bluuebunny/crossref_metadata_2025 huggingface dataset:
Intron length increases oscillatory periods of gene expression in animal cells
Authors: Swinburne Ian A. , Miguez David G. , Landgraf Dirk , Silver Pamela A.
Published: August 2008

Introns may affect gene expression by increasing the time required to transcribe the gene. One way for extended transcription times to affect the behavior of a gene expression program is through a negative feedback loop. Here, we show that a logically engineered negative feedback loop in animal cells produces expression pulses, which have a broad time distribution that increases with intron length. These results in combination with mathematical models provide insight into what may produce the intron-dependent pulse distributions. We conclude that the long production time required for large intron-containing genes is significant for the behavior of gene expression programs.
Investigation of Adhesively Bonded Joints for Composite Propeller Shafts
Authors: Kim Jin Kook , Lee Dai Gil , Cho Durk Hyun
Published: August 2008

Substituting composite structures for conventional metallic structures has many advantages because of higher specific stiffness and specific strength of composite materials. In this work, one-piece propeller shafts composed of carbon/epoxy composites were designed and manufactured for a rear wheel drive automobile satisfying three design specifications, such as static torque transmission capability, torsional buckling and the fundamental natural bending frequency. Single lap adhesively bonded joint was used to join the composite shaft and the aluminum yoke.

The torque transmission capability of the adhesively bonded composite shaft was calculated with respect to bonding length and yoke thickness by finite element method and compared with the experimental result. Torque transmission capability was based on the Tsai-Wu failure index for composite shaft and the failure model which incorporated the nonlinear mechanical behavior of aluminum yoke and epoxy adhesive. From the experiments and FEM analyses, it was found that the static torque transmission capability of the composite propeller shaft was highest at the critical yoke thickness, and saturated beyond the critical length. Also, it was found that the one-piece composite propeller shaft had 40% weight saving effect compared with a conventional two-piece steel propeller shaft.
A Micromechanical Model for X-Ray Stress Analysis of Fiber Reinforced Composites
Authors: Meske R. , Schnack E.
Published: August 2008

The structural and residual stress of fibrous composites can be evaluated by measuring the strain in embedded particles which are sensitive to X-ray diffraction. The main advantage is that three-dimensional stresses in the interior can be measured. To evaluate the stress in the material a micromechanical model is proposed for the effective stressstrain relationship between the strain in the particles and the stress in the composite. The consistency of the model is checked by Finite-Element computations of representative volume elements. The predictions of the model are compared with experimental results and conclusions about the validity of the model are drawn.
Spin echo scattering angle measurement at a pulsed neutron source
Authors: Pynn Roger , Fitzsimmons M. R. , Lee W. T. , Shah V. R. , Washington A. L. , Stonaha P. , Littrell Ken
Published: August 2008

Two experiments were performed to adapt spin echo scattering angle measurement (SESAME) to pulsed neutron sources. SESAME is an interferometric method that provides enhanced resolution of neutron scattering angles without the loss of neutron intensity that results when collimation is used to improve angular resolution. The method uses the neutron equivalent of optical wave plates to produce a phase difference between the two neutron spin components of a polarized neutron beam. Because the wave plate is inclined to the neutron beam, this phase difference depends sensitively on the trajectory of the neutron. In the absence of a sample, a second wave plate, which is parallel to the first, undoes the phase difference introduced by the first wave plate, producing a polarization identical to that of the incident neutron beam. When a scattering sample is placed between the two neutron wave plates, the cancellation of the phase difference between the neutron spin states is not perfect and the resulting neutron-beam polarization is a measure of the distribution of scattering angles. In the first experiment, thin (30 and 60 µm-thick) magnetized Permalloy films were used as neutron wave plates. In a second experiment, current-carrying solenoids with triangular cross sections were used as birefringent prisms for neutrons. The arrangement of these prisms was such that they mimicked the effect of the neutron wave plates in the first experiment. In both experiments, correlation lengths in the scattering sample of about 1000 Å were probed using very simple and inexpensive equipment. These experiments brought to light a number of advantages and disadvantages of implementing SESAME at pulsed neutron sources and provided insights into the relative merits of SESAME and traditional small-angle neutron scattering.
Study of the effect of nano-sized precipitates on the mechanical properties of boron-added low-carbon steels by neutron scattering techniques
Authors: Seong B. S. , Cho Y. R. , Shin E. J. , Kim S. I. , Choi S.-H. , Kim H. R. , Kim Y. J.
Published: August 2008

Small-angle neutron scattering (SANS) and neutron powder diffraction (ND) techniques were used to study quantitatively the effect of nano-sized precipitates and boron addition on the mechanical properties of low-carbon steels. SANS was used to evaluate nano-sized precipitates, smaller than about 600 Å in diameter, and ND was used to determine the weight fraction of the cementite precipitates. Fine core–shell structured spherical precipitates with an average radius of ~50 Å, such as MnS and/or CuS, surrounded by BN layers were observed in the boron-added (BA) low-carbon steels; fine spherical precipitates with an average radius of ~48 Å were mainly observed in the boron-free (BF) low-carbon steels. In the BA steels, the number of boron precipitates, such as BN, Fe3(C,B) and MnS, surrounded by BN layers increased drastically at higher hot-rolling temperatures. The volume fraction of the fine precipitates of the BA steels was higher than that of the BF steels; this difference is related to the rapid growth of the BN layers on the MnS and CuS precipitates. Boron addition to low-carbon steels resulted in a reduction in strength and an improvement in elongation; this behaviour is related to the reduction of the solute carbon and the nitrogen contents in the ferrite matrix caused by the precipitation of BN, as well by the increase in the volume fraction of the cementites.
Automated sample-changing robot for solution scattering experiments at the EMBL Hamburg SAXS station X33
Authors: Round A. R. , Franke D. , Moritz S. , Huchler R. , Fritsche M. , Malthan D. , Klaering R. , Svergun D. I. , Roessle M.
Published: August 2008

