DNA mismatch binding and antiproliferative activity of rhodium metalloinsertors

Deficiencies in mismatch repair (MMR) are associated with carcinogenesis. Rhodium metalloinsertors bind to DNA base mismatches with high specificity and inhibit cellular proliferation preferentially in MMR-deficient cells versus MMR-proficient cells. A family of chrysenequinone diimine complexes of rhodium with varying ancillary ligands that serve as DNA metalloinsertors has been synthesized, and both DNA mismatch binding affinities and antiproliferative activities against the human colorectal carcinoma cell lines HCT116N and HCT116O, an isogenic model system for MMR deficiency, have been determined. DNA photocleavage experiments reveal that all complexes bind to the mismatch sites with high specificities; DNA binding affinities to oligonucleotides containing single base CA and CC mismatches, obtained through photocleavage titration or competition, vary from 10^4 to 10^8 M^−1 for the series of complexes. Significantly, binding affinities are found to be inversely related to ancillary ligand size and directly related to differential inhibition of the HCT116 cell lines. The observed trend in binding affinity is consistent with the metalloinsertion mode where the complex binds from the minor groove with ejection of mismatched base pairs. The correlation between binding affinity and targeting of the MMR-deficient cell line suggests that rhodium metalloinsertors exert their selective biological effects on MMR-deficient cells through mismatch binding in vivo

Exploring the cellular accumulation of metal complexes

Transition metal complexes offer great potential as diagnostic and therapeutic agents, and a growing number of biological applications have been explored. To be effective, these complexes must reach their intended target inside the cell. Here we review the cellular accumulation of metal complexes, including their uptake, localization, and efflux. Metal complexes are taken up inside cells through various mechanisms, including passive diffusion and entry through organic and metal transporters. Emphasis is placed on the methods used to examine cellular accumulation, to identify the mechanism(s) of uptake, and to monitor possible efflux. Conjugation strategies that have been employed to improve the cellular uptake characteristics of metal complexes are also described

Selective Cytotoxicity of Rhodium Metalloinsertors in Mismatch Repair-Deficient Cells

Mismatches in DNA occur naturally during replication and as a result of endogenous DNA damaging agents, but the mismatch repair (MMR) pathway acts to correct mismatches before subsequent rounds of replication. Rhodium metalloinsertors bind to DNA mismatches with high affinity and specificity and represent a promising strategy to target mismatches in cells. Here we examine the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands in cells deficient in MMR versus those that are MMR-proficient. These complexes are shown to exhibit accelerated cellular uptake which permits the observation of various cellular responses, including disruption of the cell cycle, monitored by flow cytometry assays, and induction of necrosis, monitored by dye exclusion and caspase inhibition assays, that occur preferentially in the MMR-deficient cell line. These cellular responses provide insight into the mechanisms underlying the selective activity of this novel class of targeted anticancer agents

Numerical Evidence for Divergent Burnett Coefficients

In previous papers [Phys. Rev. A {\bf 41}, 4501 (1990), Phys. Rev. E {\bf 18}, 3178 (1993)], simple equilibrium expressions were obtained for nonlinear Burnett coefficients. A preliminary calculation of a 32 particle Lennard-Jones fluid was presented in the previous paper. Now, sufficient resources have become available to address the question of whether nonlinear Burnett coefficients are finite for soft spheres. The hard sphere case is known to have infinite nonlinear Burnett coefficients (ie a nonanalytic constitutive relation) from mode coupling theory. This paper reports a molecular dynamics caclulation of the third order nonlinear Burnett coefficient of a Lennard-Jones fluid undergoing colour flow, which indicates that this term is diverges in the thermodynamic limit.Comment: 12 pages, 9 figure

Resolved Imagery as a Tool for Space Science and Exploration

Of all the instruments commonly flown on exploration spacecraft, few are as flexible as the camera in the breadth of science problems they ad-dress. Even fewer instruments are so frequently called upon to simultaneously support scientific analysis, mission-critical navigation, and day-to-day operations. Thus, the authors find study of space imagery to be a naturally interdisciplinary endeavor where the pursuit of science and exploration are intertwined

