Stratification and Monitoring of Juvenile Idiopathic Arthritis Patients by Synovial Proteome Analysis

Juvenile idiopathic arthritis (JIA) comprises a poorly understood group of chronic, childhood onset, autoimmune diseases with variable clinical outcomes. We investigated whether profiling of the synovial fluid (SF) proteome by a fluorescent dye based, two-dimensional gel (DIGE) approach could distinguish patients in whom inflammation extends to affect a large number of joints, early in the disease process. SF samples from 22 JIA patients were analyzed: 10 with oligoarticular arthritis, 5 extended oligoarticular and 7 polyarticular disease. SF samples were labeled with Cy dyes and separated by two-dimensional electrophoresis. Multivariate analyses were used to isolate a panel of proteins which distinguish patient subgroups. Proteins were identified using MALDI-TOF mass spectrometry with expression further verified by Western immunoblotting and immunohistochemistry. Hierarchical clustering based on the expression levels of a set of 40 proteins segregated the extended oligoarticular from the oligoarticular patients (p <0.05). Expression patterns of the isolated protein panel have also been observed over time, as disease spreads to multiple joints. The data indicates that synovial fluid proteome profiles could be used to stratify patients based on risk of disease extension. These protein profiles may also assist in monitoring therapeutic responses over time and help predict joint damage. © 2009 American Chemical Society.

Sedentary aging increases resting and exercise-induced intramuscular free radical formation

Mitochondrial free radical formation has been implicated as a potential mechanism underlying degenerative senescence, although human data are lacking. Therefore, the present study was designed to examine if resting and exercise-induced intramuscular free radical-mediated lipid peroxidation is indeed increased across the spectrum of sedentary aging. Biopsies were obtained from the vastus lateralis in six young (26 ± 6 yr) and six aged (71 ± 6 yr) sedentary males at rest and after maximal knee extensor exercise. Aged tissue exhibited greater (P < 0.05 vs. the young group) electron paramagnetic resonance signal intensity of the mitochondrial ubisemiquinone radical both at rest (+138 ± 62%) and during exercise (+143 ± 40%), and this was further complemented by a greater increase in a-phenyl-tert-butylnitrone adducts identified as a combination of lipid-derived alkoxyl-alkyl radicals (+295 ± 96% and +298 ± 120%). Lipid hydroperoxides were also elevated at rest (0.190 ± 0.169 vs. 0.148 ± 0.071 nmol/mg total protein) and during exercise (0.567 ± 0.259 vs. 0.320 ± 0.263 nmol/mg total protein) despite a more marked depletion of ascorbate and uptake of a/ß-carotene, retinol, and lycopene (P < 0.05 vs. the young group). The impact of senescence was especially apparent when oxidative stress biomarkers were expressed relative to the age-related decline in mitochondrial volume density and absolute power output at maximal exercise. In conclusion, these findings confirm that intramuscular free radical-mediated lipid peroxidation is elevated at rest and during acute exercise in aged humans.

Anatomy and facies association of a drumlin in Co. Down, Northern Ireland, from seismic and electrical resistivity surveys

Seismic refraction and electrical resistivity geophysical techniques were used to reconstruct the internal architecture of a drumlin in Co. Down, Northern Ireland. Geophysical results were both validated and complemented by borehole drilling, ground water flow modelling, and geologic mapping. The geophysical anatomy of the drumlin consists of five successive layers with depth including; topsoil, partially saturated and saturated glacial tills, and weathered and more competent greywacke bedrock. There are numerous, often extensive inclusions of clay, sand, gravel, cobbles, and boulders within the topsoil and the till units. Together geophysical and geotechnical findings imply that the drumlin is part of the subglacial lodgement, melt-out, debris flow, sheet flow facies described by previous authors, and formed by re-sedimentation and streamlining of pre-existing sediments during deglaciation of the Late Devensian ice sheet. Seismic refraction imaging is particularly well suited to delineating layering within the drumlin, and is able to reconstruct depths to interfaces to within ± 0.5 m accuracy. Refraction imaging ascertained that the weathered bedrock layer is continuous and of substantial thickness, so that it acts as a basal aquifer which underdrains the bulk of the drumlin. Electrical resistivity imaging was found to be capable of delineating relative spatial changes in the moisture content of the till units, as well as mapping sedimentary inclusions within the till. The moisture content appeared to be elevated near the margins of the drumlin, which may infer a weakening of the drumlin slopes. Our findings advocate the use of seismic refraction and electrical resistivity methods in future sedimentological and geotechnical studies of internal drumlin architecture and drumlin formation, owing particularly to the superior, 3- D spatial coverage of these methods.

