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Tag Archives: McGill University

Friday Science Review: March 18, 2011

Alum Explained

University of Calgary ♦ Published in Nature Medicine, Mar. 13, 2011

During the administration of a vaccine, an antigen is delivered along with another substance, known as an adjuvant, which arouses the immune system and increases overall effectiveness. The most common adjuvant in use today is alum, a trivalent aluminum-containing salt in crystal form.

Many questions related to alum’s mechanisms of action remain unanswered, or were mostly unanswered until the emergence of recent findings from the lab of Dr. Yan Shi at the University of Calgary. Dr. Shi and his lab group discovered that alum interacts with dendritic cells, a specific cell-type in the immune system that specializes in digesting antigenic material and presenting it on the cell surface. There is no specific receptor for alum however, instead it interacts with lipids on the plasma membrane eliciting a lipid sorting mechanism. Sorting of lipids induces a phagocytic response causing an influx of antigen into dendritic cells and an increase in affinity for CD4+ T cells.

Alum has massive implications for human health given the size and importance of the vaccine market. This new insight into dendritic cell response to alum will likely be leveraged to improve upon the efficacy of future vaccines.

Suicide Gene Delivers the Blow

Jewish General Hospital ♦ McGill University ♦ Published in Cancer Gene Therapy, Mar.11, 2011

Combination treatment paradigms for cancer have been under investigation for some time, but the suicide gene approach outlined in this recent research exemplifies the advances that have been made in the area. In this approach a tumour-specific oncolytic virus delivering a fusion construct is paired with a non-toxic prodrug. When the prodrug enters an infected cell containing the suicide transgene it is broken down by the cell’s machinery into toxic metabolites. In essence, the cell commits suicide.

Oncolytic viruses target cancer cells by taking advantage of their genetic abnormalities. A perfect example is vesicular stomatitis virus (VSV), a single stranded RNA virus that grows like wildfire in cancer cells but is unable to populate healthy cells. How? VSV is extraordinarily sensitive to type-1 interferon mediated immune responses. In normal cells that have interferon signaling cascades intact the virus cannot replicate. However, in cancer cells, which have genetic alterations affecting the interferon pathway, the virus survives with relative ease. Researchers utilized a suicide gene (CD::UPRT) in combination with 5-FC, a non-toxic prodrug that is metabolized to the toxic 5-flourocytosine (5-FU) form in the presence of cytosine deaminase. The deamination of 5-FC leads to its conversation to 5-FU, a small molecule drug commonly used in chemotherapeutic regimes for the eradication of cancer. The introduction of 5-FU into the cellular system prevents normal DNA replication, and hence causes cell cycle arrest. In this study researchers showed that the suicide gene strategy was able to trigger oncolysis in a number of VSV-resistant cell strains, including prostate PC3, breast MCF7, B-lymphoma Karpas, and melanoma B16-F10.

The combination scheme investigated here allows for the targeted removal of tumour cells while preserving healthy cells. As such, it circumvents one of the primary barriers associated with the development of efficacious cancer therapeutics − non-selective toxicity. 5-FU is also highly soluble, which causes detriment to neighbouring tumour cells that have been weakly infected, producing a particularly powerful treatment.

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 26, 2010

Ivermectin Nails Neurotransmission in Brugia malayi

McGill University

Published in PNAS, November 16, 2010

Well over 100 million people are currently infected with Brugia malayi, a microscopic nematode that causes lymphatic filariasis. Infection can eventually lead to the chronic inflammatory disease known as elephantiasis. In an effort to better understand this parasitic creature Dr. Timothy Geary and his team in the Institute of Parasitology at McGill University took a closer look at its glutamate-gated chloride channels (GluCls). These channels are localized to a very specific muscle structure surrounding an excretory vesicle in B. malayi and are essential for controlling protein release. Researchers show that ivermectin, a broad-spectrum anti-parasitic medication commonly deployed to reduce B. malayi infection, directly interferes with GluCl function preventing excretion of proteins from this excretory site. As protein excretion is known to be a very important aspect of the parasites survival system, allowing it to evade the immune system of the host it colonizes, researchers attribute the effectiveness of ivermectin to its ability to interfere with neurotransmission at GluCls. Screening for additional compounds that interact with GuCls could provide new treatment paradigms for B. malayi infection in the future.

Prion Disease: A Sticky Situation

University of Toronto ♦ University of British Columbia

Published in PNAS, November 16, 2010

Prion diseases include the infamous mad-cow disease (bovine spongiform encephalopathy), fatal familial insomnia, and the human disease ‘kuru’. The latter of these, believe it or not, being caused by human cannibalism and documented in small tribes located in Papua New Guinea that partake in strange funeral rituals following the deaths of relatives (I’ll spare you the details). These neurodegenerative diseases are often terminal and are caused by proteins, known as a prions, that have a propensity to aggregate together forming dangerous plaques that ultimately destroy neural tissue. Not all prion proteins are bad however, their behaviour depends on structural state. A switch from the α-helical conformation to the pathological β-form leads to rogue prion proteins that ‘stick’ to one another. Researchers at the University of Toronto were curious as to why animals of different sizes have different susceptibilities to prion diseases. In this study led by Dr. Avijit Chakrabartty, scientists used X-ray crystallographic structure analysis and a rabbit model to identify cellular mechanisms that explain the rabbit’s relative immunity to prion diseases. A helix-capping motif found in rabbits prevents folding of prion proteins into the pathological state. Findings like these, elucidating the underlying mechanisms driving transformation to the pathological state, should help us brainstorm future therapies for these deadly diseases.

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