30 days wild: development and evaluation of a large-scale nature engagement campaign to improve well-being

There is a need to increase people’s engagement with and connection to nature, both for human well-being and the conservation of nature itself. In order to suggest ways for people to engage with nature and create a wider social context to normalise nature engagement, The Wildlife Trusts developed a mass engagement campaign, 30 Days Wild. The campaign asked people to engage with nature every day for a month. 12,400 people signed up for 30 Days Wild via an online sign-up with an estimated 18,500 taking part overall, resulting in an estimated 300,000 engagements with nature by participants. Samples of those taking part were found to have sustained increases in happiness, health, connection to nature and pro-nature behaviours. With the improvement in health being predicted by the improvement in happiness, this relationship was mediated by the change in connection to nature

Orientation of Vortices in a Superconducting Thin-Film: Quantitative Comparison of Spin-Polarized Neutron Reflectivity and Magnetization

We present a quantitative comparison of the magnetization measured by spin-polarized neutron reflectivity (SPNR) and DC magnetometry on a 1370 \AA\ -thick Nb superconducting film. As a function of magnetic field applied in the film plane, SPNR exhibits reversible behavior whereas the DC magnetization shows substantial hysteresis. The difference between these measurements is attributed to a rotation of vortex magnetic field out of the film plane as the applied field is reduced. Since SPNR measures only the magnetization parallel to the film plane whereas DC magnetization is strongly influenced by the perpendicular component of magnetization when there is a slight sample tilt, combining the two techniques allows one to distinguish two components of magnetization in a thin film.Comment: 12 pages, 8 figures, It will be printed in PRB, Oct. 200

Fire History from Life-History: Determining the Fire Regime that a Plant Community Is Adapted Using Life-Histories

Wildfire is a fundamental disturbance process in many ecological communities, and is critical in maintaining the structure of some plant communities. In the past century, changes in global land use practices have led to changes in fire regimes that have radically altered the composition of many plant communities. As the severe biodiversity impacts of inappropriate fire management regimes are recognized, attempts are being made to manage fires within a more ‘natural’ regime. In this aim, the focus has typically been on determining the fire regime to which the community has adapted. Here we take a subtly different approach and focus on the probability of a patch being burnt. We hypothesize that competing sympatric taxa from different plant functional groups are able to coexist due to the stochasticity of the fire regime, which creates opportunities in both time and space that are exploited differentially by each group. We exploit this situation to find the fire probability at which three sympatric grasses, from different functional groups, are able to co-exist. We do this by parameterizing a spatio-temporal simulation model with the life-history strategies of the three species and then search for the fire frequency and scale at which they are able to coexist when in competition. The simulation gives a clear result that these species only coexist across a very narrow range of fire probabilities centred at 0.2. Conversely, fire scale was found only to be important at very large scales. Our work demonstrates the efficacy of using competing sympatric species with different regeneration niches to determine the probability of fire in any given patch. Estimating this probability allows us to construct an expected historical distribution of fire return intervals for the community; a critical resource for managing fire-driven biodiversity in the face of a growing carbon economy and ongoing climate change

Large Scale Comparison of Innate Responses to Viral and Bacterial Pathogens in Mouse and Macaque

Viral and bacterial infections of the lower respiratory tract are major causes of morbidity and mortality worldwide. Alveolar macrophages line the alveolar spaces and are the first cells of the immune system to respond to invading pathogens. To determine the similarities and differences between the responses of mice and macaques to invading pathogens we profiled alveolar macrophages from these species following infection with two viral (PR8 and Fuj/02 influenza A) and two bacterial (Mycobacterium tuberculosis and Francisella tularensis Schu S4) pathogens. Cells were collected at 6 time points following each infection and expression profiles were compared across and between species. Our analyses identified a core set of genes, activated in both species and across all pathogens that were predominantly part of the interferon response pathway. In addition, we identified similarities across species in the way innate immune cells respond to lethal versus non-lethal pathogens. On the other hand we also found several species and pathogen specific response patterns. These results provide new insights into mechanisms by which the innate immune system responds to, and interacts with, invading pathogens