Identification of gene networks associated with acute myeloid leukemia by comparative molecular methylation and expression profiling

Around 80% of acute myeloid leukemia (AML) patients achieve a complete remission, however many will relapse and ultimately die of their disease. The association between karyotype and prognosis has been studied extensively and identified patient cohorts as having favourable [e.g. t(8; 21), inv (16)/t(16; 16), t(15; 17)], intermediate [e.g. cytogenetically normal (NK-AML)] or adverse risk [e.g. complex karyotypes]. Previous studies have shown that gene expression profiling signatures can classify the sub-types of AML, although few reports have shown a similar feature by using methylation markers. The global methylation patterns in 19 diagnostic AML samples were investigated using the Methylated CpG Island Amplification Microarray (MCAM) method and CpG island microarrays containing 12,000 CpG sites. The first analysis, comparing favourable and intermediate cytogenetic risk groups, revealed significantly differentially methylated CpG sites (594 CpG islands) between the two subgroups. Mutations in the NPM1 gene occur at a high frequency (40%) within the NK-AML subgroup and are associated with a more favourable prognosis in these patients. A second analysis comparing the NPM1 mutant and wild-type research study subjects again identified distinct methylation profiles between these two subgroups. Network and pathway analysis revealed possible molecular mechanisms associated with the different risk and/or mutation sub-groups. This may result in a better classification of the risk groups, improved monitoring targets, or the identification of novel molecular therapies.

Wildlife tracking data management: a new vision

To date, the processing of wildlife location data has relied on a diversity of software and file formats. Data management and the following spatial and statistical analyses were undertaken in multiple steps, involving many time-consuming importing/exporting phases. Recent technological advancements in tracking systems have made large, continuous, high-frequency datasets of wildlife behavioral data available, such as those derived from the global positioning system (GPS) and other animal-attached sensor devices. These data can be further complemented by a wide range of other information about the animals’ environment. Management of these large and diverse datasets for modelling animal behaviour and ecology can prove challenging, slowing down analysis and increasing the probability of mistakes in data handling. We address these issues by critically evaluating the requirements for good management of GPS data for wildlife biology. We highlight that dedicated data management tools and expertise are needed. We explore current research in wildlife data management. We suggest a general direction of development, based on a modular software architecture with a spatial database at its core, where interoperability, data model design and integration with remote-sensing data sources play an important role in successful GPS data handling.

Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies

Objectives: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).
Background: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers.
Methods: The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Results: A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of <2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups.
Conclusions: The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.

The Cambridge Companion to Vaughan Williams

An icon of British national identity and one of the most widely performed twentieth-century composers, Ralph Vaughan Williams has been as much misunderstood as revered; his international impact, and enduring influence on areas as diverse as church music, film scores, and popular music, has been insufficiently appreciated. This volume brings together a team of leading scholars, examining all areas of the composer’s output from new perspectives, and re-evaluating the cultural politics of his lifelong advocacy for the music-making of ordinary people. Surveys of major genres are complemented by chapters exploring such topics as the composer’s relationship with the BBC, and his studies with Ravel; uniquely, the book also includes specially commissioned interviews with major living composers Peter Maxwell Davies, Piers Hellawell, Nicola Lefanu, and Anthony Payne.

Discrete breathers in hexagonal dusty plasma lattices

The occurrence of single-site or multisite localized vibrational modes, also called discrete breathers, in two-dimensional hexagonal dusty plasma lattices is investigated. The system is described by a Klein-Gordon hexagonal lattice characterized by a negative coupling parameter epsilon in account of its inverse dispersive behavior. A theoretical analysis is performed in order to establish the possibility of existence of single as well as three-site discrete breathers in such systems. The study is complemented by a numerical investigation based on experimentally provided potential forms. This investigation shows that a dusty plasma lattice can support single-site discrete breathers, while three-site in phase breathers could exist if specific conditions, about the intergrain interaction strength, would hold. On the other hand, out of phase and vortex three-site breathers cannot be supported since they are highly unstable.

