Mitochondrial pathway polygenic risk scores are associated with Alzheimer's Disease.

Genetic, animal and epidemiological studies involving biomolecular and clinical endophenotypes implicate mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis. Polygenic risk scores (PRS) provide a novel approach to assess biological pathway-associated disease risk by combining the effects of variation at multiple, functionally related genes. We investigated the associations of PRS for genes involved in 12 mitochondrial pathways (pathway-PRS) with AD in 854 participants from Alzheimer's Disease Neuroimaging Initiative.

A globally diverse reference alignment and panel for imputation of mitochondrial DNA variants.

Background: Variation in mitochondrial DNA (mtDNA) identified by genotyping microarrays or by sequencing only the hypervariable regions of the genome may be insufficient to reliably assign mitochondrial genomes to phylogenetic lineages or haplogroups. This lack of resolution can limit functional and clinical interpretation of a substantial body of existing mtDNA data. To address this limitation, we developed and evaluated a large, curated reference alignment of complete mtDNA sequences as part of a pipeline for imputing missing mtDNA single nucleotide variants (mtSNVs).

The WHO FCTC and global governance: effects and implications for future global public health instruments.

Introduction: This article analyses experience with the WHO Framework Convention on Tobacco Control (WHO FCTC) in the context of global governance. It examines ways in which the WHO FCTC has been addressed by international institutions, particularly within the UN system at the international and national levels. It seeks to understand the extent to which the WHO FCTC as an international legal obligation has contributed to its integration in the strategies, policies and programmes of UN system organisations.

SketchSnakes: sketch-line initialized Snakes for efficient interactive medical image segmentation.

We present an intuitive, fast and accurate 2D interactive segmentation method that combines a general subdivision-curve Snake possessing powerful editing capabilities, with a novel sketch-line user initialization process, and a pen input device. Using the pen (or a mouse), the Snake is quickly and precisely initialized with a few quick sketch lines drawn across the width of the target object. The smooth contour constructed using these lines is extremely close to the position and shape of the object boundary.

United snakes.

Since their debut in 1987, snakes (active contour models) have become a standard image analysis technique with several variants now in common use. We present a framework called "United Snakes", which has two key features. First, it unifies the most popular snake variants, including finite difference, B-spline, and Hermite polynomial snakes in a consistent finite element formulation, thus expanding the range of object modeling capabilities within a uniform snake construction process.

Deformable organisms for automatic medical image analysis.

We introduce a new approach to medical image analysis that combines deformable model methodologies with concepts from the field of artificial life. In particular, we propose "deformable organisms", autonomous agents whose task is the automatic segmentation, labeling, and quantitative analysis of anatomical structures in medical images. Analogous to natural organisms capable of voluntary movement, our artificial organisms possess deformable bodies with distributed sensors, as well as (rudimentary) brains with motor, perception, behavior, and cognition centers.

Postattachment neutralization of a primary strain of HIV type 1 in peripheral blood mononuclear cells is mediated by CD4-specific antibodies but not by a glycoprotein 120-specific antibody that gives potent standard neutralization.

De novo infecting HIV-1 or virus released from an infected cell in vivo attaches relatively quickly to a target cell, but the rate of fusion-entry of such virus is slow, with 50% entry taking > or =2 hr. It is thus desirable that antibodies stimulated by any vaccine or given in immunotherapy are able to neutralize not only free virus, but also virus attached to the target cell. Here we investigated postattachment neutralization (PAN) of a primary HIV-1 strain (JRCSF) in peripheral blood mononuclear cells and of a T cell line-adapted strain (IIIB) in C8166 T lymphoblastoid cells, using the highly potent gp120-specific human monoclonal b12 monoclonal IgG, and monoclonal antibodies specific for the CD4 primary cell receptor.

T-snakes: topology adaptive snakes.

We present a new class of deformable contours (snakes) and apply them to the segmentation of medical images. Our snakes are defined in terms of an affine cell image decomposition (ACID). The 'snakes in ACID' framework significantly extends conventional snakes, enabling topological flexibility among other features.

Topology adaptive deformable surfaces for medical image volume segmentation.

Deformable models, which include deformable contours (the popular snakes) and deformable surfaces, are a powerful model-based medical image analysis technique. We develop a new class of deformable models by formulating deformable surfaces in terms of an affine cell image decomposition (ACID). Our approach significantly extends standard deformable surfaces, while retaining their interactivity and other desirable properties.

Immunogenic and antigenic dominance of a nonneutralizing epitope over a highly conserved neutralizing epitope in the gp41 envelope glycoprotein of human immunodeficiency virus type 1: its deletion leads to a strong neutralizing response.