There is a rapidly increasing interest in the use of synchrotron small-angle X-ray scattering (SAXS) for large-scale studies of biological macromolecules in solution, and this requires an adequate means of automating the experiment. A prototype has been developed of an automated sample changer for solution SAXS, where the solutions are kept in thermostatically controlled well plates allowing for operation with up to 192 samples. The measuring protocol involves controlled loading of protein solutions and matching buffers, followed by cleaning and drying of the cell between measurements. The system was installed and tested at the X33 beamline of the EMBL, at the storage ring DORIS-III (DESY, Hamburg), where it was used by over 50 external groups during 2007. At X33, a throughput of approximately 12 samples per hour, with a failure rate of sample loading of less than 0.5%, was observed. The feedback from users indicates that the ease of use and reliability of the user operation at the beamline were greatly improved compared with the manual filling mode. The changer is controlled by a client–server-based network protocol, locally and remotely. During the testing phase, the changer was operated in an attended mode to assess its reliability and convenience. Full integration with the beamline control software, allowing for automated data collection of all samples loaded into the machine with remote control from the user, is presently being implemented. The approach reported is not limited to synchrotron-based SAXS but can also be used on laboratory and neutron sources.
WAP(version 2.0): an updated computing and visualization server for water molecules
Authors: Praveen S. , Ramesh J. , Sivasankari P. , Sowmiya G. , Sekar K.
Published: August 2008

By exploiting the fast-growing Internet technology, the interactive computing serverWater Analysis Package(WAP, version 2.0) has been updated with more flexible options to better understand the role of the water O atoms present in three-dimensional macromolecular (protein or nucleic acid) structures. The updated robust server facilitates the computation and visualization of water molecules from various hydration shells, interfacial water molecules and those water molecules that stabilize various secondary structural elements. It is also possible to detect the interactions of water molecules with various parts (polar atoms, nonpolar atoms, main-chain and side-chain atoms) of the protein molecule. Furthermore, a molecular graphics visualization program is interfaced to display the nature of the interactions of the water molecules. The Protein Data Bank archive interfaced with the server is updated every week; hence users get to analyse the latest structures. The computing server can be obtained from http://dicsoft2.physics.iisc.ernet.in/wap/.
Tormat: a program for the automated structural alignment of molecular conformations
Authors: Weng Ze F. , Motherwell W. D. Sam , Cole Jacqueline M.
Published: August 2008

A method is described which enables automated superimposition of molecular conformations by the matching of chemical graphs, allowing for topological symmetry in the molecular structure. This algorithm is implemented in the programTormat. The implemented method makes allowance for enantiomer inversion, explicit and implicit treatment of H atoms, and partial structure alignment.
Nondestructive characterization of ferrofluids by wide-angle synchrotron light diffraction: crystalline structure and size distribution of colloidal nanoparticles
Authors: Vorobiev Alexei , Chernyshov Dmitry , Gordeev Gennady , Orlova Diana
Published: August 2008

The combination of magnetic and nonmagnetic interactions between the colloidal particles in ferrofluids results in various local inter-particle correlations that, in turn, change the macroscopic properties of the whole system. Therefore, characterization of the particle ensemble is a crucial point, allowing optimization of a ferrofluid for a particular application. Here it is shown how the crystal structure of the particles can be easily obtained in a fast synchrotron light diffraction experiment without any special treatment of the ferrofluid sample. Moreover, from the same diffraction patterns, such important parameters as particle mean size and dispersion are retrieved; these are compared with the corresponding parameters obtained from electron microscopy data. A particular problem of magnetite–maghemite transformation in nanoparticles stabilized by the surfactant shell is pointed out.
(E)-Ethyl N′-[1-(2-hydroxyphenyl)ethylidene]hydrazinecarboxylate
Authors: Gao Bo
Published: August 2008

In the molecule of the title compound, C11H14N2O3, the dihedral angle between the benzene ring and the hydrazinecarboxylate mean plane is 3.65 (12)°. Intramolecular C—H...N and O—H...N hydrogen bonds result in the formation of a nearly planar six-membered ring, which is oriented at a dihedral angle of 2.38 (3)° with respect to the benzene ring, and a five-membered ring having an envelope conformation. In the crystal structure, intermolecular N—H...O and C—H...N hydrogen bonds link the molecules. There is a C—H...π contact between the benzene ring and the methyl group of the ethyl substituent.
(E,E)-2,2′-[1,1′-(Cyclohexane-1,2-diyldinitrilo)diethylidyne]diphenol
Authors: Chen Fang , Ye Heng-Yun
Published: August 2008

The title compound, C22H26N2O2, is chiral; the absolute configuration follows from the known chirality of the input reagents. The asymmetric unit contains two crystallographically independent molecules in different orientations. The two molecules are related to each other by a non-crystallographic twofold rotation axis, while each molecule exhibits a further pseudo-twofold axis. Bond distances and angles are similar in the two molecules. Intermolecular C—H...π(ring) interactions and intramolecular O—H...N hydrogen bonds are observed in the crystal structure.
(Z)-3-Ferrocenyl-2-(3-pyridyl)acrylonitrile
Authors: Chen Fang , Ye Heng-Yun
Published: August 2008