Existence and stability of multisite breathers in honeycomb and hexagonal lattices

We study the existence and stability of multisite discrete breathers in two prototypical non-square Klein-Gordon lattices, namely a honeycomb and a hexagonal one. In the honeycomb case we consider six-site configurations and find that for soft potential and positive coupling the out-of-phase breather configuration and the charge-two vortex breather are linearly stable, while the in-phase and charge-one vortex states are unstable. In the hexagonal lattice, we first consider three-site configurations. In the case of soft potential and positive coupling, the in-phase configuration is unstable and the charge-one vortex is linearly stable. The out-of-phase configuration here is found to always be linearly unstable. We then turn to six-site configurations in the hexagonal lattice. The stability results in this case are the same as in the six-site configurations in the honeycomb lattice. For all configurations in both lattices, the stability results are reversed in the setting of either hard potential or negative coupling. The study is complemented by numerical simulations which are in very good agreement with the theoretical predictions. Since neither the form of the on-site potential nor the sign of the coupling parameter involved have been prescribed, this description can accommodate inverse-dispersive systems (e. g. supporting backward waves) such as transverse dust-lattice oscillations in dusty plasma (Debye) crystals or analogous modes in molecular chains.

Nonlinear Dynamics of Rotating Multi-Component Pair Plasmas and e-p-i Plasmas

The propagation of small amplitude stationary profile nonlinear electrostatic excitations in a pair plasma is investigated, mainly drawing inspiration from experiments on fullerene pair-ion plasmas. Two distinct pair ion species are considered of opposite polarity and same mass, in addition to a massive charged background species, which is assumed to be stationary, given the frequency scale of interest. In the pair-ion context, the third species is thought of as a background defect (e.g. charged dust) component. On the other hand, the model also applies formally to electron-positron-ion (e-p-i) plasmas, if one neglects electron-positron annihilation. A two-fluid plasma model is employed, incorporating both Lorentz and Coriolis forces, thus taking into account the interplay between the gyroscopic (Larmor) frequency ?c and the (intrinsic) plasma rotation frequency O0. By employing a multi-dimensional reductive perturbation technique, a Zakharov-Kuznetsov (ZK) type equation is derived for the evolution of the electric potential perturbation. Assuming an arbitrary direction of propagation, with respect to the magnetic field, we derive the exact form of nonlinear solutions, and study their characteristics. A parametric analysis is carried out, as regards the effect of the dusty plasma composition (background number density), species temperature(s) and the relative strength of rotation to Larmor frequencies. It is shown that the Larmor and mechanical rotation affect the pulse dynamics via a parallel-to-transverse mode coupling diffusion term, which in fact diverges at ?c ? ±2O0. Pulses collapse at this limit, as nonlinearity fails to balance dispersion. The analysis is complemented by investigating critical plasma compositions, in fact near-symmetric (T- ˜ T+) “pure” (n- ˜ n+) pair plasmas, i.e. when the concentration of the 3rd background species is negligible, case in which the (quadratic) nonlinearity vanishes, so one needs to resort to higher order nonlinear theory. A modified ZK equation is derived and analyzed. Our results are of relevance in pair-ion (fullerene) experiments and also potentially in astrophysical environments, e.g. in pulsars.

