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Tag Archives: University of Montreal

Friday Science Review: March 4, 2011

The Origin of Meier-Gorlin Syndrome

Dalhousie University ♦ University of Montreal ♦ University of British Columbia

Published in Nature Genetics, Feb. 27, 2011

Researchers have mapped a locus for Meier-Gorlin syndrome (MGS), a rare genetic condition characterized by short stature, small ears, and reduced or absent kneecaps. A mutation in the ORC4 gene seems to be at the root of the disorder. ORC4 is a component of the eukaryotic origin recognition complex.

To map the locus responsible for MGS researchers performed high density genome-wide SNP genotyping using a panel of 600,000 markers provided by Illumina. The next stop involved PLINK, a whole genome analysis toolset, which was able to identify a haplotype on chromosome 2 within a number of affected individuals. Sequencing of coding exons located in the ORC4 gene led to the identification of a missense mutation that causes a tyrosine (residue 174) to cysteine switch in the ORC4 protein. The tyrosine residue affected in MGS is completely conserved across eukaryotes suggesting it has an important function; the amino acid is also believed to interact with a conserved arginine residue on a nearby helix motif in the protein structure. In the absence of this interaction the structural integrity of the protein could be compromised in part.

The origin recognition complex consists of six proteins in humans and is essential for DNA replication. It plays a critical role in recognizing origin sites on DNA and in the formation of DNA replication forks. This is the first report of an inherited mutation in any gene of the origin recognition complex in the vertebrate literature.

The Human Serum Metabolome

University of Alberta ♦ National Institute of Nanotechnology

Published in PLoS ONE, Feb. 16, 2011

Human biofluids are very important from a clinical standpoint given the insight they can provide into the disease conditions of a human being. The study of metabolomics attempts to identify, on a large scale, the composition of metabolites found in these biofluids. The advent of advanced analytical techniques along with mounting pressures for scientists in the metabolomics community to document the entire human metabolome, led to the development of the Human Metabolome Project. The project is supported by Genome Alberta and Genome Canada, the latter of which is a private, non-profit, corporation that received $600 million in funding from the Canadian government to develop and implement a national strategy in genomics and proteomics.

The most recent contribution to the project is a comprehensive multicentre study led by Dr. David Wishart at the University of Alberta. Using a diversity of metabolomics platforms researchers were able to identify, and quantify, metabolites found in human serum. The use of different methods, including nuclear magnetic resonance (NMR), and various mass-spectrometry platforms (GC-MS, LC-MS), increased the overall coverage of the serum metabolome. Data gathered via these platforms was linked to computer-aided literature mining which allowed for the development of a virtually complete set of metabolites. In total the group found 4,229 metabolites, but this number may increase in coming years as more powerful characterization techniques are developed.

Dr. Wishart and his colleagues previously characterized the human cerebrospinal fluid metabolome.

Friday Science Review: December 31, 2010

Just a couple papers to squeeze in this year before the clock strikes 12. I look forward to 2011 and the research it will bring in the Canadian realm. For those readers heading out tonight for some fun on the city, enjoy! More science reviews to come in the new year..

Porcine Adenovirus PAV3, A Novel and Promising Candidate for H5N1 Protection

National Microbiology Laboratory, Winnipeg ♦ Published in PLoS ONE, Dec. 16, 2010

Researchers have provided evidence that suggests a porcine adenovirus, PAV3, has greater vaccine efficacy than the human adenovirus AdHu5 in protecting against H5N1. An avian influenza H5N1 mouse model was used to compare immune response and protection following vaccination with the two different vectors. Mice that were vaccinated with a replication defective PAV3 vector carrying an H5N1 antigen expressed higher concentrations of neutralizing antibody post-vaccination and had stronger cellular immune responses than mice vaccinated with AdHu5. After challenging vaccinated mice with H5N1 infection, Dr. Gary Kobinger and his team demonstrated that mice inoculated with PAV3 showed higher overall survival. Another notable finding was that the porcine adenovirus did not become significantly neutralized when exposed to a pool of antibodies generated from 10,000 humans.

