bluuebunny/crossref_metadata_2025 huggingface dataset:
Wolbachiauses host microRNAs to manipulate host gene expression and facilitate colonization of the dengue vectorAedes aegypti
Authors: Hussain Mazhar , Frentiu Francesca D. , Moreira Luciano A. , O'Neill Scott L. , Asgari Sassan
Published: May 2011

The obligate endosymbiontWolbachia pipientisis found in a wide range of invertebrates where they are best known for manipulating host reproduction. Recent studies have shown thatWolbachiaalso can modulate the lifespan of host insects and interfere with the development of human pathogens in mosquito vectors. Despite considerable study, very little is known about the molecular interactions betweenWolbachiaand its hosts that might mediate these effects. Using microarrays, we show that the microRNA (miRNA) profile of the mosquito,Aedes aegypti, is significantly altered by thewMelPop-CLA strain ofW. pipientis. We found that a host miRNA (aae-miR-2940) is induced afterWolbachiainfection in both mosquitoes and cell lines. One target of aae-miR-2940 is theAe. aegyptimetalloprotease gene. Interestingly, expression of the target gene was induced afterWolbachiainfection, ectopic expression of the miRNA independent ofWolbachia, or transfection of an artificial mimic of the miRNA into mosquito cells. We also confirmed the interaction of aae-miR-2940 with the target sequences using GFP as a reporter gene. Silencing of the metalloprotease gene in bothWolbachia-infected cells and adult mosquitoes led to a significant reduction inWolbachiadensity, as did inhibition of the miRNA in cells. These results indicate that manipulation of the mosquito metalloprotease gene via aae-miR-2940 is crucial for efficient maintenance of the endosymbiont. This report shows howWolbachiaalters the host miRNA profile and provides insight into the mechanisms of host manipulation used by this widespread endosymbiont.
Evolution of sodium channels predates the origin of nervous systems in animals
Authors: Liebeskind Benjamin J. , Hillis David M. , Zakon Harold H.
Published: May 2011

Voltage-dependent sodium channels are believed to have evolved from calcium channels at the origin of the nervous system. A search of the genome of a single-celled choanoflagellate (the sister group of animals) identified a gene that is homologous to animal sodium channels and has a putative ion selectivity filter intermediate between calcium and sodium channels. Searches of a wide variety of animal genomes, including representatives of each basal lineage, revealed that similar homologs were retained in most lineages. One of these, the Placozoa, does not possess a nervous system. We cloned and sequenced the full choanoflagellate channel and parts of two placozoan channels from mRNA, showing that they are expressed. Phylogenetic analysis clusters the genes for these channels with other known sodium channels. From this phylogeny we infer ancestral states of the ion selectivity filter and show that this state has been retained in the choanoflagellate and placozoan channels. We also identify key gene duplications and losses and show convergent amino acid replacements at important points along the animal lineage.
The Bordetella pertussis adenylate cyclase toxin binds to T cells via LFA-1 and induces its disengagement from the immune synapse
Authors: Paccani Silvia Rossi , Finetti Francesca , Davi Marilyne , Patrussi Laura , D'Elios Mario M. , Ladant Daniel , Baldari Cosima T.
Published: May 2011

The Bordetella pertussis adenylate cyclase toxin (CyaA) assists infection by potently suppressing the host immune response. Although CyaA effectively targets T lymphocytes, its putative receptor on these cells is unknown. Here, we show that CyaA binds to T cells via the β2 integrin LFA-1 in its active conformation. CyaA clusters with LFA-1 at the immune synapse (IS), from which it induces the premature disengagement of LFA-1 concomitant with the dissipation of talin, which tethers the integrin to the underlying actin cytoskeleton. The CyaA-induced redistribution of LFA-1 was cAMP- and protein kinase A (PKA)–dependent. These results not only identify LFA-1 as a CyaA receptor on T cells but unveil a novel mechanism of immunosuppression whereby the toxin parasitizes its interaction with LFA-1 to inhibit signaling at the IS through the local production of cAMP. The data also provide novel insights into the role of cAMP/PKA signaling in controlling the dynamics of the IS.
IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease
Authors: Geremia Alessandra , Arancibia-Cárcamo Carolina V. , Fleming Myles P.P. , Rust Nigel , Singh Baljit , Mortensen Neil J. , Travis Simon P.L. , Powrie Fiona
Published: May 2011

Results of experimental and genetic studies have highlighted the role of the IL-23/IL-17 axis in the pathogenesis of inflammatory bowel disease (IBD). IL-23–driven inflammation has been primarily linked to Th17 cells; however, we have recently identified a novel population of innate lymphoid cells (ILCs) in mice that produces IL-17, IL-22, and IFN-γ in response to IL-23 and mediates innate colitis. The relevance of ILC populations in human health and disease is currently poorly understood. In this study, we have analyzed the role of IL-23–responsive ILCs in the human intestine in control and IBD patients. Our results show increased expression of the Th17-associated cytokine genes IL17A and IL17F among intestinal CD3− cells in IBD. IL17A and IL17F expression is restricted to CD56− ILCs, whereas IL-23 induces IL22 and IL26 in the CD56+ ILC compartment. Furthermore, we observed a significant and selective increase in CD127+CD56− ILCs in the inflamed intestine in Crohn’s disease (CD) patients but not in ulcerative colitis patients. These results indicate that IL-23–responsive ILCs are present in the human intestine and that intestinal inflammation in CD is associated with the selective accumulation of a phenotypically distinct ILC population characterized by inflammatory cytokine expression. ILCs may contribute to intestinal inflammation through cytokine production, lymphocyte recruitment, and organization of the inflammatory tissue and may represent a novel tissue-specific target for subtypes of IBD.
A dynamic T cell–limited checkpoint regulates affinity-dependent B cell entry into the germinal center
Authors: Schwickert Tanja A. , Victora Gabriel D. , Fooksman David R. , Kamphorst Alice O. , Mugnier Monica R. , Gitlin Alexander D. , Dustin Michael L. , Nussenzweig Michel C.
Published: May 2011

