Roles for Hippo pathway effectors Taz and Yap in cancer and fibrosis

The Hippo pathway is a well-conserved signaling pathway composed of a series of kinases, ending in the LATS1 and LATS2 kinases (LATS1/2), that control the activity of the transcriptional effectors TAZ and YAP (TAZ/YAP). The Hippo pathway is responsive to several external cues, including mechanical stiffness and cell-cell contact. The transcriptional targets of TAZ/YAP have a wide range of effects, including promotion of cell growth, inhibition of apoptosis, regulation of cell fate, and secretion of growth factors. Due to their wide-ranging effects, in these studies we investigated the roles for TAZ and YAP in several disease areas. First, we explored the roles of TAZ/YAP in glutamine addiction, a phenomenon in which cancer cells rely on glutamine for cell growth, in breast cancer. We demonstrated that breast cancer cells with high TAZ/YAP expression exhibit more reliance on glutamine as an energy source than those with low TAZ/YAP. Depletion of TAZ/YAP in high-TAZ/YAP breast cancer cell lines reduced their reliance on glutamine. We showed that TAZ/YAP promote increased transcription of the transaminases GOT1 and PSAT1, which allow for the carbon from glutamine to enter the tricarboxylic acid cycle and generate energy, providing a mechanism by which TAZ/YAP allow for increased processing of glutamine. Second, we explored whether and how loss of Hippo pathway activity contributes to the formation of melanoma. The most common genetic mutation found in melanoma patients is BrafV600E, but this mutation alone is insufficient to drive melanomagenesis, instead promoting an initial proliferative burst that ends in senescence. We found that BrafV600E activates the Hippo pathway to inhibit TAZ/YAP, contributing to the observed growth arrest phenotype in precancerous nevi. We found that deletion of Lats1/2 in melanocytes alone or in combination with BrafV600E expression lead to the rapid development of melanoma in mice. Third, we assessed how TAZ/YAP mediate homeostasis, injury response, and fibrosis in the lung. We explored TAZ/YAP responses in tissue regeneration and fibrosis using the bleomycin injury model in mice. We found that nuclear levels of TAZ/YAP dynamically increase in the epithelium and mesenchyme of the lung after injury; nuclear TAZ/YAP decreases in these populations as the injury resolves. We conditionally deleted Taz and/or Yap in a subset of mesenchymal cells marked by Platelet-Derived Growth Factor Receptor β (PDGFRβ) in adult mice and found that TAZ and YAP play essential roles in lung homeostasis and responses to bleomycin-injury, with TAZ/YAP-deleted animals showing reduced survival. Notable defects included disorganization of lung epithelial and endothelial cells, indicating that TAZ/YAP in PDGFRβ-expressing cells direct signals that coordinate cellular homeostasis in the lung. In total, these studies detail new mechanisms for TAZ/YAP and Hippo signaling in lung homeostasis and injury repair, melanoma development, and metabolic reprogramming in breast cancer

Polyomic tools for an emerging livestock parasite, the rumen fluke Calicophoron daubneyi; identifying shifts in rumen functionality

Full polyomic data. Table S1. Top C. daubneyi transcriptomic hits. Table S2. The full C. daubneyi transcriptomic hits. Table S3. BLAST searches of C. daubneyi transcripts against P. cervi. BLAST searches of C. daubneyi transcripts. Table S4. The full analysis of putative protein identifications from the excretory/secretory proteome profile of adult C. daubneyi. Table S5. The full analysis of putative proteins identified from the soluble somatic proteome profile of adult C. daubneyi. (XLSX 12697 kb

Pollination by the locally endangered island flying fox (Pteropus hypomelanus) enhances fruit production of the economically important durian (Durio zibethinus)