Study of Human Heart Microsomes Gives Insight into Cardiac CYP450s

University of Montreal ♦ Published in PLoS ONE, Dec. 14, 2010

Enzymes from the cytochrome P450 (CYP450) superfamily play an important role in drug metabolism. Variation in CYP450 isoforms can lead to inter-subject and inter-organ variability in drug metabolism, thus their study is crucial to understanding the metabolism of specific drugs. Dr. Jacques Turgeon and his colleagues at the University of Montreal gathered data on CYP450 mRNA levels in left and right ventricular samples taken from the explanted hearts of patients with end-stage heart failure. Samples were processed in the lab to extract microsomes, small vesicle-like structures composed of endoplasmic reticulum that contain large quantities of CYP450s. Among the interesting findings of this body of work is that CYP2J2 was the most abundant isoform found in cardiac tissue samples. Levels of CYP450 mRNA were similar across ischemic and non-ischemic samples and between left and right ventricles. Another principal and interesting finding was that the stereoselectivity of cardiac CYP450s was reversed compared to those in the liver. After exposing heart microsomes to the calcium channel blocker verapamil, higher levels of CYP450-dependent metabolites were observed in the presence of the R-enantiomer.

Friday Science Review: December 3, 2010

It’s all about microscopic machinery this week with two articles in Molecular Cell (Cell Press) and a third in Nature Cell Biology.

The MMS22L-TONSL Complex to the Rescue: A Sine Qua Non for Genome Integrity

Samuel Lunenfeld Research Institute ♦ University of Toronto

Published in Molecular Cell, November 24, 2010

In order for DNA replication to occur smoothly, a large complex of DNA polymerases and other proteins must work in harmony and navigate their way down the length of double-stranded DNA to synthesize daughter strands. This machinery, known as the ‘replisome’, frequently stumbles upon genomic glitches and other impediments that have the potential to hinder its progress. As a result, the cell has evolved a basket of mechanisms to ensure that the replisome avoids stalling and the replication fork continues to move. In a study led by Dr. Anne-Claude Gingras of the Samuel Lunenfeld Research Insitute, scientists use an RNAi screen to identify MMS22L-TONSL — a complex that appears to rescue the replisome during times of replicative stress. The newly identified complex exerts its rescue effects by interacting with single-stranded DNA (ssDNA) during end processing or in regions where the replication fork has stalled. After seeking out ssDNA MMS22L-TONSL goes to work catalyzing the repair of faulty DNA lesions, opening a path forward for the replisome.

MicroRNA Families Modulate Embryonic Messenger Transcripts

McGill University

Published in Molecular Cell, November 24, 2010

It appears microRNA (miRNA) controls expression of messenger RNA targets at the embryonic stage. These special RNA molecules originate in the nucleus, much like mRNA, but are subsequently modified by the enzyme RNaseIII and then exported to the cytoplasm. It is here that they are cleaved and manipulated into their mature form by the enzyme Dicer. After being processed miRNAs are incorporated into silencing complexes that then sort through the mRNA content of the cytoplasm, silencing specific transcripts as they go.  Dr. Thomas Duchaine and his colleagues utilized a C. elegans model to show that two embryonic miRNA families contribute to a natural RNAi process by suppressing expression of target mRNAs. The group also shows that silencing, achieved through epigenetic modification of targets, occurs in a target-specific manner with a unique modification pattern provided to each mRNA target.

Molecular Maintenance of Centromeres, GTPase Pulls the Switch

University of Montreal

Published in Nature Cell Biology, November 21, 2010

The central region of the chromosome has the responsibility of controlling chromosomal separation during cellular division. Like almost all parts of the genome, this region, known as the centromere, is subject to epigenetic regulation. The specialized H3 histone CENP-A is found exclusively at centromeres and is believed to be the epigenetic label of the region. Dr. Paul Maddox and his team at the University of Montreal have recently discovered new agents that maintain the assembly of CENP-A following its addition to the centromere region. A GTPase activating protein interacts with a CENP-A factor to recruit a number of auxiliary proteins that play an essential role in stabilizing newly added CENP-A. This stabilization process early on in the cell cycle is critical in ensuring that each new chromosome receives a sufficient quantity of CENP-A following cell division.