The germinal center (GC) reaction is essential for the generation of the somatically hypermutated, high-affinity antibodies that mediate adaptive immunity. Entry into the GC is limited to a small number of B cell clones; however, the process by which this limited number of clones is selected is unclear. In this study, we demonstrate that low-affinity B cells intrinsically capable of seeding a GC reaction fail to expand and become activated in the presence of higher-affinity B cells even before GC coalescence. Live multiphoton imaging shows that selection is based on the amount of peptide–major histocompatibility complex (pMHC) presented to cognate T cells within clusters of responding B and T cells at the T–B border. We propose a model in which T cell help is restricted to the B cells with the highest amounts of pMHC, thus allowing for a dynamic affinity threshold to be imposed on antigen-binding B cells.
Lipid phosphate phosphatase 3 enables efficient thymic egress
Authors: Bréart Béatrice , Ramos-Perez Willy D. , Mendoza Alejandra , Salous Abdelghaffar K. , Gobert Michael , Huang Yong , Adams Ralf H. , Lafaille Juan J. , Escalante-Alcalde Diana , Morris Andrew J. , Schwab Susan R.
Published: May 2011

The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte egress from lymphoid organs, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. We have found that lipid phosphate phosphatase 3 (LPP3) enables efficient export of mature T cells from the thymus into circulation, and several lines of evidence suggest that LPP3 promotes exit by destroying thymic S1P. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for the loss of LPP3. Moreover, conditional deletion of LPP3 in either epithelial cells or endothelial cells is sufficient to inhibit egress. These results suggest that S1P generation and destruction are tightly regulated and that LPP3 is essential to establish the balance.
Performance characterization of a helicon double layer thruster using direct thrust measurements
Authors: Pottinger Sabrina , Lappas Vaios , Charles Christine , Boswell Rod
Published: May 2011

The performance of a helicon double layer thruster (HDLT) has been characterized using a pendulum type thrust stand and retarding field energy analyser. Data recorded for a fixed propellant flow rate of 16 sccm of krypton and fixed magnetic field topology show that the thrust generated increases linearly with increasing radio frequency input power over a range 250–650 W. Over the power range investigated thrust levels of approximately 1–2.8 mN were achieved. A maximum effective specific impulse of 280 s was determined using the thrust data. Ion energy distribution functions indicate that increasing power corresponds to improved plasma generation processes as general trends show increasing plasma and beam currents with increasing power.
Harmonic functions on hyperbolic graphs
Authors: Petit Camille
Published: May 2011

We consider admissible random walks on hyperbolic graphs. For a given harmonic function on such a graph, we prove that asymptotic properties of non-tangential boundedness and non-tangential convergence are almost everywhere equivalent. The proof is inspired by the works of F. Mouton in the cases of Riemannian manifolds of pinched negative curvature and infinite trees. It involves geometric and probabilitistic methods.
SCORER 2.0: an algorithm for distinguishing parallel dimeric and trimeric coiled-coil sequences
Authors: Armstrong Craig T. , Vincent Thomas L. , Green Peter J. , Woolfson Derek N.
Published: May 2011

Motivation: The coiled coil is a ubiquitous α-helical protein structure domain that directs and facilitates protein–protein interactions in a wide variety of biological processes. At the protein-sequence level, coiled coils are quite straightforward and readily recognized via the conspicuous heptad repeats of hydrophobic and polar residues. However, structurally they are more complicated, existing in a range of oligomer states and topologies. Here, we address the issue of predicting coiled-coil oligomeric state from protein sequence.

Results: The predominant coiled-coil oligomer states in Nature are parallel dimers and trimers. Here, we improve and retrain the first-published algorithm, SCORER, that distinguishes these states, and test it against the current standard, MultiCoil. The SCORER algorithm has been revised in two key respects: first, the statistical basis for SCORER is improved markedly. Second, the training set for SCORER has been expanded and updated to include only structurally validated coiled coils. The result is a much-improved oligomer state predictor that outperforms MultiCoil, particularly in assigning oligomer state to short coiled coils, and those that are diverse from the training set.

Availability: SCORER 2.0 is available via a web interface at http://coiledcoils.chm.bris.ac.uk/Scorer. Source code, training sets and Supporting Information can be downloaded from the same site.