The Kennedy peptide, (731)PRGPDRPEGIEEEGGERDRDRS(752), from the cytoplasmic domain of the gp41 transmembrane envelope glycoprotein of HIV-1 contains a conformationally dependent neutralizing epitope (ERDRD) and a linear nonneutralizing epitope (IEEE). No recognized murine T cell epitope is present. The peptide usually stimulates virus-specific antibody, but this is not always neutralizing.

Analysis of the ability of five adjuvants to enhance immune responses to a chimeric plant virus displaying an HIV-1 peptide.

The ability of five different adjuvants (alum, complete Freund's adjuvant, Quil A, AdjuPrime and Ribi) to stimulate humoral and T-cell mediated immune responses against a purified chimeric virus particle was investigated. Each adjuvant was administered subcutaneously to adult mice together with 10 microg of wildtype (wt) cowpea mosaic virus (CPMV) or a chimeric CPMV displaying the HIV-1 gp41 peptide, residues 731-752. All preparations elicited strong antibody responses to CPMV, but Quil A elicited the highest and most consistent responses to the HIV-1 peptide.

Intranasal immunization with a plant virus expressing a peptide from HIV-1 gp41 stimulates better mucosal and systemic HIV-1-specific IgA and IgG than oral immunization.

Control of pandemic human immunodeficiency virus type 1 (HIV-1) infection ideally requires specific mucosal immunity to protect the genital regions through which transmission more often occurs. Thus a vaccine that stimulates a disseminated mucosal and systemic protective immune response would be extremely useful. Here we have investigated the ability of a chimeric plant virus, cowpea mosaic virus (CPMV), expressing a 22 amino acid peptide (residues 731-752) of the transmembrane gp41 protein of HIV-1 IIIB (CPMV-HIV/1), to stimulate HIV-1-specific and CPMV-specific mucosal and serum antibody following intranasal or oral immunization together with the widely used mucosal adjuvant, cholera toxin.

Approaching physician recruitment systematically.

Physician recruitment has become increasingly competitive. Organizations that recruit physicians need to establish a systematic recruitment approach that includes determining the organization's recruitment objectives, using various recruiting sources, assessing the skills and "fit" of all candidates, explaining the benefits to candidates early in the process, checking references carefully, and acting quickly to make an offer. Following a systematic physician recruitment plan can help healthcare organizations hire the best person for the job.

Mutation-directed chemical cross-linking of human immunodeficiency virus type 1 gp41 oligomers.

The human immunodeficiency virus type 1 transmembrane protein gp41 oligomer anchors the attachment protein, gp120, to the viral envelope and mediates viral envelope-cell membrane fusion following gp120-CD4 receptor-chemokine coreceptor binding. We have used mutation-directed chemical cross-linking with bis(sulfosuccinimidyl)suberate (BS3) to investigate the architecture of the gp41 oligomer. Treatment of gp41 with BS3 generates a ladder of four bands on sodium dodecyl sulfate-polyacrylamide gels, corresponding to monomers, dimers, trimers, and tetramers.

A human IgG1 (b12) specific for the CD4 binding site of HIV-1 neutralizes by inhibiting the virus fusion entry process, but b12 Fab neutralizes by inhibiting a postfusion event.

The human b12 IgG1, specific for the CD4 binding site of the gp120 of HIV-1, was prepared by recombinant DNA technology. It had a high neutralization rate constant (-3.5 x 10(5) M(-1) sec(-1)), although this is about 10-fold less than the values for the best poliovirus or influenza A virus MAbs.

Deformable models and the analysis of medical images.

Deformable models are a popular and vigorously researched model-based approach to computer-assisted medical image analysis. The widely recognized efficacy of deformable models stem from their ability to segment, match and track images of anatomic structures by exploiting (bottom-up) constraints derived from the image data together with (top-down) a priori knowledge about the location, size and shape of structures of interest. Deformable models are capable of accommodating the often significant variability of biological structures over time and across different individuals.

Two neutralizing anti-V3 monoclonal antibodies act by affecting different functions of human immunodeficiency virus type 1.

Monoclonal antibody (MAb) ICR41.1i (rat IgG2a) is specific for a conformation-dependent epitope of human immunodeficiency virus type 1 (HIV-1) V3 , and MAb F58 (mouse IgG1) recognizes the peptide IXXGPGR, at the tip of the V3 loop. Both MAbs neutralized HIV-1 strain IIIB in C8166 and HeLa-T4(CD4) cells.