Friday Science Review: November 19, 2010

Mobile Phones Increase Patient Adherence in HIV Clinical Study

University of Nairobi ♦ University of Manitoba ♦ University of British Columbia

Published in Lancet, November 9, 2010

Researchers recently demonstrated the effectiveness of mobile phones as a tool to bolster patient adherence to an HIV treatment regime. Better adherence to treatment reduced HIV-1 RNA load and may improve patient outcome. Patients receiving anti-retroviral therapy (ART) in Kenya were placed into one of two treatment groups. Both treatment groups received ART but only one received SMS support from healthcare workers. Clinicians sent weekly reminders to patients in the SMS intervention group, upon which they had to reply to confirm adherence within 48h. Adherence to therapy was observed in 168 of 273 patients in the SMS intervention group, and 132 of 265 in the control group, confirming that communication between healthcare workers and patients increased adherence. Suppressed viral loads were documented in 156 of 273 and 128 of 265 patients in the SMS intervention and control groups respectively, providing clear evidence that mobile phone reminders can improve outcome in patients receiving ART. Mobile phone usage is expected to be a useful mechanism to promote ART adherence in resource limiting environments, such as Africa, and is also an important measure for program cost containment. UNAIDS, the Joint United Nations Program on HIV/AIDS, is supporting the use of mobile technologies for future AIDS response.

A Molecular Circuit of Congenital Heart Disease Revealed

University of Ottawa ♦ University of Montreal

Published in PNAS, November 9, 2010

Congenital heart disease (CHD) is the primary (non-infectious) cause of death in infants within the first year of life. The incidence of CHD is now estimated to be a shocking 5% of live births, with less severe undiagnosed cases leading to increased risk of mortality, stroke, and ischemic heart disease. By elucidating a pathway contributing to congenital heart defects, researchers are now closer to grasping the causes of these developmental mishaps. Normal heart development requires differentiation, proliferation, and communication between two adjacent layers of tissue composed of endocardial and myocardial cells. The transcription factors Tbx5 and GATA4 are key players in this process, ensuring that correct myocardial patterning and chamber specification occur. In this study led by Dr. Mona Nemer of the University of Ottawa, researchers implicate Tbx5 in normal heart development by showing that its deletion in mice causes severe atrial defects. After going on the hunt for modifiers of Tbx5 they later identified the gene Nos3. Interestingly, Nos3 is known to be regulated by several factors that increase risk of congenital heart disease including stress and diabetes. These findings illustrate a direct link between environmental cues and the development of atrial defects.

Cisplatin and ING4-carrying Adenovirus Elicit Synergistic Anticancer Activity

Soochow University ♦ University of Saskatchewan

Published in Cell Gene Therapy (npg), November 5, 2010

Combinatorial approaches to the treatment of cancer have been of great interest to the scientific and medical communities as they provide a means to sensitize cancer cells to small molecule drugs. The combination of sensitizing agents and conventional chemotherapeutics has been shown to reduce tumour size more rapidly, prevent cancer cell resistance, and reduce side effects by lowering the dose of cytotoxic small molecule drugs required for therapy. In a joint study between Soochow University, China; and the University of Saskatchewan, researchers have shown that the adenoviral delivery of the tumour supressor ING4 (Ad-ING4) along with cisplatin induces synergistic growth inhibition and apoptosis in a hepatocarcinoma cell line both in vitro and in vivo. In this study researchers reported the upregulation of several protein markers associated with apoptosis and down regulation of the oncogene Bcl-2 in the presence of the Ad-ING4 vector and cisplatin. Importantly, the combination of these agents did not elicit overlapping toxicities in in vivo normal liver tissues of mice suggesting that it could have potential as a future treatment for hepatocarcinoma.

Friday Science Review: November 5, 2010

A Deadly Competitor: The marine bacterium Vibrio cholerae has built-in mechanisms that may allow it to compete with other species of bacteria and better colonize its host. Researchers recently discovered a secretion system (T6SS) in V. cholerae allowing it to inject toxic substrates directly into the cytoplasm of prey. Now a group at the University of Alberta, led by Dr. Stefan Pukatzki, has shown that this strain of bacteria aggressively competes against a number of gram-negative bacteria including Escherichia coli and Salmonella and was able to reduce E. coli survival by 100,000-fold. It would be interesting to see whether the disruption of T6SS could be used as a tool to put a damper on cholera outbreaks and/or increase the time between outbreaks. Find the study published in PNAS.

