Investigating Cytoskeletal Alterations as a Potential Marker of Retinal and Lens Drug-Related Toxicity

Actin filaments play a critical role in the normal physiology of lenticular and retinal cells in the eye. Disruption of the actin cytoskeleton has been associated with retinal pathology and lens cataract formation. Ocular toxicity is an infrequent observation in drug safety studies, yet its impact to the drug development process is significant. Recognizing compounds through screening with a potential ocular safety liability is one way to prioritize development candidates while reducing development attrition. Lens epithelial cells from human, dog, and rat origins and retinal pigmented epithelium cells from human, monkey, and rat origins were cultured and investigated with immunocytochemical techniques. Cells were treated using noncytotoxic doses of the compound, fixed, stained for actin with rhodamine phalloidin, and counterstained for nuclei with TOTO-3, followed by confocal imaging. Tamoxifen and several experimental compounds known to be in vivo lens and retinal toxicants caused a reduction in F-actin fluorescence at noncytotoxic concentrations in all cells tested as observed by confocal microscopy. Developing an assay that predicts ocular toxicity helps the development process by prioritizing compounds for further investigation. Drug-induced cytoskeletal alterations may be useful as a potential safety-screening marker of retinal and lens toxicity. The knowledge of actin molecular biology and the application of other mechanistic screens to toxicology are discussed. Reducing this work to a high-throughput platform will enable chemists to select compounds with a reduced risk of ocular toxicity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63132/1/adt.2006.4.695.pd

Evolutionary Events in a Mathematical Sciences Research Collaboration Network

This study examines long-term trends and shifting behavior in the collaboration network of mathematics literature, using a subset of data from Mathematical Reviews spanning 1985-2009. Rather than modeling the network cumulatively, this study traces the evolution of the "here and now" using fixed-duration sliding windows. The analysis uses a suite of common network diagnostics, including the distributions of degrees, distances, and clustering, to track network structure. Several random models that call these diagnostics as parameters help tease them apart as factors from the values of others. Some behaviors are consistent over the entire interval, but most diagnostics indicate that the network's structural evolution is dominated by occasional dramatic shifts in otherwise steady trends. These behaviors are not distributed evenly across the network; stark differences in evolution can be observed between two major subnetworks, loosely thought of as "pure" and "applied", which approximately partition the aggregate. The paper characterizes two major events along the mathematics network trajectory and discusses possible explanatory factors.Comment: 30 pages, 14 figures, 1 table; supporting information: 5 pages, 5 figures; published in Scientometric

Communities and patterns of scientific collaboration in Business and Management

This is the author's accepted version of this article deposited at arXiv (arXiv:1006.1788v2 [physics.soc-ph]) and subsequently published in Scientometrics October 2011, Volume 89, Issue 1, pp 381-396. The final publication is available at link.springer.com http://link.springer.com/article/10.1007%2Fs11192-011-0439-1Author's note: 17 pages. To appear in special edition of Scientometrics. Abstract on arXiv meta-data a shorter version of abstract on actual paper (both in journal and arXiv full pape

Community structure and patterns of scientific collaboration in Business and Management

This is the author's accepted version of this article deposited at arXiv (arXiv:1006.1788v2 [physics.soc-ph]) and subsequently published in Scientometrics October 2011, Volume 89, Issue 1, pp 381-396. The final publication is available at link.springer.com http://link.springer.com/article/10.1007%2Fs11192-011-0439-1Author's note: 17 pages. To appear in special edition of Scientometrics. Abstract on arXiv meta-data a shorter version of abstract on actual paper (both in journal and arXiv full pape

Linkages among runoff, dissolved organic carbon, and the stable oxygen isotope composition of seawater and other water mass indicators in the Arctic Ocean

Author Posting. © American Geophysical Union, 2005. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 110 (2005): G02013, doi:10.1029/2005JG000031.Concentrations of dissolved organic carbon (DOC) and δ18O values have been determined following sampling of runoff from a number of major arctic rivers, including the Ob, Yenisey, Lena, Kolyma, Mackenzie and Yukon in 2003-2004. These data are considered in conjunction with marine data for DOC, δ18O values, nutrients, salinity, and fluorometric indicators of DOC that were obtained as part of the Shelf-Basin Interactions program at the continental shelf-basin boundary of the Chukchi and Beaufort Seas. These marine data indicate that the freshwater component is most likely derived from regional sources, such as the Mackenzie, the Bering Strait inflow and possibly eastern Siberian rivers, including the Kolyma, or the Lena but not rivers further west in the Eurasian arctic. Contributions of freshwater from melted sea ice to marine surface waters appeared to be insignificant over annual cycles compared to runoff, although on a seasonal basis, freshwater from melted sea ice was locally dominant following a major sea-ice retreat into the Canada Basin in 2002. DOC concentrations were correlated with the runoff fraction, with an apparent meteoric water DOC concentration of 174 ± 1 μM (standard error). This concentration is lower than the flow-weighted concentrations measured at river mouths of the five largest Arctic rivers (358 to 917 μM), indicating that removal of terrigenous DOC during transport through estuaries, shelves and in the deep basin. DOC data indicate that flow-weighted concentrations in the two largest North American arctic rivers, the Yukon (625μM) and the Mackenzie (382 μM), are lower than in the three largest Eurasian arctic rivers, the Ob (825 μM), the Yenesey (858 μM) and the Lena (917 μM). A fluorometric indicator of chromophoric dissolved organic matter (CDOM) that has provided estimates of terrigenous DOC concentrations in the Eurasian Arctic was not correlated with DOC concentrations in the Amerasian marine waters studied, except below the upper Arctic Ocean halocline. Nutrient distributions and concentrations as well as derived nutrient ratios suggest the CDOM fluorometer may be responding to the release of chromophoric materials from continental shelf sediments. Shipboard incubation experiments with undisturbed sediment cores indicate that continental shelf sediments on the Bering and Chukchi Sea shelves are likely to be a net source of DOC to the Arctic Ocean.The PARTNERS and SBI projects have been supported by the Office of Polar Programs of the U.S. National Science Foundation