Potential roles for the PIM1 kinase in human cancer - A molecular and therapeutic appraisal

In vitro experiments have shown the PIM1 kinase to have diverse biological roles in cell survival, proliferation and differentiation. In humans, PIM1 is often expressed in both normal and transformed cells. The PIM1 kinase is a true oncogene implicated in early transformation and tumour progression in haematopoietic malignancies and prostate carcinomas. it is associated with aggressive subgroups of lymphoma, is a marker of poor prognosis in prostate carcinomas and has been suggested to have a role in hormone insensitivity of prostate malignancies. PIM1 has a possible role in other carcinomas with 6p21 genomic alterations. On one hand, PIM1 (due to its role in malignancy) appears to be a promising target for drug development programmes but, on the other hand, the complexity of its molecular structure has posed challenges in the development of PIM1 inhibitors. In this review we discuss PIM1 expression in human tissues (including some new data from our laboratory), its role in human malignancies, as well as the possibilities and challenges in the development of target therapy for PIM1. (c) 2008 Elsevier Ltd. All rights reserved.

Tissue microarray study for classification of breast tumors

Clinical and pathological heterogeneity of breast cancer hinders selection of appropriate treatment for individual cases. Molecular profiling at gene or protein levels may elucidate the biological variance of tumors and provide a new classification system that correlates better with biological, clinical and prognostic parameters. We studied the immunohistochemical profile of a panel of seven important biomarkers using tumor tissue arrays. The tumor samples were then classified with a monothetic (binary variables) clustering algorithm. Two distinct groups of tumors are characterized by the estrogen receptor (ER) status and tumor grade (p = 0.0026). Four biomarkers, c-erbB2, Cox-2, p53 and VEGF, were significantly overexpressed in tumors with the ER-negative (ER-) phenotype. Eight subsets of tumors were further identified according to the expression status of VEGF, c-erbB2 and p53. The malignant potential of the ER-/VEGF+ subgroup was associated with the strong correlations of Cox-2 and c-erb132 with VEGF. Our results indicate that this molecular classification system, based on the statistical analysis of immunohistochemical profiling, is a useful approach for tumor grouping. Some of these subgroups have a relative genetic homogeneity that may allow further study of specific genetically-controlled metabolic pathways. This approach may hold great promise in rationalizing the application of different therapeutic strategies for different subgroups of breast tumors. (C) 2003 Elsevier Inc. All rights reserved.

Prognostic and Predictive Biomarkers in Resected Colon Cancer: Current Status and Future Perspectives for Integrating Genomics into Biomarker Discovery

The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era. The Oncologist 2010; 15: 390-404

Mesoscale flux-closure domain formation in single-crystal BaTiO3

Over 60 years ago, Charles Kittel predicted that quadrant domains should spontaneously form in small ferromagnetic platelets. He expected that the direction of magnetization within each quadrant should lie parallel to the platelet surface, minimizing demagnetizing fields, and that magnetic moments should be configured into an overall closed loop, or flux-closure arrangement. Although now a ubiquitous observation in ferromagnets, obvious flux-closure patterns have been somewhat elusive in ferroelectric materials. This is despite the analogous behaviour between these two ferroic subgroups and the recent prediction of dipole closure states by atomistic simulations research. Here we show Piezoresponse Force Microscopy images of mesoscopic dipole closure patterns in free-standing, single-crystal lamellae of BaTiO3. Formation of these patterns is a dynamical process resulting from system relaxation after the BaTiO3 has been poled with a uniform electric field. The flux-closure states are composed of shape conserving 90° stripe domains which minimize disclination stresses.

ESC and KAIT observations of the transitional type Ia SN 2004eo

We present optical and infrared observations of the unusual Type Ia supernova (SN) 2004eo. The light curves and spectra closely resemble those of the prototypical SN 1992A, and the luminosity at maximum (M-B = -19.08) is close to the average for a Type Ia supernova (SN Ia). However, the ejected Ni-56 mass derived by modelling the bolometric light curve (about 0.45M(circle dot)) lies near the lower limit of the Ni-56 mass distribution observed in normal SNe Ia. Accordingly, SN 2004eo shows a relatively rapid post-maximum decline in the light curve [Delta m(15)(B)(true) = 1.46], small expansion velocities in the ejecta and a depth ratio Si II lambda 5972/ Si II lambda 6355 similar to that of SN 1992A. The physical properties of SN 2004eo cause it to fall very close to the boundary between the faint, low-velocity gradient and high-velocity gradient subgroups proposed by Benetti et al. Similar behaviour is seen in a few other SNe Ia. Thus, there may in fact exist a few SNe Ia with intermediate physical properties.