The molecular structure of the title compound, [Fe(C5H5)(C13H9N2)], (I), is analogous to that of the compound (Z)-3-ferrocenyl-2-phenylacrylonitrile [Cao & Ye (2008). Acta Cryst. E64, m822], (II), with the pyridine ring in (I) replacing the benzene ring in (II). While the corresponding bond distances and angles in the two compounds show no significant differences, the two dihedral angles between the planes through the acrylonitrile group and the two rings attached to it (substituted Cp and pyridine) of 16.8 (4) and 20.1 (4)° in (I) are different from the corresponding dihedral angles [19.6 (3) and 6.5 (4)°] in (II). The unsubstituted ring is disordered over two positions, with site-occupancy factors of 0.70 (1) and 0.30 (1). The major and minor components of the disordered ring are almost coplanar and are also parallel to the substituted cyclopentadiene ring plane, with a dihedral angle of 0.3 (6)°.
6-Cyclohexylmethyl-2-cyclohexylsulfanyl-5-isopropylpyrimidin-4(3H)-one
Authors: Zhang Chun-Sheng , Li Da-Xiong , Zhang De-Hua , He Yan-Ping , Li Cong
Published: August 2008

The title compound, C20H32N2OS, was obtained during the course of our investigation on 2-alkylsulfanyl-6-benzyl-3,4-dihydropyrimidin-4(3H)-ones (S–DABOs) showing favourable anti-HIV-1 activity. Both cyclohexane rings adopt chair conformations. The angle at the methylene C atom linking the pyrimidine and cyclohexane ring is 113.7 (3)°, which is in the range considered optimal for maximum activity of non-nucleoside reverse transcriptase inhibitors. Intermolecular N—H...O hydrogen bonds link the molecules into dimers and stabilize the crystal structure of the compound. In addition, an intramolecular C—H...O hydrogen bond is observed.
Diaquabis(3,7-dichloroquinoline-8-carboxylato)zinc(II) monohydrate
Authors: An Li-Tao , Zhou Jian , Zhou Jian-Feng , Xia Min
Published: August 2008

In the title compound, [Zn(C10H4Cl2NO2)2(H2O)2]·H2O, the Zn atom has a distorted square-pyramidal geometry comprising two O atoms and one N atom from two distinct 3,7-dichloroquinoline-8-carboxylate ligands, and two water molecules. The free water molecules are involved in intermolecular O—H...O hydrogen bonding with the coordinated water molecules and carboxylate O atoms, to give a one-dimensional helical chain along the [100] direction.
10-(4-Chlorophenyl)-9-(4-fluorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione
Authors: Zhao Ling-Ling , Teng Da
Published: August 2008

The title compound, C29H29ClFNO2, was synthesized by the reaction of 4-fluorobenzaldehyde, 5,5-dimethylcyclohexane-1,3-dione and 3-(4-chlorophenylamino)-5,5-dimethylcyclohex-2-enone in an ionic liquid (1-butyl-3-methylimidazolium bromide). X-ray analysis reveals that the 1,4-dihydropyridine ring adopts a boat conformation, while each of the attached partially saturated six-membered rings adopts a half-chair conformation. The structure is stabilized by weak C—H...O and C—H...F hydrogen bonds. The molecule has approximate mirror symmetry; the largest deviation from this symmetry concerns the fluoro- and chlorophenyl rings.
2-Methoxy-4-methylphenyl 4-toluenesulfonate
Authors: Ramachandran G. , Kanakam Charles Christopher , Gunasekaran B. , Manivannan V.
Published: August 2008

In the title molecule, C15H16O4S, the interplanar angle between the two aromatic rings is 45.07 (7)°. The crystal packing is stabilized by weak intermolecular C—H...O interactions.
Tetramethyl biphenyl-2,3,3′,4′-tetracarboxylate
Authors: Gao Guo-wei , Ma Xiao-yan , Jiang Yan , Chen Wei , Men Jian
Published: August 2008

The asymmetric unit of the title compound, C20H18O8, contains two molecules with small geometric differences. The dihedral angles between the benzene rings are 62.94 (12) and 59.99 (12)°. The dihedral angles between the carboxylate groups in the 2- and 3-positions are 81.72 (13) and 65.54 (15)°, respectively. However, the dihedral angles between the carboxylate groups in the 3′ and 4′-positions are 67.24 (15) and 59.98 (17)°, respectively.
3-(4-Fluorophenyl)-1-[1′-(4-fluorophenyl)-2-oxo-5′,6′,7′,7a′-tetrahydro-1H-indole-3(2H)-spiro-3′(2′H)-1H′-pyrrolizin-2′-yl]prop-2-en-1-one
Authors: Nirmala S. , Murugan R. , Kamala E. Theboral Sugi , Sudha L. , Sriman Narayanan S.
Published: August 2008

In the title compound, C29H24F2N2O2, one of the pyrrolidine rings of the pyrrolizine system is disordered over two sites, with occupancy factors 0.734:0.266 (12). Both components of the disordered pyrrolidine ring adopt envelope conformations, whereas the other pyrrolidine ring adopts a twist conformation. The molecules are linked into centrosymmetric dimers by N—H...O hydrogen bonds and the dimers are connectedviaC—H...π interactions. The crystal structure is also stabilized by intermolecular C—H...F hydrogen bonds.
Diaqua-μ3-oxido-hexakis(μ2-trichloroacetato-κ2
O:O′)(trichloroacetato-κO)trichromium(III) acetonitrile trisolvate
Authors: Soume B. B. Mougang D. , Yahya Rosiyah , Gan Seng Neon , Ng Seik Weng
Published: August 2008