Modeling transport and fate of riverine dissolved organic carbon in the Arctic Ocean

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 23 (2009): GB4006, doi:10.1029/2008GB003396.The spatial distribution and fate of riverine dissolved organic carbon (DOC) in the Arctic may be significant for the regional carbon cycle but are difficult to fully characterize using the sparse observations alone. Numerical models of the circulation and biogeochemical cycles of the region can help to interpret and extrapolate the data and may ultimately be applied in global change sensitivity studies. Here we develop and explore a regional, three-dimensional model of the Arctic Ocean in which, for the first time, we explicitly represent the sources of riverine DOC with seasonal discharge based on climatological field estimates. Through a suite of numerical experiments, we explore the distribution of DOC-like tracers with realistic riverine sources and a simple linear decay to represent remineralization through microbial degradation. The model reproduces the slope of the DOC-salinity relationship observed in the eastern and western Arctic basins when the DOC tracer lifetime is about 10 years, consistent with published inferences from field data. The new empirical parameterization of riverine DOC and the regional circulation and biogeochemical model provide new tools for application in both regional and global change studies.I.M.M. and M.J.F. are grateful to National Science Foundation for financial support

Regulatory Effect of Connexin 43 on Basal Ca2+ Signaling in Rat Ventricular Myocytes

Background: It has been found that gap junction-associated intracellular Ca 2+ [Ca 2+]i disturbance contributes to the arrhythmogenesis and hyperconstriction in diseased heart. However, whether functional gaps are also involved in the regulation of normal Ca 2+ signaling, in particular the basal [Ca 2+] i activities, is unclear. Methods and Results: Global and local Ca 2+ signaling and gap permeability were monitored in cultured neonatal rat ventricular myocytes (NRVMs) and freshly isolated mouse ventricular myocytes by Fluo4/AM and Lucifer yellow (LY), respectively. The results showed that inhibition of gap communication by heptanol, Gap 27 and flufenamic acid or interference of connexin 43 (Cx43) with siRNA led to a significant suppression of LY uptake and, importantly, attenuations of global Ca 2+ transients and local Ca 2+ sparks in monolayer NRVMs and Ca 2+ sparks in adult ventricular myocytes. In contrast, overexpression of rat-Cx43 in NRVMs induced enhancements in the above measurements, and so did in HEK293 cells expressing rat Cx43. Additionally, membrane-permeable inositol 1,4,5-trisphosphate (IP3 butyryloxymethyl ester) and phenylephrine, an agonist of adrenergic receptor, could relieve the inhibited Ca 2+ signal and LY uptake by gap uncouplers, whereas blockade of IP 3 receptor with xestospongin C or 2-aminoethoxydiphenylborate mimicked the effects of gap inhibitors. More importantly, all these gap-associated effects on Ca 2+ signaling were also found in single NRVMs that only have hemichannels instead of gap junctions. Further immunostaining/immunoblotting single myocytes with antibod

The promoter of ZmMRP-1, a maize transfer cell-specific transcriptional activator, is induced at solute exchange surfaces and responds to transport demands

Transfer cells have specializations that facilitate the transport of solutes across plant exchange surfaces. ZmMRP-1 is a maize (Zea mays) endosperm transfer cell-specific transcriptional activator that plays a central role in the regulatory pathways controlling transfer cell differentiation and function. The present work investigates the signals controlling the expression of ZmMRP-1 through the production of transgenic lines of maize, Arabidopsis, tobacco and barley containing ZmMRP-1promoter:GUS reporter constructs. The GUS signal predominantly appeared in regions of active transport between source and sink tissues, including nematode-induced feeding structures and at sites of vascular connection between developing organs and the main plant vasculature. In those cases, promoter induction was associated with the initial developmental stages of transport structures. Significantly, transfer cells also differentiated in these regions suggesting that, independent of species, location or morphological features, transfer cells might differentiate in a similar way under the influence of conserved induction signals. In planta and yeast experiments showed that the promoter activity is modulated by carbohydrates, glucose being the most effective inducer