Miocene waterfowl and other birds from central Otago, New Zealand

Copyright © The Natural History Museum 2007Abundant fossil bird bones from the lower Bannockburn Formation, Manuherikia Group, an Early-Middle Miocene lacustrine deposit, 16–19 Ma, from Otago in New Zealand, reveal the “St Bathans Fauna” (new name), a first Tertiary avifauna of land and freshwater birds from New Zealand. At least 23 species of birds are represented by bones, and probable moa, Aves: Dinornithiformes, by eggshell. Anatids dominate the fauna with four genera and five species described as new: a sixth and largest anatid species is represented by just one bone. This is the most diverse Early-Middle Miocene duck fauna known worldwide. Among ducks, two species of dendrochenines are most numerous in the fauna, but a tadornine is common as well. A diving petrel (Pelecanoididae: Pelecanoides) is described, so extending the geological range of this genus worldwide from the Pliocene to the Middle Miocene, at least. The remaining 16 taxa are left undescribed but include: a large species of gull (Laridae); two small waders (Charadriiformes, genus indet.), the size of Charadrius bicinctus and Calidris ruficollis, respectively; a gruiform represented by one specimen similar to Aptornis; abundant rail (Rallidae) bones, including a common flightless rail and a rarer slightly larger taxon, about the size of Gallirallus philippensis; an ?eagle (Accipitridae); a pigeon (Columbidae); three parrots (Psittacidae); an owlet nightjar (Aegothelidae: Aegotheles sp.); a swiftlet (Apodidae: Collocalia sp.); and three passerine taxa, of which the largest is a member of the Cracticidae. The absence of some waterbirds, such as anserines (including swans), grebes (Podicipedidae) and shags (Phalacrocoracidae), among the abundant bones, indicates their probable absence from New Zealand in the Early-Middle Miocene.T. H. Worthy, A. J. D. Tennyson, C. Jones, J. A. McNamara and B. J. Dougla

Cooperative Drug Combinations Target Oncogenes and Tumor Suppressors in Cancer

Multiple myeloma (MM)is a neoplasm involving plasma cells in the bone marrow. Drug resistance and progression are common, underscoring the need for new drug combinations. We utilized a high-throughput screen of tool compounds to limit growth of 47 human MM cell lines. In silicorobust regression analysis of drug responses revealed 43 potential synergistic combinations. We hypothesized that effective combinations would reduce oncogene expression and/or enhance tumor suppressor gene activity based on earlier genetic and drug studies that identified p16, Myc and mTOR as appropriate targets in myeloma. Thus, candidate combinations were evaluated for cooperative reductions in MYC protein expression in MM cells. Ten combinations cooperatively reduced MYC expression, which is frequently over-expressed in MM. Cooperative reductions in viability were observed with top combinations in proteasome inhibitor-resistant and sensitive MM cell lines but did not limit normal fibroblast viability. The combinations cooperatively increased p16 activity, while also enhancing cleaved caspase 3, leading to increased apoptosis. Combinationassociated survival was evaluated in a transplantable Ras-driven allograft model of advanced MM that closely recapitulates myeloma in humans. Three combinations significantly prolonged survival in sublethally-irradiated C57BL/6 mice injected intracardiac with donor MM cells compared to control mice. Furthermore, the top three combinations reduced viability of ex vivo treated patient cells. Common genetic pathways similarly affected by the top drug combinations were those implicated in promoting cell cycle transition and pathways most upregulated by all combinations were involved in TGFB and SMAD3 signaling. These data identify potentially useful drug combinations for preclinical evaluation in drug-resistant MM and may ultimately reveal novel mechanisms of combined drug sensitivity

Mouse tumor susceptibility genes identify drug combinations for multiple myeloma

Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning strategies and functional studies identified Cdkn2a, Mtor, and Mndal as mouse plasmacytoma susceptibility/resistance genes. Tumor incidence data in congenic strains carrying the resistance alleles of Cdkn2a and Mtor led us to hypothesize that drug combinations affecting these pathways are likely to have an additive, if not synergistic effect in inhibiting tumor cell growth. Traditional and novel systems-level genomic approaches were used to assess combination activity, disease specificity, and clinical potential of a drug combination involving rapamycin/everolimus, an Mtor inhibitor, with entinostat, an histone deacetylase inhibitor. The combination synergistically repressed oncogenic MYC and activated the Cdkn2a tumor suppressor. The identification of MYC as a primary upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in the NHEIII region of the MYC promoter. These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes

A water soluble parthenolide analogue suppresses in vivo tumor growth of two tobacco associated cancers, lung and bladder cancer, by targeting NF-κB and generating reactive oxygen species