Contact:  coiledcoils-scorer@sympa.bristol.ac.uk; d.n.woolfson@bristol.ac.uk

Supplementary information:Supplementary data are available at Bioinformatics online.
The Guild of Surgeons as a Tradition of Moral Enquiry
Authors: Hall Daniel E.
Published: May 2011

Alisdair MacIntyre argues that the virtues necessary for good work are everywhere and always embodied by particular communities of practice. As a general surgeon, MacIntyre’s work has deeply influenced my own understanding of the practice of good surgery. The task of this essay is to describe how the guild of surgeons functions as a more-or-less coherent tradition of moral enquiry, embodying and transmitting the virtues necessary for the practice of good surgery. Beginning with an example of surgeons engaged in a process of moral discernment, I describe how the practice of surgery depends on the cultivation of a certain kind of practical wisdom (phronesis) that effectively orders the techniques of surgery toward particular notions of human flourishing within the limits of what is possible with the particular body on which the surgeon operates. I then argue that one reason why surgeons train in an apprenticeship model of “residency” is to cultivate not only the technical skill but also the practical wisdom to perform good surgery. I conclude by noting that the surgical profession is enduring necessary, but unprecedented, changes in the way it practices and transmits its art; and without deliberate and sustained attention to the character formation of surgeons, the profession runs the risk of creating excellent technicians who are nonetheless ill-equipped to practice wise and good surgery.
Gastrointestinal Release of β‐Glucan and Pectin Using an In Vitro Method
Authors: Ulmius Matilda , Johansson‐Persson Anna , Nordén Tina Immerstrand , Bergenståhl Björn , Önning Gunilla
Published: May 2011

The release of soluble dietary fiber is a prerequisite for viscous effects and hence beneficial health properties. A simple in vitro method was adapted to follow the release during gastrointestinal digestion, and the percentage of solubilized fiber was measured over time. β‐Glucan from oat bran was mainly released during gastric digestion while the release of pectin from sugar beet fiber continued in the small intestine. Unmilled fractions of sugar beet fiber released more soluble fiber than oat bran flakes, probably due to the porous structure of sugar beet fiber as a result of manufacturing processes, but also due to differences in source. Milling to smaller fiber particles significantly improved releasability (from 20 to 55% released β‐glucan and from 50 to 70% released pectin, respectively, after digestion). When milled fibers were included in individual food matrices, the release was reduced by protein and starch matrices (5% β‐glucan and 35% pectin released, respectively) and slowed by fat (45% β‐glucan and 60% pectin released). This may result in a too low or too late release in the upper small intestine to be able to interfere with macronutrient uptake. The method may be suitable for predicting the gastrointestinal release of soluble dietary fibers from food matrices in the development of healthy food products.
The Ectopic Expression of a Pectin Methyl Esterase Inhibitor Increases Pectin Methyl Esterification and Limits Fungal Diseases in Wheat
Authors: Volpi Chiara , Janni Michela , Lionetti Vincenzo , Bellincampi Daniela , Favaron Francesco , D'Ovidio Renato
Published: May 2011

Cell wall pectin methyl esterification can influence plant resistance because highly methyl-esterified pectin can be less susceptible to the hydrolysis by pectic enzymes such as fungal endopolygalacturonases (PG). Pectin is secreted into the cell wall in a highly methyl-esterified form and, here, is de-methyl esterified by pectin methyl esterase (PME). The activity of PME is controlled by specific protein inhibitors called PMEI; consequently, an increased inhibition of PME by PMEI might modify the pectin methyl esterification. In order to test the possibility of improving wheat resistance by modifying the methyl esterification of pectin cell wall, we have produced durum wheat transgenic lines expressing the PMEI from Actinidia chinensis (AcPMEI). The expression of AcPMEI endows wheat with a reduced endogenous PME activity, and transgenic lines expressing a high level of the inhibitor showed a significant increase in the degree of methyl esterification. These lines showed a significant reduction of disease symptoms caused by the fungal pathogens Bipolaris sorokiniana or Fusarium graminearum. This increased resistance was related to the impaired ability of these fungal pathogens to grow on methyl-esterified pectin and to a reduced activity of the fungal PG to hydrolyze methyl-esterified pectin. In addition to their importance for wheat improvement, these results highlight the primary role of pectin despite its low content in the wheat cell wall.
Control of Tobacco mosaic virus by PopW as a Result of Induced Resistance in Tobacco Under Greenhouse and Field Conditions
Authors: Li Jian-Gang , Cao Jing , Sun Fei-Fei , Niu Dong-Dong , Yan Fang , Liu Hong-Xia , Guo Jian-Hua
Published: May 2011

In a previous study, we isolated a new harpin protein, PopW, from the bacterium Ralstonia solanacearum ZJ3721 that can induce a hypersensitive response in tobacco, Nicotiana tabacum, leaves. In the current study, we demonstrate that, in a greenhouse experiment, PopW induced tobacco-acquired resistance against the Tobacco mosaic virus (TMV) with a biocontrol efficacy of 80.9 to 97.4% at a concentration as low as 25 μg/ml in both PopW-treated and neighboring leaves. The resistance induced by PopW is systemic acquired resistance mediated by salicylic acid, which was certified by the development of resistance being accompanied by the expression of the pathogenesis-related-1 gene (PR1) 8 h after PopW was sprayed onto the tobacco leaves. In addition, hydrogen peroxide began to accumulate 10 h after PopW spraying, peaking at 24 h with a maximum concentration of 1.97 μM/g fresh weight. The activities of phenylalanine ammonia lyase (EC4.3.1.5), polyphenoloxidase (EC1.14.18.1), and peroxidase (EC1.11.1.7) also increased, peaking at different times in the PopW-treated tobacco leaves. PopW also reduced the level of TMV disease in field trials with a biocontrol efficacy of 45.2%. Furthermore, PopW both increased tobacco yield (by 30.4 more than in control plants) and improved tobacco foliar quality, with an increase of 50.2% in the number of first-class tobacco leaves from treated compared with untreated plants. All of these results indicate that the new harpin protein PopW has the potential to be an effective biocontrol agent against TMV in tobacco.
Hypertonic Saline Hydroxyethylstarch Restores Right Ventricular-Arterial Coupling after Normovolemic Hemodilution in Piglets
Authors: Kerbaul François , Rondelet Benoît , Bénas Vincent , Grisoli Dominique , De Waroquier Arnaud , Fesler Pierre , Fusai Thierry , Brimioulle Serge
Published: May 2011