Fruit bats provide valuable pollination services to humans through a unique coevolutionary relationship with chiropterophilous plants. However, chiropterophily in the Old World and the pollination roles of large bats, such as flying foxes (Pteropus spp., Acerodon spp., Desmalopex spp.), are still poorly understood and require further elucidation. Efforts to protect these bats have been hampered by a lack of basic quantitative information on their role as ecosystem service providers. Here, we investigate the role of the locally endangered island flying fox Pteropus hypomelanus in the pollination ecology of durian (Durio zibethinus), an economically important crop in Southeast Asia.On Tioman Island, Peninsular Malaysia, we deployed 19 stations of paired infrared camera and video traps across varying heights at four individual flowering trees in a durian orchard. We detected at least nine species of animal visitors, but only bats had mutualistic interactions with durian flowers. There was a clear vertical stratification in the feeding niches of flying foxes and nectar bats, with flying foxes feeding at greater heights in the trees. Flying foxes had a positive effect on mature fruit set and therefore serve as important pollinators for durian trees. As such, semi-wild durian trees—particularly tall ones—may be dependent on flying foxes for enhancing reproductive success. Our study is the first to quantify the role of flying foxes in durian pollination, demonstrating that these giant fruit bats may have far more important ecological, evolutionary, and economic roles than previously thought. This has important implications and can aid efforts to promote flying fox conservation, especially in Southeast Asian countries

Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling, human myelofibrosis

Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showing that bone marrow-specific deletion of Abi1 in a novel mouse model leads to development of an MPNlike phenotype resembling human PMF. Abi1 loss resulted in a significant increase in the activity of the Src family kinases (SFKs), STAT3, and NF-κB signaling. We also observed impairment of hematopoietic stem cell self-renewal and fitness, as evidenced in noncompetitive and competitive bone marrow transplant experiments. CD34 + hematopoietic progenitors and granulocytes from patients with PMF showed decreased levels of ABI1 transcript as well as increased activity of SFKs, STAT3, and NF-κB. In aggregate, our data link the loss of Abi-1 function to hyperactive SFKs/STAT3/NF-κB signaling and suggest that this signaling axis may represent a regulatory module involved in the molecular pathophysiology of PMF

Canvass: a crowd-sourced, natural-product screening library for exploring biological space

