association studies under a variety of sample sizes and sampling schemes. First, we find that while studies sampling from extremes have excellent power to discover rare variants, they have limited power to associate them to phenotype—suggesting high false‐negative rates for upcoming studies. Second, consistent with previous studies, we find that the effect sizes estimated in these studies are expected to be systematically larger compared with the overall population effect size; in a well‐cited lipids study, we estimate the reported effect to be twofold larger. Third, replication studies require large samples from the general population to have sufficient power; extreme sampling could reduce the required sample size as much as fourfold. Our observations offer practical guidance for the design and interpretation of studies that utilize extreme sampling. Genet. Epidemiol. 35: 236‐246, 2011.  © 2011 Wiley‐Liss, Inc.
Maintenance and regulation of extracellular volume and the ion environment in Drosophila larval nerves
Authors: Leiserson William M. , Keshishian Haig
Published: February 2011

In mammals and insects, paracellular blood barriers isolate the nervous system from the rest of the animal. Glia and accessory cells of the nervous system use pumps, channels, cotransporters, and exchangers collectively to maintain the extracellular ion environment and osmotic balance in the nervous system. At present, the molecular mechanisms that regulate this process remain unclear. In humans, loss of extracellular ion and volume regulation in the nervous system poses serious health threats. Drosophila is a model genetic organism with a proven track record for uncovering molecular mechanisms relevant to human health and disease. Here, we review what is known about extracellular ion and volume regulation in larval abdominal nerves, present some new data about the impact of neural activity on the extracellular environment, and relate the findings to mammalian systems. Homologies have been found at the level of morphology, physiology, molecular mechanisms, and mutant phenotypes. The Fray‐Ncc69 module regulates extracellular volume in larval nerves. Genetic rescue experiments with the mammalian orthologs prove this module has a direct correlate in humans. This and other molecular homologies, together with the similar physiological needs, suggest that uncovering the molecular mechanisms of ion and volume regulation in larval nerves will likely provide significant insights into this process in mammalian systems. © 2011 Wiley‐Liss, Inc.
Pattern of invasion of the embryonic mouse spinal cord by microglial cells at the time of the onset of functional neuronal networks
Authors: Rigato C. , Buckinx R. , Le‐Corronc H. , Rigo J. M. , Legendre P.
Published: February 2011

Microglial cells invade the central nervous system during embryonic development, but their developmental functional roles in vivo remain largely unknown. Accordingly, their invasion pattern during early embryonic development is still poorly understood. To address this issue, we analyzed the initial developmental pattern of microglial cell invasion in the spinal cord of CX3CR1‐eGFP mouse embryos using immunohistochemistry. Microglial cells began to invade the mouse embryonic spinal cord at a developmental period corresponding to the onset of spontaneous electrical activity and of synaptogenesis. Microglial cells reached the spinal cord through the peripheral vasculature and began to invade the parenchyma at 11.5 days of embryonic age (E11.5). Remarkably, at E12.5, activated microglial cells aggregated in the dorsolateral region close to terminals of dying dorsal root ganglia neurons. At E13.5, microglial cells in the ventral marginal zone interacted with radial glial cells, whereas ramified microglial cells within the parenchyma interacted with growing capillaries. At this age, activated microglial cells (Mac‐2 staining) also accumulated within the lateral motor columns at the onset of the developmental cell death of motoneurons. This cell aggregation was still observed at E14.5, but microglial cells no longer expressed Mac‐2. At E15.5, microglial cells were randomly distributed within the parenchyma. Our results provide the essential basis for further studies on the role of microglial cells in the early development of spinal cord neuronal networks in vivo. © 2011 Wiley‐Liss, Inc.
Involvement of glutamate in rest‐stimulus interaction between perigenual and supragenual anterior cingulate cortex: A combined fMRI‐MRS study
Authors: Duncan Niall W. , Enzi Björn , Wiebking Christine , Northoff Georg
Published: February 2011

The brain shows a high degree of activity at rest. The significance of this activity has come increasingly into focus. At present, however, the interaction between this activity and stimulus‐induced activity is not well defined. The interaction between a task‐negative (perigenual anterior cingulate cortex, pgACC) and task‐positive (supragenual anterior cingulate cortex, sgACC) region during a simple task was thus investigated using a combination of fMRI and MRS. Negative BOLD responses in the pgACC were found to show a unidirectional effective connectivity with task‐induced positive BOLD responses in the sgACC. This connectivity was shown to be related specifically with glutamate levels in the pgACC. These results demonstrate an interaction between deactivation from resting‐state and resting‐state glutamate levels in a task‐negative region (pgACC), and task‐induced activity in a task‐positive region (sgACC). This provides insight into the neuronal and biochemical mechanisms by means of which the resting state activity of the brain potentially impacts upon subsequent stimulus‐induced activity. Hum Brain Mapp, 2011. © 2011 Wiley Periodicals, Inc.
Cortical network differences in the sighted versus early blind for recognition of human‐produced action sounds
Authors: Lewis James W. , Frum Chris , Brefczynski‐Lewis Julie A. , Talkington William J. , Walker Nathan A. , Rapuano Kristina M. , Kovach Amanda L.
Published: February 2011

