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On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

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Results 1-10 (10)

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1.  The MLL recombinome of acute leukemias in 2013 
Leukemia  2013;27(11):2165-2176.
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (∼90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
PMCID: PMC3826032  PMID: 23628958
MLL; chromosomal translocations; translocation partner genes; acute leukemia; ALL; AML
2.  Sequencing and Functional Annotation of Avian Pathogenic Escherichia coli Serogroup O78 Strains Reveal the Evolution of E. coli Lineages Pathogenic for Poultry via Distinct Mechanisms 
Infection and Immunity  2013;81(3):838-849.
Avian pathogenic Escherichia coli (APEC) causes respiratory and systemic disease in poultry. Sequencing of a multilocus sequence type 95 (ST95) serogroup O1 strain previously indicated that APEC resembles E. coli causing extraintestinal human diseases. We sequenced the genomes of two strains of another dominant APEC lineage (ST23 serogroup O78 strains χ7122 and IMT2125) and compared them to each other and to the reannotated APEC O1 sequence. For comparison, we also sequenced a human enterotoxigenic E. coli (ETEC) strain of the same ST23 serogroup O78 lineage. Phylogenetic analysis indicated that the APEC O78 strains were more closely related to human ST23 ETEC than to APEC O1, indicating that separation of pathotypes on the basis of their extraintestinal or diarrheagenic nature is not supported by their phylogeny. The accessory genome of APEC ST23 strains exhibited limited conservation of APEC O1 genomic islands and a distinct repertoire of virulence-associated loci. In light of this diversity, we surveyed the phenotype of 2,185 signature-tagged transposon mutants of χ7122 following intra-air sac inoculation of turkeys. This procedure identified novel APEC ST23 genes that play strain- and tissue-specific roles during infection. For example, genes mediating group 4 capsule synthesis were required for the virulence of χ7122 and were conserved in IMT2125 but absent from APEC O1. Our data reveal the genetic diversity of E. coli strains adapted to cause the same avian disease and indicate that the core genome of the ST23 lineage serves as a chassis for the evolution of E. coli strains adapted to cause avian or human disease via acquisition of distinct virulence genes.
PMCID: PMC3584874  PMID: 23275093
3.  Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort 
Thrombosis and haemostasis  2013;110(2):264-274.
Several cohort studies have investigated the molecular basis of von Willebrand disease (VWD); however these have mostly focused on European and North American populations. This study aimed to investigate mutation spectrum in 26 index cases (IC) from Turkey diagnosed with all three VWD types, the majority (73%) with parents who were knowingly related. IC were screened for mutations using multiplex ligation-dependent probe amplification and analysis of all von Willebrand factor gene (VWF) exons and exon/intron boundaries. Selected missense mutations were expressed in vitro. Candidate VWF mutations were identified in 25 of 26 IC and included propeptide missense mutations in four IC (two resulting in type 1 and two in recessive 2A), all influencing VWF expression in vitro. Four missense mutations, a nonsense mutation and a small in-frame insertion resulting in type 2A were also identified. Of 15 type 3 VWD IC, 13 were homozygous and two compound heterozygous for 14 candidate mutations predicted to result in lack of expression and two propeptide missense changes. Identification of intronic breakpoints of an exon 17–18 deletion suggested that the mutation resulted from non-homologous end joining. This study provides further insight into the pathogenesis of VWD in a population with a high degree of consanguineous partnerships.
PMCID: PMC4213552  PMID: 23702511
large-scale deletion; multiplex ligation-dependent probe amplification; mutation analysis; recessive 2A; von Willebrand disease
4.  Classifying Human Audiometric Phenotypes of Age-Related Hearing Loss from Animal Models 
Age-related hearing loss (presbyacusis) has a complex etiology. Results from animal models detailing the effects of specific cochlear injuries on audiometric profiles may be used to understand the mechanisms underlying hearing loss in older humans and predict cochlear pathologies associated with certain audiometric configurations (“audiometric phenotypes”). Patterns of hearing loss associated with cochlear pathology in animal models were used to define schematic boundaries of human audiograms. Pathologies included evidence for metabolic, sensory, and a mixed metabolic + sensory phenotype; an older normal phenotype without threshold elevation was also defined. Audiograms from a large sample of older adults were then searched by a human expert for “exemplars” (best examples) of these phenotypes, without knowledge of the human subject demographic information. Mean thresholds and slopes of higher frequency thresholds of the audiograms assigned to the four phenotypes were consistent with the predefined schematic boundaries and differed significantly from each other. Significant differences in age, gender, and noise exposure history provided external validity for the four phenotypes. Three supervised machine learning classifiers were then used to assess reliability of the exemplar training set to estimate the probability that newly obtained audiograms exhibited one of the four phenotypes. These procedures classified the exemplars with a high degree of accuracy; classifications of the remaining cases were consistent with the exemplars with respect to average thresholds and demographic information. These results suggest that animal models of age-related hearing loss can be used to predict human cochlear pathology by classifying audiograms into phenotypic classifications that reflect probable etiologies for hearing loss in older humans.
