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1.  Divergent cellular phenotypes of human and mouse cells lacking the Werner syndrome RecQ helicase 
DNA repair  2009;9(1):11.
Werner syndrome (WS) is a human autosomal recessive genetic instability and cancer predisposition syndrome with features of premature aging. Several genetically determined mouse models of WS have been generated, however none develops features of premature aging or an elevated risk of neoplasia unless additional genetic perturbations are introduced. In order to determine whether differences in cellular phenotype could explain the discrepant phenotypes of Wrn−/− mice and WRN-deficient humans, we compared the cellular phenotype of newly derived Wrn−/− mouse primary fibroblasts with previous analyses of primary and transformed fibroblasts from WS patients and with newly derived, WRN-depleted human primary fibroblasts. These analyses confirmed previously reported cellular phenotypes of WRN-mutant and WRN-deficient human fibroblasts, and demonstrated that the human WRN-deficient cellular phenotype can be detected in cells grown in 5% or in 20% oxygen. In contrast, we did not identify prominent cellular phenotypes present in WRN-deficient human cells in Wrn−/− mouse fibroblasts. Our results indicate that human and mouse fibroblasts have different functional requirements for WRN protein, and that the absence of a strong cellular phenotype may in part explain the failure of Wrn−/− mice to develop an organismal phenotype resembling Werner syndrome.
PMCID: PMC2818259  PMID: 19896421
2.  A New Approach for Measuring Single-Cell Oxygen Consumption Rates 
A novel system that has enabled the measurement of single-cell oxygen consumption rates is presented. The experimental apparatus includes a temperature controlled environmental chamber, an array of microwells etched in glass, and a lid actuator used to seal cells in the microwells. Each microwell contains an oxygen sensitive platinum phosphor sensor used to monitor the cellular metabolic rates. Custom automation software controls the digital image data collection for oxygen sensor measurements, which are analyzed using an image-processing program to yield the oxygen concentration within each microwell versus time. Two proof-of-concept experiments produced oxygen consumption rate measurements for A549 human epithelial lung cancer cells of 5.39 and 5.27 fmol/min/cell, closely matching published oxygen consumption rates for bulk A549 populations.
PMCID: PMC2971563  PMID: 21057593
Biochemistry; frequency-domain analysis; image processing; oxygen; phosphorus compounds
3.  Screening families of patients with premature coronary heart disease to identify avoidable cardiovascular risk: a cross-sectional study of family members and a general population comparison group 
BMC Research Notes  2010;3:132.
Primary prevention should be targeted at individuals with high global cardiovascular risk, but research is lacking on how best to identify such individuals in the general population. Family history is a good proxy measure of global risk and may provide an efficient mechanism for identifying high risk individuals. The aim was to test the feasibility of using patients with premature cardiovascular disease to recruit family members as a means of identifying and screening high-risk individuals.
We recruited family members of 50 patients attending a cardiology clinic for premature coronary heart disease (CHD). We compared their cardiovascular risk with a general population control group, and determined their perception of their risk and current level of screening. 103 (36%) family members attended screening (27 siblings, 48 adult offspring and 28 partners). Five (5%) had prevalent CHD. A significantly higher percentage had an ASSIGN risk score >20% compared with the general population (13% versus 2%, p < 0.001). Only 37% of family members were aware they were at increased risk and only 50% had had their blood pressure and serum cholesterol level checked in the previous three years.
Patients attending hospital for premature CHD provide a mechanism to contact family members and this can identify individuals with a high global risk who are not currently screened.
PMCID: PMC2876176  PMID: 20459771
4.  Remediation of the protein data bank archive 
Nucleic Acids Research  2007;36(Database issue):D426-D433.
The Worldwide Protein Data Bank (wwPDB; is the international collaboration that manages the deposition, processing and distribution of the PDB archive. The online PDB archive at is the repository for the coordinates and related information for more than 47 000 structures, including proteins, nucleic acids and large macromolecular complexes that have been determined using X-ray crystallography, NMR and electron microscopy techniques. The members of the wwPDB–RCSB PDB (USA), MSD-EBI (Europe), PDBj (Japan) and BMRB (USA)–have remediated this archive to address inconsistencies that have been introduced over the years. The scope and methods used in this project are presented.
PMCID: PMC2238854  PMID: 18073189
Preventing Chronic Disease  2004;1(4):A14.
PMCID: PMC1277954  PMID: 15670446
6.  Antisense inhibition of macrophage inflammatory protein 1-α blocks bone destruction in a model of myeloma bone disease 
Journal of Clinical Investigation  2001;108(12):1833-1841.
We recently identified macrophage inflammatory protein 1-α (MIP-1α) as a factor produced by multiple myeloma (MM) cells that may be responsible for the bone destruction in MM (1). To investigate the role of MIP-1α in MM bone disease in vivo, the human MM–derived cell line ARH was stably transfected with an antisense construct to MIP-1α (AS-ARH) and tested for its capacity to induce MM bone disease in SCID mice. Human MIP-1α levels in marrow plasma from AS-ARH mice were markedly decreased compared with controls treated with ARH cells transfected with empty vector (EV-ARH). Mice treated with AS-ARH cells lived longer than controls and, unlike the controls, they showed no radiologically identifiable lytic lesions. Histomorphometric analysis demonstrated that osteoclasts (OCLs) per square millimeter of bone and OCLs per millimeter of bone surface of AS-ARH mice were significantly less than in EV-ARH mice, and the percentage of tumors per total bone area was also significantly decreased. AS-ARH cells demonstrated decreased adherence to marrow stromal cells, due to reduced expression of the α5β1 integrin and diminished homing capacity and survival. These data support an important role for MIP-1α in cell homing, survival, and bone destruction in MM.
PMCID: PMC209465  PMID: 11748267

Results 1-6 (6)