In the crystal structure of the title compound, [Cr3(C2Cl3O2)7O(H2O)2]·3CH3CN, the trinuclear [Cr3O(H2O)2(Cl3CCO2)7] molecule has an oxide O atom that is connected to one monodentate trichloroacetate-coordinated and two water-coordinated CrIII atoms, the three metal atoms forming the points of an equilateral triangle. Each of the six remaining carboxylate groups bridges a Cr–O–Cr fragment. The cluster interacts with the three solvent molecules through water–acetonitrile O—H...N hydrogen bonds. Adjacent clusters are linked by a water–carboxylate O—H...O hydrogen bond to give a helical chain. One of the CCl3 groups was found to be disordered over two positions, with the major component having a site-occupancy factor of 0.64 (1).
4-Chloro-N′-(5-chloro-2-hydroxybenzylidene)benzohydrazide
Authors: Yang De-Suo
Published: August 2008

The molecule of the title compound, C14H10Cl2N2O2, displays a trans configuration with respect to the C=N double bond and has an intramolecular O—H...N hydrogen bond. The dihedral angle between the two benzene rings is 1.4 (2)°. In the crystal structure, molecules are linked through intermolecular N—H...O hydrogen bonds, forming chains running along the a direction.
4-Chloro-N′-(2-hydroxy-1-naphthylidene)benzohydrazide
Authors: Yang De-Suo
Published: August 2008

The molecule of the title compound, C18H13ClN2O2, displays a trans configuration with respect to the C=N double bond. The dihedral angle between the benzene and naphthyl ring systems is 6.0 (2)°. An O—H...N hydrogen bond is observed in the molecular structure. In the crystal structure, molecules are linked through intermolecular N—H...O hydrogen bonds and π–π stacking interactions [centroid–centroid distance = 3.603 (2) Å], forming chains running along the b axis.
(μ-2-Pyridinealdazine-κ4
N,N′:N′′,N′′′)bis[bis(N,N-di-n-propyldithiocarbamato-κ2
S,S′)cadmium(II)]
Authors: Poplaukhin Pavel , Tiekink Edward R. T.
Published: August 2008

The dinuclear centrosymmetric title compound, [Cd2(C7H14NS2)4(C12H10N4)], features a tetradentate 2-pyridinealdazine ligand that chelates two Cd centres. The coordination geometry for Cd is distorted octahedral based on a cis-N2S4 donor set. In the crystal structure, molecules are connected into a supramolecular chain aligned along the a direction via C—H...S and C—H...π contacts, and by π–π contacts [centroid-to-centroid distance 3.5708 (15) Å]. The n-propyl groups are each disordered, one equally over two sites and the other with a site-occupancy factor of 0.618 (8) for the major component.
(μ-Piperazine-1,4-dicarbodithioato-κ4
S,S′:S′′,S′′′)bis[triphenyltin(IV)] dichloromethane solvate
Authors: Poplaukhin Pavel , Tiekink Edward R. T.
Published: August 2008

The dinuclear centrosymmetric title compound, [Sn2(C6H5)6(C6H8N2S4)]·CH2Cl2, features a distorted cis-trigonal–bipyramidal coordination geometry for Sn based on a C3S2 donor set. The dinuclear molecule lies across a centre of inversion. The solvent dichloromethane molecule is disordered about a centre of inversion.
N′-(2-Hydroxy-5-nitrobenzylidene)-2-(1H-indol-3-yl)acetohydrazide
Authors: Puvaneswary Subramaniam , Ali Hapipah M. , Robinson Ward T. , Ng Seik Weng
Published: August 2008

The molecule of the title compound, C17H14N4O4, uses its amide –NH– group to form a hydrogen bond to the amido –C(=O)– group of an adjacent molecule to furnish a linear chain structure. The hydroxy group forms an intramolecular hydrogen bond; the indolyl –NH– unit does not engage in any strong hydrogen-bonding interactions.
2-(3,5-Di-tert-butyl-4-hydroxybenzylsulfanyl)nicotinic acid
Authors: Mansor Shahirah , Yehye Wagee A. , Ariffin Azhar , Rahman Noorsaadah Abdul , Ng Seik Weng
Published: August 2008

Two molecules of the title compound, C21H27NO3S, are disposed about a center of inversion, generating an O—H...O hydrogen-bonded dimer.
Driving forces behind increasing cardiovascular drug utilization: a dynamic pharmacoepidemiological model
Authors: Kildemoes Helle Wallach , Støvring Henrik , Andersen Morten
Published: August 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Several studies indicate that switch to more expensive drugs and increasing treatment intensity, rather than population ageing have been responsible for rising drug expenditures during the 1990s.

• Little is known about the driving forces behind the increasing treatment intensity with cardiovascular drugs.

WHAT THIS STUDY ADDS

• This study provides a new pharmacoepidemiological method to analyse drug utilization trends, applying dispensing data at the individual level.

• The suggested semi‐Markov model allows for quantification of the influence of changing incidence, discontinuation and user mortality on rising treatment prevalence.

• Increasing treatment incidence was the main driver behind rising treatment prevalence for most cardiovascular drug categories.

• Whereas declining discontinuation drove some of the growth, declining mortality among drug users had little influence.

AIMS

To investigate the driving forces behind increasing utilization of cardiovascular drugs.