NCATS thanks Dingyin Tao for assistance with compound characterization. This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). R.B.A. acknowledges support from NSF (CHE-1665145) and NIH (GM126221). M.K.B. acknowledges support from NIH (5R01GM110131). N.Z.B. thanks support from NIGMS, NIH (R01GM114061). J.K.C. acknowledges support from NSF (CHE-1665331). J.C. acknowledges support from the Fogarty International Center, NIH (TW009872). P.A.C. acknowledges support from the National Cancer Institute (NCI), NIH (R01 CA158275), and the NIH/National Institute of Aging (P01 AG012411). N.K.G. acknowledges support from NSF (CHE-1464898). B.C.G. thanks the support of NSF (RUI: 213569), the Camille and Henry Dreyfus Foundation, and the Arnold and Mabel Beckman Foundation. C.C.H. thanks the start-up funds from the Scripps Institution of Oceanography for support. J.N.J. acknowledges support from NIH (GM 063557, GM 084333). A.D.K. thanks the support from NCI, NIH (P01CA125066). D.G.I.K. acknowledges support from the National Center for Complementary and Integrative Health (1 R01 AT008088) and the Fogarty International Center, NIH (U01 TW00313), and gratefully acknowledges courtesies extended by the Government of Madagascar (Ministere des Eaux et Forets). O.K. thanks NIH (R01GM071779) for financial support. T.J.M. acknowledges support from NIH (GM116952). S.M. acknowledges support from NIH (DA045884-01, DA046487-01, AA026949-01), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (W81XWH-17-1-0256), and NCI, NIH, through a Cancer Center Support Grant (P30 CA008748). K.N.M. thanks the California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board for support. B.T.M. thanks Michael Mullowney for his contribution in the isolation, elucidation, and submission of the compounds in this work. P.N. acknowledges support from NIH (R01 GM111476). L.E.O. acknowledges support from NIH (R01-HL25854, R01-GM30859, R0-1-NS-12389). L.E.B., J.K.S., and J.A.P. thank the NIH (R35 GM-118173, R24 GM-111625) for research support. F.R. thanks the American Lebanese Syrian Associated Charities (ALSAC) for financial support. I.S. thanks the University of Oklahoma Startup funds for support. J.T.S. acknowledges support from ACS PRF (53767-ND1) and NSF (CHE-1414298), and thanks Drs. Kellan N. Lamb and Michael J. Di Maso for their synthetic contribution. B.S. acknowledges support from NIH (CA78747, CA106150, GM114353, GM115575). W.S. acknowledges support from NIGMS, NIH (R15GM116032, P30 GM103450), and thanks the University of Arkansas for startup funds and the Arkansas Biosciences Institute (ABI) for seed money. C.R.J.S. acknowledges support from NIH (R01GM121656). D.S.T. thanks the support of NIH (T32 CA062948-Gudas) and PhRMA Foundation to A.L.V., NIH (P41 GM076267) to D.S.T., and CCSG NIH (P30 CA008748) to C.B. Thompson. R.E.T. acknowledges support from NIGMS, NIH (GM129465). R.J.T. thanks the American Cancer Society (RSG-12-253-01-CDD) and NSF (CHE1361173) for support. D.A.V. thanks the Camille and Henry Dreyfus Foundation, the National Science Foundation (CHE-0353662, CHE-1005253, and CHE-1725142), the Beckman Foundation, the Sherman Fairchild Foundation, the John Stauffer Charitable Trust, and the Christian Scholars Foundation for support. J.W. acknowledges support from the American Cancer Society through the Research Scholar Grant (RSG-13-011-01-CDD). W.M.W.acknowledges support from NIGMS, NIH (GM119426), and NSF (CHE1755698). A.Z. acknowledges support from NSF (CHE-1463819). (Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH); CHE-1665145 - NSF; CHE-1665331 - NSF; CHE-1464898 - NSF; RUI: 213569 - NSF; CHE-1414298 - NSF; CHE1361173 - NSF; CHE1755698 - NSF; CHE-1463819 - NSF; GM126221 - NIH; 5R01GM110131 - NIH; GM 063557 - NIH; GM 084333 - NIH; R01GM071779 - NIH; GM116952 - NIH; DA045884-01 - NIH; DA046487-01 - NIH; AA026949-01 - NIH; R01 GM111476 - NIH; R01-HL25854 - NIH; R01-GM30859 - NIH; R0-1-NS-12389 - NIH; R35 GM-118173 - NIH; R24 GM-111625 - NIH; CA78747 - NIH; CA106150 - NIH; GM114353 - NIH; GM115575 - NIH; R01GM121656 - NIH; T32 CA062948-Gudas - NIH; P41 GM076267 - NIH; R01GM114061 - NIGMS, NIH; R15GM116032 - NIGMS, NIH; P30 GM103450 - NIGMS, NIH; GM129465 - NIGMS, NIH; GM119426 - NIGMS, NIH; TW009872 - Fogarty International Center, NIH; U01 TW00313 - Fogarty International Center, NIH; R01 CA158275 - National Cancer Institute (NCI), NIH; P01 AG012411 - NIH/National Institute of Aging; Camille and Henry Dreyfus Foundation; Arnold and Mabel Beckman Foundation; Scripps Institution of Oceanography; P01CA125066 - NCI, NIH; 1 R01 AT008088 - National Center for Complementary and Integrative Health; W81XWH-17-1-0256 - Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program; P30 CA008748 - NCI, NIH, through a Cancer Center Support Grant; California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board; American Lebanese Syrian Associated Charities (ALSAC); University of Oklahoma Startup funds; 53767-ND1 - ACS PRF; PhRMA Foundation; P30 CA008748 - CCSG NIH; RSG-12-253-01-CDD - American Cancer Society; RSG-13-011-01-CDD - American Cancer Society; CHE-0353662 - National Science Foundation; CHE-1005253 - National Science Foundation; CHE-1725142 - National Science Foundation; Beckman Foundation; Sherman Fairchild Foundation; John Stauffer Charitable Trust; Christian Scholars Foundation)Published versionSupporting documentatio

Cnidarians as a Source of New Marine Bioactive Compounds—An Overview of the Last Decade and Future Steps for Bioprospecting

Marine invertebrates are rich sources of bioactive compounds and their biotechnological potential attracts scientific and economic interest worldwide. Although sponges are the foremost providers of marine bioactive compounds, cnidarians are also being studied with promising results. This diverse group of marine invertebrates includes over 11,000 species, 7500 of them belonging to the class Anthozoa. We present an overview of some of the most promising marine bioactive compounds from a therapeutic point of view isolated from cnidarians in the first decade of the 21st century. Anthozoan orders Alcyonacea and Gorgonacea exhibit by far the highest number of species yielding promising compounds. Antitumor activity has been the major area of interest in the screening of cnidarian compounds, the most promising ones being terpenoids (monoterpenoids, diterpenoids, sesquiterpenoids). We also discuss the future of bioprospecting for new marine bioactive compounds produced by cnidarians