Background

Normovolemic hemodilution is known to inhibit hypoxic pulmonary vasoconstriction. How the coupling between the pulmonary arterial (PA) circulation and the right ventricle (RV) is affected by normovolemic hemodilution and by the composition of replacement solutions remains unknown. Therefore, the effects of isotonic and hypertonic saline hydroxyethylstarch solutions on the pulmonary circulation and RV, in control and hypoxic conditions, were compared.

Methods

Anesthetized piglets (n = 14) were equipped with manometer-tipped catheters in the RV and main PA and an ultrasonic flow probe around the main PA. The pulmonary circulation was assessed by pressure-flow relations and vascular impedance, RV afterload by effective arterial elastance (Ea), RV contractility by end-systolic elastance (Ees), and RV-PA coupling by the Ees/Ea ratio. Measurements were done in control (Fio2 0.40) and hypoxic (Fio2 0.12) conditions before and after acute normovolemic hemodilution with either 20 ml/kg isotonic saline hydroxyethylstarch (hydroxyethylstarch 130/0.4 6% in NaCl 0.9%, Voluven, Fresenius-Kabi, Sevres, France) or 5 ml/kg hypertonic saline hydroxyethylstarch (hydroxyethylstarch 200/0.5 6% in NaCl 7.2%, HyperHES, Fresenius-Kabi) solutions.

Results

Hypoxic pulmonary vasoconstriction was associated with proportional increases in Ea and Ees and did not affect RV-PA coupling. Hemodilution attenuated the hypoxic response. Hemodilution with isotonic saline hydroxyethylstarch did not affect the RV-PA coupling, whereas hemodilution with hypertonic saline hydroxyethylstarch increased Ees and the Ees/Ea ratio.

Conclusion

In experimental normovolemic hemodilution, both in control and in hypoxic conditions, RV-PA coupling is unaffected by isotonic saline hydroxyethylstarch but improved by hypertonic saline hydroxyethylstarch, mainly because of an increase in RV contractility.
HLA‐DQ Genotyping Combined With Serological Markers for the Diagnosis of Celiac Disease: Is Intestinal Biopsy Still Mandatory?
Authors: Clouzeau‐Girard Haude , Rebouissoux Laurent , Taupin Jean‐Luc , Le Bail Brigitte , Kalach Nicolas , Michaud Laurent , Dabadie Alain , Olives Jean‐Pierre , Blanco Patrick , Morali Alain , Moreau Jean‐François , Lamireau Thierry
Published: May 2011

Objectives:

The aim of this study was to evaluate the value of HLA‐DQ2/DQ8 allelic genotyping combined with serologic testing for the diagnosis of celiac disease (CD).

Patients and Methods:

One hundred seventy children, who underwent jejunal biopsy for digestive symptoms or malnutrition, were tested for HLA‐DQ2/DQ8 and serologic markers (tTG and/or anti‐endomysial antibodies). Children were classified in 2 groups, according to jejunal histology: group 1, when partial or total villous atrophy was associated with an increased intraepithelial lymphocytosis suggesting CD, and group 2, when these histological criteria were absent.

Results:

Eight children were excluded from the study because their intestinal histology was not informative; 82 children were classified in group 1 and 80 in group 2. Eighty‐one of 82 children in group 1 were positive for HLA and serologic testing. The other child had negative HLA and serologic testing but marked villous atrophy, and further investigation showed an allergic disease. Among the 80 children in group 2, 53 were negative for both HLA and serologic testing, 22 were positive for HLA but negative for serologic testing, 2 were negative for HLA and positive for serologic testing, and 3 patients were positive for both HLA and serologic testing. The last 3 children were shown to have an autoimmune background and had probably a latent form of CD. The association of HLA‐DQ2/DQ8 and serologic markers had a sensitivity of 98.8%, a specificity of 96.2%, a positive likelihood ratio of 26.3, and a negative likelihood ratio of 0.013.

Conclusions:

The association of positive HLA‐DQ2/DQ8 and serologic testing has a high predictive value for CD. We suggest that symptomatic children with high titers of immunoglobulin (Ig)A tTG could be diagnosed as patients with CD without performing jejunal biopsy. In other children, HLA‐DQ2/DQ8 could be useful to exclude the diagnosis of CD if negative. In cases of low IgA tTG titers or in patients with IgA deficiency, intestinal biopsy remains mandatory.
Do Children With IBD Really Respond Better Than Adults to Thiopurines?
Authors: Goodhand JR , Tshuma N , Rao A , Kotta S , Wahed M , Croft NM , Sanderson IR , Epstein J , Rampton DS
Published: May 2011

Background and Objectives:

Children and adolescents with inflammatory bowel disease (IBD) have more extensive and severe disease than adults. Despite a lack of comparative studies, thiopurines are frequently cited as being more efficacious in children. To test this assertion, we compared the efficacy of thiopurines in children with IBD with that in adults matched for disease phenotype.