METHODS

Using register data, all Danish residents as of 1 January 1996 were followed until 2006. Cohort members were censored at death or emigration. Cardiovascular drug utilization on the individual level was traced, applying registered out‐of‐hospital dispensing. The impact of population ageing on cardiovascular drug utilization was investigated using standardized intensities and prevalences. Based on a three‐state (untreated, treated and dead) semi‐Markov model, we explored to what extent increasing treatment prevalence was driven by changing incidence, discontinuation and mortality. Expected treatment prevalences were modelled, applying stratum‐specific cohort prevalence in 1996 along with incidence, discontinuation and drug user mortality either throughout 1996–2004 or at fixed 1996 levels.

RESULTS

Treatment prevalence (ages ≥20 years) with cardiovascular drugs increased by 39% during 1996–2005 from 192.4 to 256.9 per 1000 inhabitants (95% confidence interval 256.5, 257.3). Treatment intensity grew by 109% from 272 to 569 defined daily doses 1000−1 day−1. Population ‘middle‐ageing’ accounted for 11.5 and 20.3%, respectively. Increasing treatment incidence was the main driver of the rising treatment prevalence in most drug categories. Declining discontinuation drove some of the growth, declining drug user mortality less. Even with fixed incidence in the model, treatment prevalence continued to increase.

CONCLUSIONS

Age‐related increases in treatment intensity and prevalence, rather than population ageing, drove the increasing treatment intensity with cardiovascular drugs. Increasing treatment prevalence in subgroups was primarily caused by increasing incidence. Due to pharmacoepidemiological disequilibrium, treatment prevalence will continue to grow even with unchanged incidence.
Characterization of PRF1, STX11 and UNC13D genotype‐phenotype correlations in familial hemophagocytic lymphohistiocytosis
Authors: Horne AnnaCarin , Ramme Kim Göransdotter , Rudd Eva , Zheng Chengyun , Wali Yasser , Al‐Lamki Zakia , Gürgey Aytemiz , Yalman Nevin , Nordenskjöld Magnus , Henter Jan‐Inge
Published: August 2008

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defect apoptosis triggering and lymphocyte cellular cytotoxicity. Thus far three disease‐causing genes (PRF1, UNC13D, STX11) have been identified. We performed a genotype‐phenotype study in a large, multi‐ethnic cohort of 76 FHL patients originating from 65 unrelated families. Biallelic mutations in PRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%) and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed for all three genes, no molecular diagnosis was established. STX11 mutations were most common in Turkish families (7/28, 25%), whereas in Middle East families, PRF1 mutations were most frequent (6/13, 46%). No biallelic mutation was identified in most families of Nordic origin (13/14, 93%). Patients carrying PRF1 mutations had higher risk of early onset (age <6 months) compared to patients carrying STX11 mutations [adjusted odds ratio 8·23 (95% confidence interval [CI] = 1·20–56·40), P = 0·032]. Moreover, patients without identified mutations had increased risk of pathological cerebrospinal fluid (CSF) at diagnosis compared to patients with STX11 mutations [adjusted odds ratio 26·37 (CI = 1·90–366·82), P = 0·015]. These results indicate that the disease‐causing mutations in FHL have different phenotypes with regard to ethnic origin, age at onset, and pathological CSF at diagnosis.
Serum autotaxin measurement in haematological malignancies: a promising marker for follicular lymphoma
Authors: Masuda Akiko , Nakamura Kazuhiro , Izutsu Koji , Igarashi Koji , Ohkawa Ryunosuke , Jona Masahiro , Higashi Katsumi , Yokota Hiromitsu , Okudaira Shinichi , Kishimoto Tatsuya , Watanabe Takuro , Koike Yukako , Ikeda Hitoshi , Kozai Yasushi , Kurokawa Mineo , Aoki Junken , Yatomi Yutaka
Published: August 2008

Autotaxin (ATX) is a tumour cell motility‐stimulating factor originally isolated from melanoma cell supernatants. ATX is identical to lysophospholipase D, which produces a bioactive lipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine. ATX is overexpressed in various malignancies, including Hodgkin lymphoma, and ATX may stimulate tumour progression via LPA production. The present study measured the serum ATX antigen levels in patients with haematological malignancies using a recently developed automated enzyme immunoassay. The serum ATX antigen levels in patients with B‐cell neoplasms, especially follicular lymphoma (FL), were higher than those in healthy subjects. Serum ATX antigen levels in FL patients were associated with tumour burden and changed in parallel with the patients’ clinical courses. The serum ATX antigen levels were little affected by inflammation, unlike the soluble interleukin‐2 receptor and β2‐microglobulin levels. As expected, the plasma LPA levels in FL patients were correlated with the serum ATX antigen levels. Given that leukaemic tumour cells from FL patients expressed ATX, the shedding of ATX from lymphoma cells probably leads to the elevation of serum ATX antigen levels. Our results suggest that the serum ATX antigen level may be a promising and novel marker for FL.
Polymorphisms of the Z protein protease inhibitor and risk of venous thromboembolism: a meta‐analysis
Authors: Dentali Francesco , Gianni Monica , Lussana Federico , Squizzato Alessandro , Cattaneo Marco , Ageno Walter
Published: August 2008