Signature of Kidney Disease: The most common form of glomerular-based kidney disease is IgA nephropathy (IgAN). Roughly 40% of patients suffering from the disease will experience kidney failure in 10 years. The strongest predictor of clinical outcome in IgAN is proteinuria, or elevated levels of protein in the blood – often albumin. Researchers at the University of Toronto have identified what appears to be a genetic signature of the disease. An in vitro model of proteinuria was created by exposing primary human kidney tubular epithelial cells to high levels of albumin. Gene expression in these cells was then measured with a microarray to derive a panel of 231 “albumin-regulated genes” that were upregulated or repressed as a result of albumin exposure. Researchers then translated this to the clinic by analyzing biopsy samples from patients with IgAN. What they found is that they were able to perfectly segregate biopsy samples from control samples. Convincingly, the panel could be reduced to 11 genes and be used to distinguish any form of primary glomerulonephritis from control, suggesting that this signature could have great utility in predicting clinical outcome in glomerular-based kidney disease in the future. This study included researchers from the University of Toronto, University of Michigan, and University Hospital Zurich in Switzerland. Find it here in PLoS ONE.

Thyroid On the Move: The congenital endocrine disorder hypothyroidism results from improper differentiation, migration, or growth of thyroid tissue. In a majority of cases (~80%), incomplete migration leads to ectopic thyroid tissue. Previous studies with identical twins suggest that the disease is almost certainly caused by somatic mutations or epigenetics as in some cases there have been discordance rates of up to 92%. In a recent study published in PLoS ONE, scientists used microarray analysis to uncover 1011 genes that were either induced or repressed by a factor of 2-fold in ectopic thyroid nodules. Grouping of these genes into gene ontology groups using DAVID (Database for Annotation, Visualization, and Integrated Discovery) identified several clusters of genes related to development and organogenesis. After validating many of these genes, 19 were isolated as being exclusively related to thyroid ectopy. Genes involved in embyronic development (TXNIP) and the Wnt pathway were among those that contributed most to formation. Further work on a larger cohort of patients may allow for elucidation of the molecular mechanisms behind defective thyroid migration during early embryogenesis.

Friday Science Review: October 22, 2010

Some great research to touch on this week in top-notch journals including Science, Cell, and NEJM. The first publication really emphasizes the strength of collaborative research projects around the globe.

Understanding Endometriosis: Ovarian clear-cell carcinomas are less common than high-grade serous carcinomas (12% and 70% of total respectively), but still remain the second leading cause of death from ovarian cancer. It is important that the mechanisms behind the formation of this rare subtype are elucidated because it is not responsive to conventional platinum-taxane chemotherapeutic regimes that are currently the first-line treatment for ovarian cancer. In a comprehensive study published in The New England Journal of Medicine, researchers sequence the entire transcriptomes of 18 ovarian clear-cell carcinomas  and identify frequent somatic mutations in the tumor suppressor gene ARID1A (the AT-rich interactive domain 1A). ARID1A encodes the protein BAF250a which in turn is part of the chromatin remodeling complex SWI-SNF that regulates a diversity of cellular processes including DNA repair and tumor suppression. Interestingly, the mutation appears specific to the clear-cell and endometrioid subtypes. After identifying the ARID1A mutation, researchers carried out targeted re-sequencing in a mutation-validation cohort consisting of an additional 210 carcinoma samples from all subtypes. Combining the discovery cohort and validation cohort, the ARID1A mutation was found in 55 of 119 clear cell carcinomas (46%), 10 of 33 endometrioid  carcinomas (30%), but not one of 76 high-grade serous ovarian carcinomas. These findings strongly implicate ARID1A mutation in the early transformation of endometriosis into cancer and the genesis of clear-cell and endometrioid ovarian carcinomas. This exhaustive work was carried out by some 45 researchers in a dozen or so institutions found in Canada, the United States, and Australia.

Danger Signaling: Physical injury to tissue leads to cell necrosis and the release of special patterning molecules, including proteins, nucleic acids, extra-cellular matrix proteins, and various lipids as a complex milieu of chemotaxic signals. Neutrophils are able to use these unique signals to guide themselves to the site of a wound, and play an important role in recycling debris from dying cells. In a study published in Science, led by Dr. Paul Kubes of the Immunology Research Group at the University of Calgary, researchers used a mouse model of sterile injury and an in vivo imaging technique known as spinning disk confocal microscopy to observe the kinetics of eGFP-expressing neutrophils in response to thermal induced necrotic injury. Experiments revealed that necrotic cells activated a multistep hierarchy of cues that lured neutrophils to the site of danger. Another interesting finding of the study is that neutrophils appear to travel to the site of injury intravascularly as opposed to taking the most direct route through tissue. The group proposes that danger sensing and recruitment mechanisms may have evolved to prioritize intravascular travel in order to reduce the collateral damage incurred if neutrophils were to migrate directly through healthy tissue.