Dimethylaminoparthenolide (DMAPT) is a water soluble parthenolide analogue with preclinical activity in hematologic malignancies. Using NSCLC cell lines (A549, H522) and an immortalized human bronchial epithelial cell line (BEAS2B) and TCC cell lines (UMUC-3, HT-1197, HT-1376) and a bladder papilloma (RT-4), we aimed to characterize DMAPT's anti-cancer activity in tobacco associated neoplasms. Flow cytometric, electrophorectic mobility gel shift assays (EMSA), and western blot studies measured generation of reactive oxygen species (ROS), inhibition of NFκB DNA binding, and changes in cell cycle distribution and apoptotic proteins. DMAPT generated ROS with subsequent JNK activation and also decreased NFκB DNA binding and anti-apoptotic proteins, TRAF-2 and XIAP. DMAPT induced apoptotic cell death and altered cell cycle distribution with upregulation of p21 and p73 levels in a cell type dependent manner. DMAPT suppressed cyclin D1 in BEAS2B. DMAPT retained NFκB and cell cycle inhibitory activity in the presence of the tobacco carcinogen nitrosamine ketone, 4(methylnitrosamino)-1-(3–pyridyl)-1-butanone (NNK). Using a BrdU accumulation assay, 5 to 20μM of DMAPT was shown to inhibit cellular proliferation of all cell lines by more than 95%. Oral dosing of DMAPT suppressed in vivo A549 and UMUC-3 subcutaneous xenograft growth by 54% (p=0.015) and 63% (p<0.01) respectively and A549 lung metastatic volume by 28% (p=0.043). In total this data demonstrates DMAPT's novel anti-cancer properties in both early and late stage tobacco associated neoplasms as well as its significant in vivo activity. The data provides support for the conduct of clinical trials in TCC and NSCLC

Conventional Co-Housing Modulates Murine Gut Microbiota and Hematopoietic Gene Expression

Specific-pathogen-free (SPF) mice have improved hematopoietic characteristics relative to germ-free mice, however, it is not clear whether improvements in hematopoietic traits will continue when the level of microorganism exposure is further increased. We co-housed SPF C57BL/6 mice in a conventional facility (CVT) and found a significant increase in gut microbiota diversity along with increased levels of myeloid cells and T cells, especially effector memory T cells. Through single cell RNA sequencing of sorted KL (c-Kit+Lin&minus;) cells, we imputed a decline in long-term hematopoietic stem cells and an increase in granulocyte-monocyte progenitors in CVT mice with up-regulation of genes associated with cell survival. Bone marrow transplantation through competitive repopulation revealed a significant increase in KSL (c-Kit+Sca-1+Lin&minus;) cell reconstitution in recipients of CVT donor cells which occurred when donors were co-housed for both one and twelve months. However, there was minimal to no gain in mature blood cell engraftment in recipients of CVT donor cells relative to those receiving SPF donor cells. We conclude that co-housing SPF mice with mice born in a conventional facility increased gut microbiota diversity, augmented myeloid cell production and T cell activation, stimulated KSL cell reconstitution, and altered hematopoietic gene expression

Temperature regimes, growth, and food consumption for female and male adult walleye in Lake Huron and Lake Erie: a bioenergetics analysis

Bioenergetics modeling was used to assess the relative importance of food availability and water temperature in determining walleye (Sander vitreus) growth. Temperature regimes experienced by both female and male adult walleye in three basins of Lake Huron and in Lake Erie were determined by use of surgically implanted temperature loggers and acoustic telemetry. Temperatures experienced by walleye were higher in Lake Erie than in Lake Huron. Walleye from Lake Erie grew at nearly double the rate of walleye from Lake Huron, and weight at age for adult females averaged about 50% greater than that for adult males in both lakes. Food consumption rate for an average adult walleye in Lake Erie was nearly twice as high as that in Lake Huron. Interbasin and interlake variability in temperature regimes accounted for a moderate degree of variability in walleye growth. We concluded that the driver for faster growth in Lake Erie compared with Lake Huron was higher food availability in Lake Erie compared with Lake Huron. The sex difference in temperature regimes explained 15% of the sex difference in Lake Erie walleye growth.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Comparative thermal biology and depth distribution of largemouth bass (Micropterus salmoides) and northern pike (Esox lucius) in an urban harbour of the laurentian great lakes

Understandinghowindividuals are distributed in space and time, as well ashowthey interact with dynamic environmental conditions, represent fundamental knowledge gaps for many fish species. Using acoustic telemetry tags, we monitored the temperatures and depths used by northern pike (Esox lucius L., 1758) and largemouth bass (Micropterus salmoides (Lacepède, 1802)) in Toronto Harbour (Lake Ontario). Northern pike and largemouth bass had similar thermal experiences throughout the year, except during summer, when northern pike were observed in cooler waters than largemouth bass. Both species used different depths throughout the year, with northern pike occupying deeper depths. Statistical modelling indicated that depth usage was influenced by all variables (season, species, and body size) and interactions between them, whereas thermal preferences were influenced by the main effects and interactions between species:season and species: body size. Both species were observed at temperatures warmer than those in the vicinity of nearby telemetry stations, but as station temperatures exceede