Protecting 30% of the planet for nature: costs, benefits and economic implications

A. Waldron, K. Nakamura, J. Sze, T. Vilela, A. Escobedo, P. Negret Torres, R. Button, K. Swinnerton, A. Toledo, P. Madgwick, N. Mukherjee were supported by National Geographic and the Resources Legacy Fund. V. Christensen was supported by NSERC Discovery Grant RGPIN-2019-04901. M. Coll and J. Steenbeek were supported by EU Horizon 2020 research and innovation programme under grant agreement No 817578 (TRIATLAS). D. Leclere was supported by TradeHub UKRI CGRF project. R. Heneghan was supported by Spanish Ministry of Science, Innovation and Universities, Acciones de Programacion Conjunta Internacional (PCIN-2017-115). M. di Marco was supported by MIUR Rita Levi Montalcini programme. A. Fernandez-Llamazares was supported by Academy of Finland (grant nr. 31176). S. Fujimori and T. Hawegawa were supported by The Environment Research and Technology Development Fund (2-2002) of the Environmental Restoration and Conservation Agency of Japan and the Sumitomo Foundation. V. Heikinheimo was supported by Kone Foundation, Social Media for Conservation project. K. Scherrer was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 682602. U. Rashid Sumaila acknowledges the OceanCanada Partnership, which funded by the Social Sciences and Humanities Research Council of Canada (SSHRC). T. Toivonen was supported by Osk. Huttunen Foundation & Clare Hall college, Cambridge. W. Wu was supported by The Environment Research and Technology Development Fund (2-2002) of the Environmental Restoration and Conservation Agency of Japan. Z. Yuchen was supported by a Ministry of Education of Singapore Research Scholarship Block (RSB) Research Fellowship

Working paper analysing the economic implications of the proposed 30% target for areal protection in the draft post-2020 Global Biodiversity Framewor

58 pages, 5 figures, 3 tables- The World Economic Forum now ranks biodiversity loss as a top-five risk to the global economy, and the draft post-2020 Global Biodiversity Framework proposes an expansion of conservation areas to 30% of the earth’s surface by 2030 (hereafter the “30% target”), using protected areas (PAs) and other effective area-based conservation measures (OECMs). - Two immediate concerns are how much a 30% target might cost and whether it will cause economic losses to the agriculture, forestry and fisheries sectors. - Conservation areas also generate economic benefits (e.g. revenue from nature tourism and ecosystem services), making PAs/Nature an economic sector in their own right. - If some economic sectors benefit but others experience a loss, high-level policy makers need to know the net impact on the wider economy, as well as on individual sectors. [...]A. Waldron, K. Nakamura, J. Sze, T. Vilela, A. Escobedo, P. Negret Torres, R. Button, K. Swinnerton, A. Toledo, P. Madgwick, N. Mukherjee were supported by National Geographic and the Resources Legacy Fund. V. Christensen was supported by NSERC Discovery Grant RGPIN-2019-04901. M. Coll and J. Steenbeek were supported by EU Horizon 2020 research and innovation programme under grant agreement No 817578 (TRIATLAS). D. Leclere was supported by TradeHub UKRI CGRF project. R. Heneghan was supported by Spanish Ministry of Science, Innovation and Universities, Acciones de Programacion Conjunta Internacional (PCIN-2017-115). M. di Marco was supported by MIUR Rita Levi Montalcini programme. A. Fernandez-Llamazares was supported by Academy of Finland (grant nr. 311176). S. Fujimori and T. Hawegawa were supported by The Environment Research and Technology Development Fund (2-2002) of the Environmental Restoration and Conservation Agency of Japan and the Sumitomo Foundation. V. Heikinheimo was supported by Kone Foundation, Social Media for Conservation project. K. Scherrer was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 682602. U. Rashid Sumaila acknowledges the OceanCanada Partnership, which funded by the Social Sciences and Humanities Research Council of Canada (SSHRC). T. Toivonen was supported by Osk. Huttunen Foundation & Clare Hall college, Cambridge. W. Wu was supported by The Environment Research and Technology Development Fund (2-2002) of the Environmental Restoration and Conservation Agency of Japan. Z. Yuchen was supported by a Ministry of Education of Singapore Research Scholarship Block (RSB) Research FellowshipPeer reviewe