Patients and Methods:

Fifty paediatric and adult patients with IBD started on a thiopurine were matched for sex, disease type, and extent. Retrospective data were obtained by electronic case note review, and corticosteroid‐free clinical remission and tolerance rates at 6 months as well as relapse rates during the subsequent year were recorded.

Results:

Adverse effects caused discontinuation of thiopurines in 1 of 50 children and 16% (8/50) of adults (P < 0.05). At 6 months, steroid‐free remission was achieved in 30% (15/50) of children and 38% (19/50) of adults (P = 0.53). No differences in remission rates were seen according to disease type. At the end of the following year, 73% (11/15) of children and 68% (13/19) of adults remained in remission (P = 1).

Conclusions:

Thiopurines are tolerated better by children. When phenotype is matched, there is no difference in the therapeutic response to thiopurines between children and adults with IBD.
Variation in Care for Children With Esophageal Varices: A Study of Physicians', Patients', and Families' Approaches and Attitudes
Authors: Gana Juan Cristóbal , Valentino Pamela L , Morinville Veronique , O'Connor Constance , Ling Simon C
Published: May 2011

Background and Aims:

Inadequate evidence to guide the management of children with esophageal varices may lead to variation in care and the provision of poor‐quality care to some children. The aims of the study were to describe approaches taken by pediatric gastroenterologists for the management of esophageal varices in children, and to determine the attitudes of children, parents, and physicians toward screening endoscopy for identification of varices.

Methods:

Canadian pediatric gastroenterologists and hepatologists were questioned about their approaches to screening for esophageal varices and therapy to prevent or treat variceal hemorrhage. Consecutive children with portal hypertension and their parents were surveyed about attitudes to screening endoscopy.

Results:

Forty‐seven of 72 (65%) physicians responded. Seventy percent of respondents screen for esophageal varices in selected children, most using endoscopy (77%). Fifty‐eight percent of respondents who screen for varices would provide primary prophylactic treatment. Most would treat an acute variceal bleed with antibiotics, acid suppression, octreotide, and endoscopy within 24 hours (76%) and then secondary prophylaxis with endoscopic variceal ligation (96%) or β‐blockers (28%). Among 29 families surveyed, 63% of parents and 50% of patients would agree to screening endoscopy to understand their risk of variceal bleeding and 67% if prophylactic therapy were available. Families were more concerned about the risk of endoscopic adverse events than were gastroenterologists.

Conclusions:

Pediatric gastroenterologists vary in the care they provide for children at risk for esophageal varices and their attitudes toward the role of screening endoscopy differ from that of their patients. Further evidence is required to support practice guidelines that may reduce variation in care and thus improve its quality.
Gene Expression Profiling Reveals Upregulated UCA1 and BMF in Gallbladder Epithelia of Children With Pancreaticobiliary Maljunction
Authors: Kaneko Kenitiro , Ito Yoshinori , Ono Yasuyuki , Tainaka Takahisa , Tsuchiya Hironori , Shimoyama Yoshie , Ando Hisami
Published: May 2011

Background:

Pancreaticobiliary maljunction is usually associated with choledochal cysts and often causes biliary carcinoma; however, the mechanism of carcinogenesis remains unknown. No study has analyzed overall changes in genetic expression beginning during childhood in gallbladder epithelia with pancreaticobiliary maljunction.

Patients and Methods:

The genomewide expression of gallbladder epithelia was analyzed in 6 children with pancreaticobiliary maljunction and in 4 pediatric controls. Selected genes that were expressed differentially were further analyzed by the real‐time reverse transcription‐polymerase chain reaction (RT‐PCR). The products of upregulated genes confirmed by real‐time RT‐PCR were immunohistochemically analyzed using gallbladders from 19 children with pancreaticobiliary maljunction, 5 pediatric controls, and 5 children with gallstones.

Results:

Microarray analysis identified 188 upregulated and 160 downregulated genes. RT‐PCR confirmed upregulation in 5 of 6 genes and downregulation in 1 of 5 genes, including UCA1, DUOX2, DUOXA2, ID1, BMF, and GP2. Immunohistochemistry showed a significantly higher expression of BMF in the pancreaticobiliary maljunction patients than in the controls and gallstone patients.