PMCID: PMC3767874  PMID: 23740184
metabolic presbyacusis; sensory presbyacusis; endocochlear potential; animal models; audiogram classification; supervised machine learning classifiers
5.  White Matter Hyperintensities Predict Low Frequency Hearing in Older Adults 
Vascular disease has been proposed as a contributing factor for presbyacusis (age-related hearing loss). While this hypothesis is supported by pathological evidence of vascular decline in post-mortem human and animal studies, evidence in human subjects has been mixed with associations typically reported between a measure of vascular health and low frequency hearing in older women. Given the difficulty of characterizing the in vivo health of the cochlear artery in humans, an estimate of cerebral small vessel disease was used to test the prediction that age-related change in low frequency hearing and not high frequency hearing is related to a global decline in vascular health. We examined the extent to which these associations were specific to women and influenced by a history of high blood pressure in 72 older adults (mean age 67.12 years, SD = 8.79). Probability estimates of periventricular white matter hyperintensities (WMH) from T1- and fluid attenuated T2-weighted magnetic resonance images were significantly associated with a low frequency hearing metric across the sample, which were independent of age, but driven by women and people with a history of high blood pressure. These results support the premise that vascular declines are one mechanism underlying age-related changes in low frequency hearing.
PMCID: PMC3642278  PMID: 23512682
low-frequency hearing loss; vessel disease; white matter hyperintensity; high blood pressure; hypertension
6.  The Cingulo-Opercular Network Provides Word-Recognition Benefit 
The Journal of Neuroscience  2013;33(48):18979-18986.
Recognizing speech in difficult listening conditions requires considerable focus of attention that is often demonstrated by elevated activity in putative attention systems, including the cingulo-opercular network. We tested the prediction that elevated cingulo-opercular activity provides word-recognition benefit on a subsequent trial. Eighteen healthy, normal-hearing adults (10 females; aged 20–38 years) performed word recognition (120 trials) in multi-talker babble at +3 and +10 dB signal-to-noise ratios during a sparse sampling functional magnetic resonance imaging (fMRI) experiment. Blood oxygen level-dependent (BOLD) contrast was elevated in the anterior cingulate cortex, anterior insula, and frontal operculum in response to poorer speech intelligibility and response errors. These brain regions exhibited significantly greater correlated activity during word recognition compared with rest, supporting the premise that word-recognition demands increased the coherence of cingulo-opercular network activity. Consistent with an adaptive control network explanation, general linear mixed model analyses demonstrated that increased magnitude and extent of cingulo-opercular network activity was significantly associated with correct word recognition on subsequent trials. These results indicate that elevated cingulo-opercular network activity is not simply a reflection of poor performance or error but also supports word recognition in difficult listening conditions.
PMCID: PMC3841458  PMID: 24285902
7.  Initiation of Phage Infection by Partial Unfolding and Prolyl Isomerization*♦ 
The Journal of Biological Chemistry  2013;288(18):12979-12991.
Background: Bacteriophage fd is activated for infection by partial unfolding and prolyl isomerization.
Results: NMR spectroscopy localized Pro-213-coupled unfolding to regions of the interdomain hinge of the phage gene-3-protein.
Conclusion: Pro-213 regulates phage infectivity by a specific long-range effect on the conformational stability of the gene-3-protein.
Significance: A proline switch controls the biological function in a remote part of a protein.
Infection of Escherichia coli by the filamentous phage fd starts with the binding of the N2 domain of the phage gene-3-protein to an F pilus. This interaction triggers partial unfolding of the gene-3-protein, cis → trans isomerization at Pro-213, and domain disassembly, thereby exposing its binding site for the ultimate receptor TolA. The trans-proline sets a molecular timer to maintain the binding-active state long enough for the phage to interact with TolA. We elucidated the changes in structure and local stability that lead to partial unfolding and thus to the activation of the gene-3-protein for phage infection. Protein folding and TolA binding experiments were combined with real-time NMR spectroscopy, amide hydrogen exchange measurements, and phage infectivity assays. In combination, the results provide a molecular picture of how a local unfolding reaction couples with prolyl isomerization not only to generate the activated state of a protein but also to maintain it for an extended time.