Both sighted and blind individuals can readily interpret meaning behind everyday real‐world sounds. In sighted listeners, we previously reported that regions along the bilateral posterior superior temporal sulci (pSTS) and middle temporal gyri (pMTG) are preferentially activated when presented with recognizable action sounds. These regions have generally been hypothesized to represent primary loci for complex motion processing, including visual biological motion processing and audio–visual integration. However, it remained unclear whether, or to what degree, life‐long visual experience might impact functions related to hearing perception or memory of sound‐source actions. Using functional magnetic resonance imaging (fMRI), we compared brain regions activated in congenitally blind versus sighted listeners in response to hearing a wide range of recognizable human‐produced action sounds (excluding vocalizations) versus unrecognized, backward‐played versions of those sounds. Here, we show that recognized human action sounds commonly evoked activity in both groups along most of the left pSTS/pMTG complex, though with relatively greater activity in the right pSTS/pMTG by the blind group. These results indicate that portions of the postero‐lateral temporal cortices contain domain‐specific hubs for biological and/or complex motion processing independent of sensory‐modality experience. Contrasting the two groups, the sighted listeners preferentially activated bilateral parietal plus medial and lateral frontal networks, whereas the blind listeners preferentially activated left anterior insula plus bilateral anterior calcarine and medial occipital regions, including what would otherwise have been visual‐related cortex. These global‐level network differences suggest that blind and sighted listeners may preferentially use different memory retrieval strategies when hearing and attempting to recognize action sounds. Hum Brain Mapp , 2011. © 2011 Wiley Periodicals, Inc.
Minimizing within‐experiment and within‐group effects in activation likelihood estimation meta‐analyses
Authors: Turkeltaub Peter E. , Eickhoff Simon B. , Laird Angela R. , Fox Mick , Wiener Martin , Fox Peter
Published: February 2011

Activation Likelihood Estimation (ALE) is an objective, quantitative technique for coordinate‐based meta‐analysis (CBMA) of neuroimaging results that has been validated for a variety of uses. Stepwise modifications have improved ALE's theoretical and statistical rigor since its introduction. Here, we evaluate two avenues to further optimize ALE. First, we demonstrate that the maximum contribution of an experiment makes to an ALE map is related to the number of foci it reports and their proximity. We present a modified ALE algorithm that eliminates these within‐experiment effects. However, we show that these effects only account for 2–3% of cumulative ALE values, and removing them has little impact on thresholded ALE maps. Next, we present an alternate organizational approach to datasets that prevents subject groups with multiple experiments in a dataset from influencing ALE values more than others. This modification decreases cumulative ALE values by 7–9%, changes the relative magnitude of some clusters, and reduces cluster extents. Overall, differences between results of the standard approach and these new methods were small. This finding validates previous ALE reports against concerns that they were driven by within‐experiment or within‐group effects. We suggest that the modified ALE algorithm is theoretically advantageous compared with the current algorithm, and that the alternate organization of datasets is the most conservative approach for typical ALE analyses and other CBMA methods. Combining the two modifications minimizes both within‐experiment and within‐group effects, optimizing the degree to which ALE values represent concordance of findings across independent reports. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.
Identification of human gustatory cortex by activation likelihood estimation
Authors: Veldhuizen Maria G. , Albrecht Jessica , Zelano Christina , Boesveldt Sanne , Breslin Paul , Lundström Johan N.
Published: February 2011

Over the last two decades, neuroimaging methods have identified a variety of taste‐responsive brain regions. Their precise location, however, remains in dispute. For example, taste stimulation activates areas throughout the insula and overlying operculum, but identification of subregions has been inconsistent. Furthermore, literature reviews and summaries of gustatory brain activations tend to reiterate rather than resolve this ambiguity. Here, we used a new meta‐analytic method [activation likelihood estimation (ALE)] to obtain a probability map of the location of gustatory brain activation across 15 studies. The map of activation likelihood values can also serve as a source of independent coordinates for future region‐of‐interest analyses. We observed significant cortical activation probabilities in: bilateral anterior insula and overlying frontal operculum, bilateral mid dorsal insula and overlying Rolandic operculum, and bilateral posterior insula/parietal operculum/postcentral gyrus, left lateral orbitofrontal cortex (OFC), right medial OFC, pregenual anterior cingulate cortex (prACC) and right mediodorsal thalamus. This analysis confirms the involvement of multiple cortical areas within insula and overlying operculum in gustatory processing and provides a functional “taste map” which can be used as an inclusive mask in the data analyses of future studies. In light of this new analysis, we discuss human central processing of gustatory stimuli and identify topics where increased research effort is warranted. Hum Brain Mapp, 2011. © 2011 Wiley Periodicals, Inc.