Conclusions:

This study identified several deregulated genes in the gallbladder of children with pancreaticobiliary maljunction, which may contribute to the pathophysiology. UCA1, a noncoding RNA, is an oncofetal gene, and its upregulation may be important for biliary carcinogenesis. The elevated expression of BMF may function as an apoptotic activator in proliferative gallbladder epithelia.
mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry
Authors: Dai Ning , Rapley Joseph , Angel Matthew , Yanik M. Fatih , Blower Michael D. , Avruch Joseph
Published: May 2011

Variants in the IMP2 (insulin-like growth factor 2 [IGF2] mRNA-binding protein 2) gene are implicated in susceptibility to type 2 diabetes. We describe the ability of mammalian target of rapamycin (mTOR) to regulate the cap-independent translation of IGF2 mRNA through phosphorylation of IMP2, an oncofetal RNA-binding protein. IMP2 is doubly phosphorylated in a rapamycin-inhibitable, amino acid-dependent manner in cells and by mTOR in vitro. Double phosphorylation promotes IMP2 binding to the IGF2 leader 3 mRNA 5′ untranslated region, and the translational initiation of this mRNA through eIF-4E- and 5′ cap-independent internal ribosomal entry. Unexpectedly, the interaction of IMP2 with mTOR complex 1 occurs through mTOR itself rather than through raptor. Whereas depletion of mTOR strongly inhibits IMP2 phosphorylation in cells, comparable depletion of raptor has no effect; moreover, the ability of mTOR to phosphorylate IMP2 in vitro is unaffected by the elimination of raptor. Dual phosphorylation of IMP2 at the mTOR sites is evident in the mouse embryo, likely coupling nutrient sufficiency to IGF2 expression and fetal growth. Doubly phosphorylated IMP2 is also widely expressed in adult tissues, including islets of Langerhans.
Post-training intrahippocampal inhibition of class I histone deacetylases enhances long-term object-location memory
Authors: Hawk Joshua D. , Florian Cédrick , Abel Ted
Published: May 2011

Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance long-term memory have focused on the fear-conditioning task using broad-spectrum HDAC inhibitors. We have found that post-training intrahippocampal administration of the broad-spectrum HDAC inhibitor trichostatin A (TSA) or the class I HDAC-selective inhibitor MS275 enhances long-term object-location memory, supporting a role for class I HDACs in the enhancement of hippocampus-dependent memory induced by HDAC inhibition.
Disrupting reconsolidation: Pharmacological and behavioral manipulations
Authors: Soeter Marieke , Kindt Merel
Published: May 2011

We previously demonstrated that disrupting reconsolidation by pharmacological manipulations “deleted” the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited modifications. At the same time, the fear-erasing effects should not be restricted to the feared cue itself considering that fear generalization is a main characteristic of anxiety disorders. In Experiment I and Experiment Ib, we addressed these issues using a within-subject differential startle fear conditioning paradigm and a test of fear generalization. In Experiment II, we tested whether a behavioral approach targeting the reconsolidation through extinction learning was also effective in weakening the original fear memory. A behavioral procedure is evidently preferred over drug manipulations provided that similar effects can be obtained. Here, the extinction procedure subsequent to retrieval did not “erase” the emotional expression of the fear memory as the retrieval techniques (i.e., reminder shocks and reacquisition) unveiled a return of the startle fear response to the fear-relevant stimuli. In contrast, β-adrenergic receptor blockade during reconsolidation selectively deleted the fear-arousing aspects of the memory (i.e., startle fear response) along with its category-related information. The pharmacological manipulation rendered the core memory trace too weak to observe fear generalization after successful reacquisition. Hence, relearning following the disruption of reconsolidation seems to be qualitatively different from initial learning. Our findings demonstrate that disrupting reconsolidation by pharmacological manipulations, although selective, undermines the generalization of fear, a key feature of anxiety disorders.
A mechanism‐based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects
Authors: Thai Hoai‐Thu , Veyrat‐Follet Christine , Vivier Nicole , Dubruc Catherine , Sanderink Gerard , Mentré France , Comets Emmanuelle
Published: May 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Anti‐angiogenic drugs have been developed as an effective therapeutic strategy for inhibiting tumour growth. However, their pharmacokinetics (PK) and their ligand inhibition properties have not been well characterized. The binding to a circulating target, such as vascular endothelial growth factor (VEGF), makes the PK of these drugs more complex.

WHAT THIS STUDY ADDS

• The underlying mechanism of disposition of aflibercept, where a saturable and high affinity binding of aflibercept to VEGF was adequately characterized by the Michaelis–Menten approximation of a target‐mediated drug distribution model. To our knowledge, this is the first published mechanism‐based population PK model for an anti‐VEGF drug.

AIM Aflibercept (VEGF‐Trap), a novel anti‐angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism‐based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects.

METHODS Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration−time data were analysed using a nonlinear mixed‐effects modelling approach with MONOLIX 3.1.

RESULTS The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis–Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day−1 and 0.14 l day−1, respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day−1 and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml−1. Interindividual variability of model parameters was moderate, ranging from 13.6% (Vmax) to 49.8% (Q).

CONCLUSION The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.
Thyroid incidentaloma identified by 18F‐fluorodeoxyglucose positron emission tomography with CT (FDG‐PET/CT): clinical and pathological relevance
Authors: Pagano L. , Samà M. T. , Morani F. , Prodam F. , Rudoni M. , Boldorini R. , Valente G. , Marzullo P. , Baldelli R. , Appetecchia M. , Isidoro C. , Aimaretti G.
Published: May 2011

Objective  The percentage of patients with thyroid cancer incidentally diagnosed during a 18F‐fluorodeoxyglucose Positron Emission Tomography with computed tomography (CT) (FDG‐PET/CT) for nonthyroid diseases ranges between 26% and 50%.

Design  Retrospective assessment of the clinical and pathological features of thyroid incidentalomas at FDG‐PET/CT, aiming to identify potential predictors of malignancy.