In Pursuit of Perfection: The fundamental limit of minimally invasive surgery is at the level of the single cell. In principal, lasers are capable of operating at this spatial resolution however efforts to achieve this have been limited by thermal and shock wave induced collateral damage to surrounding tissue. The long-held promise of a fine surgical laser has been delivered by two investigators in the Toronto research community with the creation of a novel laser source – the Picosecond IR Laser (PIRL). As a cutting modality the PIRL has a shorter pulse duration than conventional surgical lasers, vaporizing tissue on the picosecond timescale rather than burning on the nanosecond, and exploits a new cutting mechanism that selectively energizes water molecules. Researchers created full thickness wounds in CD1 mice using PIRL to demonstrate that it caused neither cavitation or any associated shock wave induced damage, and also showed that PIRL greatly reduced scar formation by comparison to conventional surgical laser or scalpel. The technology is expected to be useful in surgical procedures where scarring is particularly debilitating. Dr. Benjamin Alman, Head of the Division of Orthopedic Surgery at Sick Kids, and Dr. Dwayne Miller, in the Department of Chemistry at the University of Toronto, were co-principal investigators in this study published in PloS ONE.

At the Junction: The RAS/MAPK signaling pathway contributes to a number of important cellular processes including proliferation, differentiation, and survival. In its most basic form the pathway is regulated by the small GTPase RAS, and the three core kinases RAF, MEK, and ERK/MAPK. Like most signaling pathways, the RAS/MAPK pathway is controlled by a diversity of post-translational modifications but much less is known about regulation of its core protein components at the mRNA stage. Using a genome-wide RNAi screen in Drosophila S2 cells, researchers set out to identify other proteins involved in the pathway that could modulate MAPK protein levels. In doing so they identified the Exon Junction Complex (EJC) as a regulator of mapk transcripts. The complex is believed to contribute to the regulation of exon definition and suggests that the EJC has a key role in early regulation the RAS/MAPK pathway. This study, published in Cell, was led by Dr. Marc Therrien at the University of Montreal.

Friday Science Review: First Time for Everything Edition

First time for blood stem cell factors:  Dr. Guy Sauvageau of the University of Montreal produced a large number of blood stem cells in the lab from a smaller sample taken from bone marrow using a novel screening technique to identify mediators of the stem cell repopulating activity.  The study was published in this week’s Cell.  Dr. Sauvageau said that “[i]t could be possible to envision transplants for all adults from existing umbilical cord blood banks.”

First time for viral destruction of cancer stem cells:  A group out of Dalhousie used reovirus on fresh breast cancer tissue removed from a patient, while most cancer studies use cancer cell lines developed for laboratory use.  Not only does reovirus kill the cancer stem cells and cancer cells, it also stimulates the body’s anti-cancer immune system.

First time for a dual axis rotational cardiac X-ray:  The University of Ottawa Heart Institute (UOHI) has the first one of these X-ray machines for clinical use in North America.  It produces better images in less time with less dye and less radiation.

First time for driving into space:  The headlines said “Calgary scientists determine outer space only an hour’s drive away.”  Apparently all the debate about where the atmosphere stops and space begins could have been solved if the scientists involved had gotten out of the lab and into their cars a bit sooner.

First time for a meta-diet:  A group at McMaster conducted a meta-study of the effects of various diets on coronary heart disease and concluded that the Mediterranean diet is meta-good, and that trans-fats are meta-bad.  The WSJ Health blog said:  “So [the analysis] is a useful, if not particularly surprising, guide.”

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Friday Science Review: Good News, Bad News Edition

Good news: If you happen to be in Montréal on Monday, you should check out the opening of the  Centre de pharmacogénomique Beaulieu-Saucier de l’Université de Montréal (that’s the Beaulieu-Saucier Centre for Pharmacogenomics at the University of Montréal, y’all).  It will be great to see what comes out of this centre for Canadian personalized medicine.

Bad news: If you happen to have been relying on a Nature paper from 2000 in which researchers in Canada and South Korea said they used gene therapy to reverse Type 1 diabetes, you should reconsider.

Good news: If you happen to do a science fair project that dovetails with a Minister’s legislative efforts, you could be famous.  Also, don’t drive and talk.

Bad news: If you were excited about the availability of private clinics in Canada offering CT and PET scans, you should read this new study from the Canadian Center for Policy Alternatives first, which found that there are prevalent misconceptions about the safety and regulation of these screening technologies.

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Friday Science Review: February 27, 2009

Cool Canadian science developments this week:

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