Signalling cell cycle arrest and cell death through the MMR System

Loss of DNA mismatch repair (MMR) in mammalian cells, as well as having a causative role in cancer, has been linked to resistance to certain DNA damaging agents including clinically important cytotoxic chemotherapeutics. MMR-deficient cells exhibit defects in G<sub>2</sub>/M cell cycle arrest and cell killing when treated with these agents. MMR-dependent cell cycle arrest occurs, at least for low doses of alkylating agents, only after the second S-phase following DNA alkylation, suggesting that two rounds of DNA replication are required to generate a checkpoint signal. These results point to an indirect role for MMR proteins in damage signalling where aberrant processing of mismatches leads to the generation of DNA structures (single-strand gaps and/or double-strand breaks) that provoke checkpoint activation and cell killing. Significantly, recent studies have revealed that the role of MMR proteins in mismatch repair can be uncoupled from the MMR-dependent damage responses. Thus, there is a threshold of expression of MSH2 or MLH1 required for proper checkpoint and cell-death signalling, even though sub-threshold levels are sufficient for fully functional MMR repair activity. Segregation is also revealed through the identification of mutations in MLH1 or MSH2 that provide alleles functional in MMR but not in DNA damage responses and mutations in MSH6 that compromise MMR but not in apoptotic responses to DNA damaging agents. These studies suggest a direct role for MMR proteins in recognizing and signalling DNA damage responses that is independent of the MMR catalytic repair process. How MMR-dependent G<sub>2</sub> arrest may link to cell death remains elusive and we speculate that it is perhaps the resolution of the MMR-dependent G<sub>2</sub> cell cycle arrest following DNA damage that is important in terms of cell survival

Asymptotics of a small liquid drop on a cone and plate rheometer

A cone and a plate rheometer is a laboratory apparatus used to measure the viscosity and other related parameters of a non-Newtonian liquid subject to an applied force. A small drop, of order millimetres, of the liquid is located between the horizontal plate and the shallow cone of the rheometer. Rotation of the cone ensues, the liquid begins to flow and the plate starts to rotate. Liquid parameters are inferred based on the difference in the applied rotational force and the resulting rotational force of the plate. To describe the flow of the drop, the initial drop configuration, before rotation commences, must be determined. The equilibrium drop profile is given by the solution to the well-known nonlinear Young-Laplace equation. We formulate asymptotic solutions for the drop profile based on the small Bond number. The modelling of the drop exhibits a rich asymptotic structure consisting of five distinct scalings which are resolved via the method matched asymptotics

Commentary on child-adult differences in muscle activation - A review

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An activity analysis of a non-nurse administrative assistant to a nursing supervisor on one ward unit.

Thesis (M.S.)--Boston Universit

Illness in Returned Travelers and Immigrants/Refugees: The 6-Year Experience of Two Australian Infectious Diseases Units.

BACKGROUND: Data comparing returned travelers and immigrants/refugees managed in a hospital setting is lacking. METHODS: We prospectively collected data on 1,106 patients with an illness likely acquired overseas who presented to two hospital-based Australian infectious diseases units over a 6-year period. RESULTS: Eighty-three percent of patients were travelers and 17% immigrants/refugees. In travelers, malaria (19%), gastroenteritis/diarrhea (15%), and upper respiratory tract infection (URTI) (7%) were the most common diagnoses. When compared with immigrants/refugees, travelers were significantly more likely to be diagnosed with gastroenteritis/diarrhea [odds ratio (OR) 8], malaria (OR 7), pneumonia (OR 6), URTI (OR 3), skin infection, dengue fever, typhoid/paratyphoid fever, influenza, and rickettsial disease. They were significantly less likely to be diagnosed with leprosy (OR 0.03), chronic hepatitis (OR 0.04), tuberculosis (OR 0.05), schistosomiasis (OR 0.3), and helminthic infection (OR 0.3). In addition, travelers were more likely to present within 1 month of entry into Australia (OR 96), and have fever (OR 8), skin (OR 6), gastrointestinal (OR 5), or neurological symptoms (OR 5) but were less likely to be asymptomatic (OR 0.1) or have anaemia (OR 0.4) or eosinophilia (OR 0.3). Diseases in travelers were more likely to have been acquired via a vector (OR 13) or food and water (OR 4), and less likely to have been acquired via the respiratory (OR 0.2) or skin (OR 0.6) routes. We also found that travel destination and classification of traveler can significantly influence the likelihood of a specific diagnosis in travelers. Six percent of travelers developed a potentially vaccine-preventable disease, with failure to vaccinate occurring in 31% of these cases in the pretravel medical consultation. CONCLUSIONS: There are important differences in the spectrum of illness, clinical features, and mode of disease transmission between returned travelers and immigrants/refugees presenting to hospital-based Australian infectious diseases units with an illness acquired overseas

The relationship between teachers' educational philosophies and the ability-achievement growth of their elementary school classes.

Thesis (Ed.M.)--Boston Universit

Radio Frequency Models of Novae in eruption. I. The Free-Free Process in Bipolar Morphologies

Observations of novae at radio frequencies provide us with a measure of the total ejected mass, density profile and kinetic energy of a nova eruption. The radio emission is typically well characterized by the free-free emission process. Most models to date have assumed spherical symmetry for the eruption, although it has been known for as long as there have been radio observations of these systems, that spherical eruptions are to simplistic a geometry. In this paper, we build bipolar models of the nova eruption, assuming the free-free process, and show the effects of varying different parameters on the radio light curves. The parameters considered include the ratio of the minor- to major-axis, the inclination angle and shell thickness (further parameters are provided in the appendix). We also show the uncertainty introduced when fitting spherical model synthetic light curves to bipolar model synthetic light curves. We find that the optically thick phase rises with the same power law ($S_{\nu} \propto t^2$) for both the spherical and bipolar models. In the bipolar case there is a "plateau" phase -- depending on the thickness of the shell as well as the ratio of the minor- to major-axis -- before the final decline, that follows the same power law ($S_{\nu} \propto t^{-3}$) as in the spherical case. Finally, fitting spherical models to the bipolar model synthetic light curves requires, in the worst case scenario, doubling the ejected mass, more than halving the electron temperature and reducing the shell thickness by nearly a factor of 10. This implies that in some systems we have been over predicting the ejected masses and under predicting the electron temperature of the ejecta.Comment: 9 pages, 6 figures, accepted for publication in ApJ, accompanying movie to figure 3 available at http://www.ast.uct.ac.za/~valerio/papers/radioI

The shape of a small liquid drop on a cone and plate rheometer

We construct asymptotic solutions for the shape of a small liquid sessile drop in a cone and plate rheometer. The approximation is based on small Bond number or, equivalently, on a characteristic length scale which is much smaller than the capillary length. The drop has a complicated asymptotic structure, consisting of five separate scalings, which is resolved using the method of matched asymptotic expansions. We find that the presence of a substrate above (and below) the drop gives rise to qualitatively new drop configurations