Patients  Fifty‐two patients with incidental thyroid uptake at FDG‐PET/CT were retrospectively included [38 W, age 64·1 ± 12·5 years (mean ± SD)]. An arbitrary cut‐off level of 5·0 for the ‘maximum standardized uptake value’ (SUV max) was chosen to differentiate benign from malignant tumours. Complete thyroid function, neck ultrasonography (US) features, and cyto‐histological results were reported for all cases.

Results  In our institution, the prevalence of incidental thyroid 18F‐fluorodeoxyglucose (18F‐FDG) uptake was nearly 1·76%. The prevalence of focal uptake correlated with greater risk of malignancy (P < 0·01). In particular, the euthyroidism (P < 0·003) and a SUV max >5·0 (P < 0·0001) were associated with the diagnosis of thyroid cancer. Diffusely increased FDG‐PET/CT uptake in the thyroid was related to benign conditions.

Conclusions  The presence of focal uptake with high SUV max and euthyroidism correlate with high likelihood of malignancy. Performing a neck US would have to be recommended in all patients with euthyroidism and an incidental FDG‐PET/CT focal thyroid uptake. We do not suggest to use FDG‐PET/CT as a screening tool for thyroid cancer in the general population, because of both its high cost and low incidence of thyroid incidentaloma at FDG‐PET/CT.
Body mass index and obesity in adolescents in a psychiatric medium secure service
Authors: Haw C. , Bailey S.
Published: May 2011

How to cite this article
 Haw C. & Bailey S. (2012) Body mass index and obesity in adolescents in a psychiatric medium secure service. J Hum Nutr Diet.25, 167–171

Background:  Obesity is more prevalent in adults with severe mental illness than in the general population. Little is known about the prevalence of obesity in mentally ill adolescents. The present study aimed to determine the prevalence of obesity and its complications among inpatients in a psychiatric medium secure service for adolescents and young people.

Methods:  The study comprised a cross‐sectional survey of routinely collected data, including body mass index (BMI) both currently and 3 months previously, serum cholesterol and psychotropic prescription data, as well as the number of patients known to have type II diabetes mellitus and hypertension.

Results:  Of the 95 patients studied, 33 (34.7%) were overweight and 45 (47.4%) were obese. Twenty‐six (56.5%) females were obese, including seven who were morbidly obese. Nineteen (38.8%) males were obese, one of whom was morbidly obese. Prescription of antipsychotics was associated with obesity and the total percentage dose of antipsychotic correlated with BMI. Two patients had type 2 diabetes mellitus and two had hypertension. Seventeen patients had a serum cholesterol of over 5 mm.

Conclusions:  Being overweight and obesity were very common in the young people studied and appeared to be related to the prescription of antipsychotics. Interventions are needed to reduce unhealthy raised BMI and prevent the physical complications of obesity.
Fecundity selection on ornamental plumage colour differs between ages and sexes and varies over small spatial scales
Authors: PARKER T. H. , WILKIN T. A. , BARR I. R. , SHELDON B. C. , ROWE L. , GRIFFITH S. C.
Published: May 2011

Avian plumage colours are some of the most conspicuous sexual ornaments, and yet standardized selection gradients for plumage colour have rarely been quantified. We examined patterns of fecundity selection on plumage colour in blue tits (Cyanistes caeruleus L.). When not accounting for environmental heterogeneity, we detected relatively few cases of selection. We found significant disruptive selection on adult male crown colour and yearling female chest colour and marginally nonsignificant positive linear selection on adult female crown colour. We discovered no new significant selection gradients with canonical rotation of the matrix of nonlinear selection. Next, using a long‐term data set, we identified territory‐level environmental variables that predicted fecundity to determine whether these variables influenced patterns of plumage selection. The first of these variables, the density of oaks within 50 m of the nest, influenced selection gradients only for yearling males. The second variable, an inverse function of nesting density, interacted with a subset of plumage selection gradients for yearling males and adult females, although the strength and direction of selection did not vary predictably with population density across these analyses. Overall, fecundity selection on plumage colour in blue tits appeared rare and inconsistent among sexes and age classes.
The development of pistillate and perfect florets in Xeranthemum squarrosum (Asteraceae)
Authors: Dadpour M. R. , Naghiloo S. , Neycharan S. Faridi
Published: May 2011

The formation of capitulum inflorescence with two different types of floret is an interesting issue in floral biology and evolution. Here we studied the inflorescence, floral ontogeny and development of the everlasting herb, Xeranthemum squarrosum, using epi‐illumination microscopy. The small vegetative apex enlarged and produced involucral bracts with helical phyllotaxy, which subtended floret primordia in the innermost whorl. Initiation of floret primordia was followed by an acropetal sequence, except for pistillate peripheral florets. The origin of receptacular bracts was unusual, as they derived from the floral primordia rather than the receptacular surface. The order of whorl initiation in both disc and pistillate flowers included corolla, androecium and finally calyx, together with the gynoecium. The inception of sepals and stamens occurred in unidirectional order starting from the abaxial side, whereas petals incepted unidirectionally from the adaxial or abaxial side. Substantial differences were observed in flower structure and the development between pistillate and perfect florets. Pistillate florets presented a zygomorphic floral primordium, tetramerous corolla and androecium and two sepal lobes. In these florets, two sepal lobes and four stamen primordia stopped growing, and the ovary developed neither an ovule nor a typical stigma. The results suggest that peripheral pistillate florets in X. squarrosum, which has a bilabiate corolla, could be considered as an intermediate state between ancestral bilabiate florets and the derived ray florets.
Photosynthetic acclimation to light in woody and herbaceous species: a comparison of leaf structure, pigment content and chlorophyll fluorescence characteristics measured in the field
Authors: Hallik L. , Niinemets Ü. , Kull O.
Published: May 2011