Two nonsense polymorphisms of Z‐dependent protease inhibitor (ZPI; Serpina10) have been identified. To assess the risk of venous thromboembolism (VTE) associated with W303x and R67X Serpina10 mutations, we performed a meta‐analysis of studies comparing the prevalence of these two mutations in VTE patients and in controls Odds Ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and pooled using a random‐effects model. Five studies involving 5000 patients were included. R67X and W303X mutations of Serpina10 were not associated with increased VTE risk (OR 1·63; 95% CI 0·84, 3·16 and OR 1·21; 95% CI 0·29, 4·98 respectively).
Duffy (Fy), DARC, and neutropenia among women from the United States, Europe and the Caribbean
Authors: Grann Victor R. , Ziv Elad , Joseph Cecil K. , Neugut Alfred I. , Wei Ying , Jacobson Judith S. , Horwitz Marshall S. , Bowman Natalie , Beckmann Kenneth , Hershman Dawn L.
Published: August 2008

Neutropenia associated with race/ethnicity has essentially been unexplained and, although thought to be benign, may affect therapy for cancer or other illnesses. A recent study linked a single nucleotide polymorphism (SNP) (rs2814778) in the Duffy antigen/receptor chemokine gene (DARC) with white blood cell count. We therefore analysed the association of the rs2814778 CC, TC and TT genotypes with absolute neutrophil count (ANC) among asymptomatic women from the Caribbean, Europe and the United States. Among 261 study participants, 33/47 women from Barbados/Trinidad‐Tobago, 34/49 from Haiti, 26/37 from Jamaica, and 29/38 US‐born black women, but only 4/50 from the Dominican Republic and 0/40 US‐ or European‐born whites (P = 0·0001) had the CC genotype. In a linear regression model that included percentage African ancestry, national origin, cytokines, socio‐economic factors and the ELA2 rs57834246 SNP, only the DARC rs2814778 genotype and C‐reactive protein were associated with ANC (P < 0·0001). Women with the CC genotype had lower ANC than other women. Further research is needed on the associations of rs2814778 genotype with neutropenia and treatment delay in the setting of cancer. A better understanding of these associations may help to improve cancer outcomes among individuals of African ancestry.
Reduction of B cell turnover in chronic lymphocytic leukaemia
Authors: Defoiche Julien , Debacq Christophe , Asquith Becca , Zhang Yan , Burny Arsène , Bron Dominique , Lagneaux Laurence , Macallan Derek , Willems Luc
Published: August 2008

Whether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by the unresponsiveness of leukaemic cells to antigens and polyclonal activators, recent in vivo kinetic measurements indicate that B lymphocytes do divide at significant rates in CLL. However, an important and still unanswered question is whether CLL cells proliferate faster or slower compared with their normal counterparts. This report addressed directly this point and compared B‐cell kinetics in CLL subjects and healthy controls, using a pulse‐chase approach based on incorporation of deuterium from 6,6‐2H2‐glucose into DNA. We confirmed that B cells proliferated at significant levels in CLL but found that the proliferation rates were reduced compared with healthy subjects (mean 0·47 vs. 1·31%/d respectively, P = 0·007), equivalent to an extended doubling time of circulating B cells (147 d vs. 53 d). In conclusion, CLL B cells proliferate at reduced levels compared with healthy controls. CLL is thus characterized by an aberrant B‐cell kinetics with a decrease in cell turnover, an observation that may impact on elaboration of efficient therapeutic strategies.
Status of minimal residual disease testing in childhood haematological malignancies
Authors: Campana Dario
Published: August 2008

In children with acute leukaemia, measurements of minimal residual disease (MRD) provide unique information on treatment response and have become a crucial component of contemporary treatment protocols. In acute lymphoblastic leukaemia (ALL), the most useful MRD assays are based on polymerase chain reaction (PCR) amplification of antigen‐receptor genes, and on flow cytometric detection of abnormal immunophenotypes. The latter is the only MRD assay available for most patients with acute myeloid leukaemia (AML). PCR amplification of chromosomal breakpoints and fusion transcripts can also be used to track MRD in a minority of patients with ALL or AML. Because of the strong correlation between MRD levels and risk of relapse, several ongoing regimens include treatment intensification for children with higher MRD. Treatment de‐intensification for patients with early MRD clearance is also being tested. In addition to their direct clinical application, MRD measurements can be used to better understand the molecular and cellular mechanisms of drug resistance in vivo. The identification of new markers of leukaemia and the use of increasingly sophisticated technologies for detection of rare cells should further facilitate routine monitoring of MRD and elucidate the features of drug‐resistant leukaemic cells.
Effect of exercise training on A‐FABP, lipocalin‐2 and RBP4 levels in obese women
Authors: Choi K. M. , Kim T. N. , Yoo H. J. , Lee K. W. , Cho G. J. , Hwang T. G. , Baik S. H. , Choi D. S. , Kim S. M.
Published: August 2008

Objective  Lipocalin family proteins, including adipocyte fatty acid‐binding protein (A‐FABP), lipocalin‐2 and retinol‐binding protein 4 (RBP4), have recently been identified as novel adipokines associated with obesity, type 2 diabetes and the metabolic syndrome. We have evaluated the effect of exercise training on lipocalin family proteins and inflammatory markers.

Study subjects  Thirty obese Korean women and 15 age‐matched nonobese control subjects were studied.

Design  Concentrations of the lipocalin family proteins were compared between obese and nonobese women and were evaluated before and 3 months after an exercise programme consisting of aerobic exercise (45 min/session, 300 kcal/day) and muscle strength training (20 min/session, 100 kcal/day) five times a week.

