A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence

Polycomb-like proteins 1-3 (PCL1-3) are substoichiometric components of the Polycomb-repressive complex 2 (PRC2) that are essential for association of the complex with chromatin. However, it remains unclear why three proteins with such apparent functional redundancy exist in mammals. Here we characterize their divergent roles in both positively and negatively regulating cellular proliferation. We show that while PCL2 and PCL3 are E2F-regulated genes expressed in proliferating cells, PCL1 is a p53 target gene predominantly expressed in quiescent cells. Ectopic expression of any PCL protein recruits PRC2 to repress the INK4A gene; however, only PCL2 and PCL3 confer an INK4A-dependent proliferative advantage. Remarkably, PCL1 has evolved a PRC2- and chromatin-independent function to negatively regulate proliferation. We show that PCL1 binds to and stabilizes p53 to induce cellular quiescence. Moreover, depletion of PCL1 phenocopies the defects in maintaining cellular quiescence associated with p53 loss. This newly evolved function is achieved by the binding of the PCL1 N-terminal PHD domain to the C-terminal domain of p53 through two unique serine residues, which were acquired during recent vertebrate evolution. This study illustrates the functional bifurcation of PCL proteins, which act in both a chromatin-dependent and a chromatin-independent manner to regulate the INK4A and p53 pathways.

Marker-independent identification of glioma-initiating cells.

Tumor-initiating cells with stem cell properties are believed to sustain the growth of gliomas, but proposed markers such as CD133 cannot be used to identify these cells with sufficient specificity. We report an alternative isolation method purely based on phenotypic qualities of glioma-initiating cells (GICs), avoiding the use of molecular markers. We exploited intrinsic autofluorescence properties and a distinctive morphology to isolate a subpopulation of cells (FL1(+)) from human glioma or glioma cultures. FL1(+) cells are capable of self-renewal in vitro, tumorigenesis in vivo and preferentially express stem cell genes. The FL1(+) phenotype did not correlate with the expression of proposed GIC markers. Our data propose an alternative approach to investigate tumor-initiating potential in gliomas and to advance the development of new therapies and diagnostics.

GAP-independent functions of DLC1 in metastasis.

Metastases are responsible for most cancer-related deaths. One of the hallmarks of metastatic cells is increased motility and migration through extracellular matrixes. These processes rely on specific small GTPases, in particular those of the Rho family. Deleted in liver cancer-1 (DLC1) is a tumor suppressor that bears a RhoGAP activity. This protein is lost in most cancers, allowing malignant cells to proliferate and disseminate in a Rho-dependent manner. However, DLC1 is also a scaffold protein involved in alternative pathways leading to tumor and metastasis suppressor activities. Recently, substantial information has been gathered on these mechanisms and this review is aiming at describing the potential and known alternative GAP-independent mechanisms allowing DLC1 to impair migration, invasion, and metastasis formation.

The true history regarding alleged connection of the order of ancient, free and accepted Masons: with the abduction and murder of William Morgan in western New York, in 1826... (1886)

Cover title: Masonic light on the abduction and murder of Wm. Morgan.

Proceedings of the Grand Lodge of the Province of Ontario, Canada (1893)

1893 Publisher: Dominion Odd Fellow Print. 1893, 39th annual session held at Niagara Falls. In pencil on front free endpaper of 1893 issue: Geneva Lodge #320

Proceedings of the Grand Lodge of the Province of Ontario, Canada (1914)

At head of title : Independent Order of Odd Fellows. 1893 Publisher: Dominion Odd Fellow Print. 1893, 39th annual session held at Niagara Falls. In pencil on front free endpaper of 1893 issue: Geneva Lodge #320.

Blue book for the use of subordinate divisions of the order of the Sons of Temperenance (1867)

Inscribed on front paste-down: Rothschild division No.227; and in pencil: James Jackson; and on front free endpaper: Presented to James M Clark By Mrs Amanda Burns Robert at Stayner 25 Aug. 1878.

Cholesterol-Independent Effects of Methyl-b- Cyclodextrin on Chemical Synapses

The cholesterol chelating agent, methyl-b-cyclodextrin (MbCD), alters synaptic function in many systems. At crayfish neuromuscular junctions, MbCD is reported to reduce excitatory junctional potentials (EJPs) by impairing impulse propagation to synaptic terminals, and to have no postsynaptic effects. We examined the degree to which physiological effects of MbCD correlate with its ability to reduce cholesterol, and used thermal acclimatization as an alternative method to modify cholesterol levels. MbCD impaired impulse propagation and decreased EJP amplitude by 40% (P,0.05) in preparations from crayfish acclimatized to 14uC but not from those acclimatized to 21uC. The reduction in EJP amplitude in the cold-acclimatized group was associated with a 49% reduction in quantal content (P,0.05). MbCD had no effect on input resistance in muscle fibers but decreased sensitivity to the neurotransmitter L-glutamate in both warm- and coldacclimatized groups. This effect was less pronounced and reversible in the warm-acclimatized group (90% reduction in cold, P,0.05; 50% reduction in warm, P,0.05). MbCD reduced cholesterol in isolated nerve and muscle from cold- and warmacclimatized groups by comparable amounts (nerve: 29% cold, 25% warm; muscle: 20% cold, 18% warm; P,0.05). This effect was reversed by cholesterol loading, but only in the warm-acclimatized group. Thus, effects of MbCD on glutamatesensitivity correlated with its ability to reduce cholesterol, but effects on impulse propagation and resulting EJP amplitude did not. Our results indicate that MbCD can affect both presynaptic and postsynaptic properties, and that some effects of MbCD are unrelated to cholesterol chelation.

Order of Service for the Honour Roll Unveiling - 10 June, 1945

A dedication service program for those who gave their lives during World War II from the city of St. Catharines. The list of over 150 names was to be read aloud and an address made by the Mayor (W.J. Macdonald) with prayers and hymn to follow.

Map - Probable Order of Battle

A map titled "Probable Order of Battle" and dated 28 May 1918. The map is of Montdidier.

The Order of Canada Investiture Ceremony Program (Selection of Pages)

A selection of pages from the program for the Order of Canada Investiture Ceremony in 2003 when Dorothy Wetherald Rungeling was a recipient.

Menu - Dinner on the occasion of the Investiture of the Order of Canada

A menu from the dinner of the Investiture of the Order of Canada.

Proceedings of the Court Martial Held by Order of Major Merritt

Proceedings of the court martial held by order of Major Merritt (1 double-sided page, handwritten): Captain Hamilton gave evidence against Caleb Cook (a private in Major Merritt’s Company of Light Dragoons) for disobedience and leaving quarters without leave of absence. Cook was fined and ordered to spend one month in prison. The document is stained and has holes in it along the middle fold. This does not affect the text, Aug. 7, 1812.

On the Optimal Order of Natural Resource Use When the Capacity of the Inexhaustible Substitute is Limited.

Consider a general equilibrium framework where the marginal cost of extraction from several deposits of an exhaustible resource is constant in terms of an inexhaustible perfect substitute and differs between deposits. the instantaneous rate of production form the inexhaustible resource is subject to a capacity constraint.