Acclimation of foliage photosynthetic properties occurs with varying time kinetics, but structural, chemical and physiological factors controlling the kinetics of acclimation are poorly understood, especially in field environments. We measured chlorophyll fluorescence characteristics, leaf total carotenoid (Car), chlorophyll (Chl) and nitrogen (N) content and leaf dry mass per area (LMA) along vertical light gradients in natural canopies of the herb species, Inula salicina and Centaurea jacea, and tree species, Populus tremula and Tilia cordata, in the middle of the growing season. Presence of stress was assessed on the basis of night measurements of chlorophyll fluorescence. Our aim was to compare the light acclimation of leaf traits, which respond to light availability at long (LMA and N), medium (Chl a/b ratio, Car/Chl ratio) and short time scales (fluorescence characteristics). We found that light acclimation of nitrogen content per unit leaf area (Narea), chlorophyll content per unit dry mass (Chlmass) and Chl/N ratio were related to modifications in LMA. The maximum PSII quantum yield (Fv/Fm) increased with increasing growth irradiance in I. salicina and P. tremula but decreased in T. cordata. Leaf growth irradiance, N content and plant species explained the majority of variability in chlorophyll fluorescence characteristics, up to 90% for steady‐state fluorescence yield, while the contribution of leaf total carotenoid content was generally not significant. Chlorophyll fluorescence characteristics did not differ strongly between growth forms, but differed among species within a given growth form. These data highlight that foliage acclimation to light is driven by interactions between traits with varying time kinetics.
Interchangeable effects of gibberellic acid and temperature on embryo growth, seed germination and epicotyl emergence in Ribes multiflorum ssp. sandalioticum (Grossulariaceae)
Authors: Mattana E. , Pritchard H. W. , Porceddu M. , Stuppy W. H. , Bacchetta G.
Published: May 2011

Morphophysiological dormancy was investigated in seeds of Ribes multiflorum Kit ex Roem et Schult. ssp. sandalioticum Arrigoni, a rare mountain species endemic to Sardinia (Italy). There were no differences in imbibition rates between intact and scarified seeds, suggesting a lack of physical dormancy, while methylene blue solution (0.5%) highlighted a preferential pathway for solution entrance through the raphe. Embryos were small at seed dispersal, with an initial embryo:seed ratio (E:S) of ca. 0.2 (embryo length, ca. 0.5 mm), whereas the critical E:S ratio for germination was three times longer (ca. 0.6). Gibberellic acid (GA3, 250 mg·l−1) and warm stratification (25 °C for 3 months) followed by low temperature (<15 °C) enhanced embryo growth rate (maximum of ca. 0.04 mm·day−1 at 10 °C) and subsequent seed germination (radicle emergence; ca. 80% at 10 °C). Low germination occurred at warmer temperatures, and cold stratification (5 °C for 3 months) induced secondary dormancy. After radicle emergence, epicotyl emergence was delayed for ca. 2 months for seeds from three different populations. Mean time of epicotyl emergence was affected by GA3. Seeds of this species showed non‐deep simple (root) ‐ non‐deep simple (epicotyl) morphophysiological dormancy, highlighting a high synchronisation with Mediterranean seasonality in all the investigated populations.
Esophageal motor abnormalities in eosinophilic esophagitis identified by high‐resolution manometry
Authors: Martín Martín Leticia , Santander Cecilio , Lopez Martín Mari Carmen , Espinoza‐Ríos Jorge , Chavarría‐Herbozo Carlos , Gisbert Javier P , Moreno‐Otero Ricardo
Published: May 2011

Background and Aim:  Esophageal motility abnormalities, as measured by conventional manometry (CM), are non‐specific in the majority of patients with eosinophilic esophagitis (EoE). Moreover, the study of CM is limited by poor interobserver agreement. The aims of the present study were: (i) to assess the esophageal patterns in EoE by a topographic analysis of high‐resolution manometry (HRM) data; and (ii) to establish a relationship between motility abnormalities and symptoms of EoE, such as dysphagia and bolus impaction.

Methods:  All adult patients with EoE diagnosed according to histological criteria, and controls with gastroesophageal reflux disease symptoms and dysphagia, were included. HRM was done in EoE patients and controls. For the analysis of data, the Chicago classification was followed.

Results:  HRM was performed in 21 patients with EoE, as well as in 21 controls. Of the 21 patients with EoE, 10 (48%) showed pan‐esophageal pressurization, six (28%) showed peristaltic dysfunction, and in five cases (24%), HRM was normal. There was no pan‐esophageal pressurization in controls. Nine of 10 patients with pan‐esophageal pressurization required endoscopic bolus removal (P < 0.05); none had obstructive endoscopy findings.

Conclusions:  The most frequent esophageal motor abnormality measured by HRM was a pan‐esophageal pressurization. Bolus impaction in patients with EoE was associated with pan‐esophageal pressurization.