Results  Obese women exhibited higher A‐FABP levels compared to nonobese women (21·4 ± 6·4 µg/l vs. 13·6 ± 4·4 µg/l, P < 0·001). However, neither lipocalin‐2 nor RBP4 levels were significantly different between the two groups, although the difference in lipocalin‐2 was marginally significant (P = 0·054). Circulating A‐FABP levels were significantly associated with body mass index (BMI), waist circumference, triglyceride, alanine aminotransferase (ALT), lipocalin‐2 and high‐sensitivity C‐reactive protein (hsCRP) levels. After 3 months of the exercise training programme, serum A‐FABP levels decreased significantly from 21·4 ± 6·4 µg/l to 19·3 ± 6·8 µg/l (P = 0·038), along with a reduction in weight, BMI, waist circumference, fasting glucose and total cholesterol levels. There was no significant change in the lipocalin‐2 and RBP4 levels, although IL‐6 levels increased after the exercise programme.

Conclusion  Exercise training with weight loss induced a significant reduction in circulating A‐FABP levels in obese Korean women.
Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians
Authors: Qasim Atif N. , Metkus Thomas S. , Tadesse Mahlet , Lehrke Michael , Restine Stephanie , Wolfe Megan L. , Hannenhalli Sridhar , Cappola Thomas , Rader Daniel J. , Reilly Muredach P.
Published: August 2008

Objective  Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the –420C>G putative gain‐of‐function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans.

Design and methods  We examined the association of three resistin polymorphisms, –852A>G, –420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C‐reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851).

Results  Resistin levels were higher, dose‐dependently, with the –420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The –852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor‐receptor 2 (sol‐TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol‐TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores.

Conclusions  Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.
Prevalence and functional analysis of the S107P polymorphism (rs6647476) of the monocarboxylate transporter 8 (SLC16A2) gene in the male population of north‐west Spain (Galicia)
Authors: Lago‐Lestón Ramón , Iglesias María‐José , San‐José Esther , Areal Carlos , Eiras Adolfo , Araújo‐Vilar David , Lado‐Abeal Joaquín , Domínguez‐Gerpe Lourdes
Published: August 2008

Objective  Mutations in SLC16A2, the gene encoding the thyroid hormone (TH)‐specific transporter monocarboxylate transporter 8 (MCT8), result in a thyroid phenotype and severe mental retardation caused by neuronal TH deficiency. These mutational effects raise the question of whether polymorphic variation in SLC16A2 may also be associated with differences in serum levels of TH and/or TSH.

Design  This is the first major study of the frequency of the SLC16A2 rs6647476 single nucleotide polymorphism (SNP) (amino acid change Ser107Pro). We also studied the relationships of SLC16A2 genetic variants with serum levels of TSH, T4 and T3, with their mRNA expression and with expression of the TH‐responsive genes ZAKI‐4 and BTEB in white blood cells. Experiments in cultured fibroblasts were carried out to ascertain the dynamics of the T3 response.

Methods  A total of 276 men were studied. Genotyping of the S107P SNP was carried out using polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP); serum hormone levels were determined by chemiluminescence; expression of mRNA was quantified by real‐time PCR.

Results  The SLC16A2 S107P SNP was found in 36% of Galician males. With the present sample size we did not find any association of this polymorphism with variability in serum levels of TSH, free T4 (fT4) or fT3, or with basal expression of mRNA for SLC16A2 or the two TH‐responsive genes ZAKI‐4 and BTEB, either in white blood cells or in cultured human fibroblasts from either Ser107 or Pro107 genotypes under T3 stimulation.

Conclusions  The S107P change in MCT8 is frequent in the male population in Galicia. In the population studied in this report an association with a thyroid phenotype was not demonstrated, even though the S107P SNP causes an important amino acid change.
Effects of rehabilitation treatment on thyroid function
Authors: Aprile Irene , Romitelli Federica , Piazzini Diana Barbara , Padua Luca , Lancellotti Stefano , Maggi Loredana , Zuppi Cecilia , Bertolini Carlo , Di Stasio Enrico
Published: August 2008

Objective  The aim of the study was to evaluate the effects of an intensive rehabilitation programme on thyroid metabolism, the relationship between disability and thyroid hormone level, and the occurrence of nonthyroidal illness syndrome (NTIS) before and after rehabilitation.

Design, subjects and measurements  This was a clinical prospective study. Orthopaedic surgery patients (n = 82) were classified into two groups: patients in whom early active mobilization and walking were possible (walking group, WG, n = 45), and patients in whom these were not recommended (nonwalking group, NWG, n = 37). Levels of free T3 (fT3), fT4, TSH and rT3 were measured before and after surgery, and then at 1, 3, 7, 14 and 30 days from the beginning of rehabilitation. Personal, nutritional and clinical data were acquired for all patients. The Barthel Index (BI) was used to assess disability before and after rehabilitation.

Results  Immediately after surgery, both groups of patients showed a significant decrease in mean fT3 concentrations and a significant increase in rT3; mean fT4 values decreased significantly only in NWG patients. Once rehabilitation had been completed, fT3 and rT3 levels returned to baseline values in WG patients. In NWG patients mean fT3 and fT4 levels continued to decrease significantly and rT3 values remained significantly high until the end of rehabilitation. NTIS occurred in 38% of the NWG patients. No significant changes in TSH levels were observed in either group. Finally, we observed a direct correlation between fT3 levels and the BI in WG patients.