PMCID: PMC3642341  PMID: 23486474
Nuclear Magnetic Resonance; Protein Folding; Protein Stability; Protein Structure; Signal Transduction; Gene-3-protein; Molecular Timer; Phage Infection; Prolyl Isomerization
8.  A Controlled Trial of Gluten-Free Diet in Patients with Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function 
Gastroenterology  2013;144(5):903-911.e3.
Background & Aims
Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD).
We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8–negative and 11 HLA-DQ2/8–positive) and 23 on the GFD (12 HLA-DQ2/8−negative and 11 HLA-DQ2/8–positive. We measured bowel function daily, small bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells (PBMCs) following exposure to gluten and rice. We collected rectosigmoid biopsies from 28 patients, analyzed levels of mRNAs encoding tight junction proteins, and performed hematoxylin and eosin staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups.
Subjects on the GCD had more bowel movements/day (P=.04); the GCD had a greater effect on bowel movements/day of HLA-DQ2/8–positive than −negative patients (P=.019). The GCD was associated with higher SB permeability (based on 0–2 hr levels of mannitol and lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8–positive than −negative patients (P=.018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of ZO-1 in SB mucosa and significant decreases in expression of ZO-1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8–positive patients. GCD vs GFD had no significant effects on transit or histology. PBMCs produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-a in response to gluten than rice (unrelated to HLA genotype).
Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8–positive patients. These findings reveal a reversible mechanism for the disorder.
PMCID: PMC3633663  PMID: 23357715
permeability; transit; immunity; cytokines
9.  Total IgA and IgA reactivity to antigen I/II epitopes in HLA-DRB1*04 positive subjects 
Open journal of immunology  2013;3(3):82-92.
Bacterial adherence to the acquired dental pellicle, important in dental caries (caries), is mediated by receptor-adhesins such as salivary agglutinin binding to Streptococcus mutans antigen I/II (I/II). Ten selected I/II epitopes were chosen to determine their reactivity to human salivary IgA. Previous studies suggested that a specific HLA biomarker group (HLA-DRB1*04) may have differential influence of immune responses to I/II. However, it was not known whether secretory IgA (SIgA) responses to the selected epitopes from HLA-DRB1*04 positive subjects were different compared to controls, or across other caries-related factors such as total IgA (TIgA). Thirty-two total subjects were matched according to HLA type, gender, ethnicity and age. HLA genotyping, oral bacterial, immunoglobulin and antibody analyses were performed. A large observed difference emerged with regard to the natural immune reservoir of TIgA in HLA-DRB1*04 positive subjects, specifically, a 27.6% reduction compared to controls. In contrast to all other epitopes studied, HLA-DRB1*04 positive subjects also exhibited reduced reactivity to I/II epitope 834–853. HLA-DRB1*04 positive subjects exhibited lower specific SIgA activity/TIgA to 834–853 and also a lower specific reactivity to 834–853/whole cell S. mutans UA159. Furthermore, HLA-DRB1*04 positive subjects exhibited lower responses to I/II in its entirety. The large observed difference in TIgA and the 834–853 reactivity pattern across multiple measures suggest potentially important connections pertaining to the link between HLA-DRB1*04 and caries.
PMCID: PMC3875298  PMID: 24386612
Dental Caries; Streptococcus mutans; I/II; IgA; Immunomodulation; Immunogenetics; HLA-II; DRB1; DRB1*04
10.  Identification of a Population of Epidermal Squamous Cell Carcinoma Cells with Enhanced Potential for Tumor Formation 
PLoS ONE  2013;8(12):e84324.
Epidermal squamous cell carcinoma is among the most common cancers in humans. These tumors are comprised of phenotypically diverse populations of cells that display varying potential for proliferation and differentiation. An important goal is identifying cells from this population that drive tumor formation. To enrich for tumor-forming cells, cancer cells were grown as spheroids in non-attached conditions. We show that spheroid-selected cells form faster growing and larger tumors in immune-compromised mice as compared to non-selected cells. Moreover, spheroid-selected cells gave rise to tumors following injection of as few as one hundred cells, suggesting these cells have enhanced tumor-forming potential. Cells isolated from spheroid-selected tumors retain an enhanced ability to grow as spheroids when grown in non-attached culture conditions. Thus, these tumor-forming cells retain their phenotype following in vivo passage as tumors. Detailed analysis reveals that spheroid-selected cultures are highly enriched for expression of epidermal stem cell and embryonic stem cell markers, including aldehyde dehydrogenase 1, keratin 15, CD200, keratin 19, Oct4, Bmi-1, Ezh2 and trimethylated histone H3. These studies indicate that a subpopulation of cells that possess stem cell-like properties and express stem cell markers can be derived from human epidermal cancer cells and that these cells display enhanced ability to drive tumor formation.
PMCID: PMC3869846  PMID: 24376802

Results 1-10 (10)