Deformable models in medical image analysis: a survey.

This article surveys deformable models, a promising and vigorously researched computer-assisted medical image analysis technique. Among model-based techniques, deformable models offer a unique and powerful approach to image analysis that combines geometry, physics and approximation theory. They have proven to be effective in segmenting, matching and tracking anatomic structures by exploiting (bottom-up) constraints derived from the image data together with (top-down) a priori knowledge about the location, size and shape of these structures.

Analysis of the interaction between a synthetic peptide of influenza virus hemagglutinin and monoclonal antibodies using an optical biosensor.

The interaction between two monoclonal antibodies and their corresponding Fab' fragments with a synthetic peptide, corresponding to the C-terminal 23 residues of the HA1 chain of influenza virus hemagglutinin against which they were generated, has been examined using an optical biosensor employing the detection principal of surface plasmon resonance (Pharmacia BIAcore). The data obtained has been analysed in detail by linear transformation of the primary data and nonlinear regression analysis, as well as by analysis of equilibrium binding data. The 2/1 antibodies and their Fab' fragments displayed higher affinity than the corresponding 1/1 proteins.

The assembly and immunological properties of non-linear synthetic immunogens containing T-cell and B-cell determinants.

For the rational design of synthetic vaccines, a potential immunogen must contain the appropriate helper T-cell and B-cell determinants to elicit a strong and relevant immune response. In this study we describe a method for the assembly of antigenic determinants from influenza virus hemagglutinin onto a lysine-based support, resulting in dimeric and trimeric constructs bearing both T-cell and B-cell determinants. A panel of synthetic immunogens was constructed incorporating peptides representing: (i) the B-cell determinant TLKLATG and the T-cell determinant PKYVKQNTLKLA which overlaps this sequence in the heavy chain (HA1) of the hemagglutinin; and (ii) the same B-cell determinant with an alternate T-cell determinant ALNNRFQIKGVELKS from the light chain (HA2).

A dynamic finite element surface model for segmentation and tracking in multidimensional medical images with application to cardiac 4D image analysis.

This paper presents a physics-based approach to anatomical surface segmentation, reconstruction, and tracking in multidimensional medical images. The approach makes use of a dynamic "balloon" model--a spherical thin-plate under tension surface spline which deforms elastically to fit the image data. The fitting process is mediated by internal forces stemming from the elastic properties of the spline and external forces which are produced form the data.

Analysis of antibody-antigen and antibody-anti-(idiotypic antibody) cross-reactivity using synthetic peptide probes.

The extent, nature and structural basis of immunological cross-reactivity of an anti-synthetic peptide monoclonal antibody (MAb) with the parent antigen (influenza virus haemagglutinin) from which the peptide was derived, and with a paratope-directed anti-idiotypic (anti-Id) antibody was investigated. Use of synthetic homologs and analogs of the peptide indicated that the anti-peptide MAb utilizes a common binding site to complex with peptide, haemagglutinin (HA) and anti-Id antibody, and the affinity constants for the binding of the anti-peptide MAb to peptide and to the anti-Id MAb were found to differ only by three fold. Determination of the amino acid sequence of the heavy chain variable domain (VH) of the anti-Id MAb did not reveal any obvious sequence homology with the peptide.

Equilibrium analysis of the interaction between a synthetic peptide of influenza virus hemagglutinin and monoclonal antibodies.

The affinity of interaction between two monoclonal antibodies and a synthetic peptide representing the C-terminal 23 residues of the heavy chain (HA1) of influenza virus hemagglutinin were determined using an air-driven ultracentrifuge. The technique makes use of common laboratory equipment and is based on sound theoretical principles. Because the method does not rely on the solid-phase immobilisation of one of the interacting species, it circumvents problems associated with ELISA-like assays, which, in the case of peptides, may involve the immobilisation of ligand through association of amino acid residues necessary for recognition by antibody.

Binding affinity of influenza virus N9 neuraminidase with Fab fragments of monoclonal antibodies NC10 and NC41.

Sedimentation equilibrium centrifugation has been applied to determine the affinity and stoichiometry of the interaction between Fab fragments, derived from monoclonal antibodies NC10 and NC41, with influenza virus neuraminidase N9 isolated from either tern or whale. Although the two neuraminidase epitopes recognized by NC10 and NC41 Fab overlap, crystallographic studies have shown that the modes of binding of each Fab are different. The sedimentation equilibrium experiments described here reveal that the binding affinities are also different, with NC10 Fab binding more strongly to each neuraminidase.