Conclusions  Our data suggest that early patient mobilization and physical activity during an active and intensive rehabilitation programme induce recovery of thyroid function and avoid occurrence of NTIS.
The tryptophan 620 allele of the lymphoid tyrosine phosphatase (PTPN22) gene predisposes to autoimmune Addison's disease
Authors: Roycroft Matthew , Fichna Marta , McDonald David , Owen Kate , Żurawek Magdalena , Gryczyńska Maria , Januszkiewicz‐Lewandowska Danuta , Fichna Piotr , Cordell Heather , Donaldson Peter , Nowak Jerzy , Pearce Simon
Published: August 2008

Objective  Previous studies of the association between autoimmune Addison's disease (AAD) and a nonsynonymous single nucleotide polymorphism (SNP) in the PTPN22 gene (C1858T, pR620W; SNP ID no. rs2476601) have shown conflicting results. We aimed to examine this association using additional cohorts of AAD subjects from the UK and Poland.

Design  DNA samples were obtained from UK and Polish AAD subjects (n = 251 and 87, respectively) and ethnically matched healthy controls (n = 429 and 236, respectively). Genotyping for the C1858T PTPN22 marker was performed by polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP) assay. Meta‐analysis of the results, together with those from three other populations, was performed using RevMan v5·0 software.

Results  In 251 UK AAD subjects the frequency of the PTPN22 1858T allele was 12·2% compared to 7·8% in healthy UK controls; P = 0·008. Similarly, in 87 Polish AAD subjects the PTPN22 1858T allele was found in 19·5% of alleles compared to 11·7% in healthy Polish subjects; P = 0·010. A meta‐analysis, combining these result with published data for three other populations, involving 797 AAD subjects and 2032 controls in total, showed that the 1858T allele was associated with AAD susceptibility with a pooled odds ratio (OR) of 1·44 [95% confidence interval (CI) 1·21–1·72; P = 5·6 × 10−5], under a fixed‐effects model.

Conclusion  This study confirms the association between the PTPN22 1858T allele and AAD in an expanded UK cohort and in the previously unstudied Polish population. This meta‐analysis allows for the first time a reliable estimate of the strength of effect of this autoimmune disease susceptibility allele across different European Caucasian populations.
Tumour necrosis factor (TNF)‐α primes murine neutrophils when triggered via formyl peptide receptor‐related sequence 2, the murine orthologue of human formyl peptide receptor‐like 1, through a process involving the type I TNF receptor and subcellular granule mobilization
Authors: Önnheim Karin , Bylund Johan , Boulay Francois , Dahlgren Claes , Forsman Huamei
Published: August 2008

Neutrophil granulocytes play an important role in innate host defence against microbial invasions and they are also the key effector cells in mediating host tissue damage. These functions often rely on the production of reactive oxygen species (ROS) from the membrane‐bound NADPH‐oxidase system. The magnitude of ROS production varies depending on the state of the cells, i.e. resting or primed. Many priming agents as well as potent NADPH‐oxidase activators have been identified and characterized for human neutrophils. The cytokine tumour necrosis factor (TNF)‐α is one prominent example of a priming agent and the synthetic hexapeptide WKYMVm is an agonist that triggers an activation of the NADPH‐oxidase of human neutrophils through two members of the formyl peptide family of receptors, formyl peptide receptor (FPR) and FPR‐like 1 (FPRL1). This peptide also activates murine neutrophils but the precise receptor involved has not been previously characterized. We show in this study that WKYMVm activates stably transfected HL60 cells expressing murine formyl peptide receptor‐related sequence 2 (Fpr‐rs2) and that activation of murine neutrophils with WKYMVm is blocked by an FPRL1‐specific antagonist. WKYMVm is thus an agonist for Fpr‐rs2 and we suggest that this receptor is in fact the mouse orthologue of FPRL1. In addition, we show that the WKYMVm response in murine neutrophils can be primed by TNF‐α and this priming process involves mobilization of subcellular granules. The results obtained using neutrophils derived from TNF receptor type I (TNFRI)‐deficient animals suggest that TNF‐α exerts its priming effect via the TNFRI.
Alteration of N‐glycosylation in the kidney in a mouse model of systemic lupus erythematosus: relative quantification of N‐glycans using an isotope‐tagging method
Authors: Hashii Noritaka , Kawasaki Nana , Itoh Satsuki , Nakajima Yukari , Kawanishi Toru , Yamaguchi Teruhide
Published: August 2008

Changes in the glycan structures of some glycoproteins have been observed in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. A deficiency of α‐mannosidase II, which is associated with branching in N‐glycans, has been found to induce SLE‐like glomerular nephritis in a mouse model. These findings suggest that the alteration of the glycosylation has some link with the development of SLE. An analysis of glycan alteration in the disordered tissues in SLE may lead to the development of improved diagnostic methods and may help to clarify the carbohydrate‐related pathogenic mechanism of inflammation in SLE. In this study, a comprehensive and differential analysis of N‐glycans in kidneys from SLE‐model mice and control mice was performed by using the quantitative glycan profiling method that we have developed previously. In this method, a mixture of deuterium‐labelled N‐glycans from the kidneys of SLE‐model mice and non‐labelled N‐glycans from kidneys of control mice was analysed by liquid chromatography/mass spectrometry. It was revealed that the low‐molecular‐mass glycans with simple structures, including agalactobiantennary and paucimannose‐type oligosaccharides, markedly increased in the SLE‐model mouse. On the other hand, fucosylated and galactosylated complex type glycans with high branching were decreased in the SLE‐model mouse. These results suggest that the changes occurring in the N‐glycan synthesis pathway may cause the aberrant glycosylations on not only specific glycoproteins but also on most of the glycoproteins in the SLE‐model mouse. The changes in glycosylation might be involved in autoimmune pathogenesis in the model mouse kidney.