The Mitchell Institute is a 501 non-profit organization in Portland, Maine which has as its mission to increase the likelihood that young people from Maine will aspire to, pursue and achieve a college education.The Institute was founded by George J. Mitchell and is supported by donors throughout Maine. The Institute features a quotation from George J. Mitchell that "no one should be guaranteed success ... but everyone should have a fair chance to succeed." Wikipedia.
Kamber Kaya H.E.,University of Massachusetts Medical School |
Ditzel M.,University of Edinburgh |
Meier P.,Mitchell Institute |
Bergmann A.,University of Massachusetts Medical School
PLoS Genetics | Year: 2017
Apoptosis is an evolutionary conserved cell death mechanism, which requires activation of initiator and effector caspases. The Drosophila initiator caspase Dronc, the ortholog of mammalian Caspase-2 and Caspase-9, has an N-terminal CARD domain that recruits Dronc into the apoptosome for activation. In addition to its role in apoptosis, Dronc also has non-apoptotic functions such as compensatory proliferation. One mechanism to control the activation of Dronc is ubiquitylation. However, the mechanistic details of ubiquitylation of Dronc are less clear. For example, monomeric inactive Dronc is subject to non-degradative ubiquitylation in living cells, while ubiquitylation of active apoptosome-bound Dronc triggers its proteolytic degradation in apoptotic cells. Here, we examined the role of non-degradative ubiquitylation of Dronc in living cells in vivo, i.e. in the context of a multi-cellular organism. Our in vivo data suggest that in living cells Dronc is mono-ubiquitylated on Lys78 (K78) in its CARD domain. This ubiquitylation prevents activation of Dronc in the apoptosome and protects cells from apoptosis. Furthermore, K78 ubiquitylation plays an inhibitory role for non-apoptotic functions of Dronc. We provide evidence that not all of the non-apoptotic functions of Dronc require its catalytic activity. In conclusion, we demonstrate a mechanism whereby Dronc’s apoptotic and non-apoptotic activities can be kept silenced in a non-degradative manner through a single ubiquitylation event in living cells. © 2017 Kamber Kaya et al.
News Article | May 6, 2017
Last week we saw a prime example of the difficulties Malcolm Turnbull faces when he tries to do something good. On Tuesday, while he and the education minister, Simon Birmingham, were getting ready to announce a big overhaul of school funding that would finally have the government embracing a progressive funding model, his predecessor, Tony Abbott, was doing his best impersonation of Kevin Rudd. As Rudd was apt to do whenever Julia Gillard was set to make a major announcement, Abbott posted a photo on Twitter to divert attention. It was of his appearance at the offices of the IPA, and depicted a scene so pathetic you could almost detect from the faces present a befuddlement at the life choices they had made that led them to such a sad position. The IPA is a thinktank that exists to talk up white western civilisation, deny climate change and argue for small government – low taxes and even lower welfare and services. It was its type of thinking that was behind Joe Hockey and Abbott’s first budget, one so lacking in political and policy intelligence that it ended Hockey’s political career and resulted in Abbott going from being prime minister to a backbench MP reduced to attending lame morning teas. The next day, Abbott continued his sniping on radio as he complained that the school spending proposals had yet to go through the party room and that “at this stage it’s hard to see that any of this extra funding is specifically tied to better academic outcomes and better student performance”. He’s Tony, and he’s here to help. Since taking over the prime ministership, Turnbull has for the most part embraced the hard right wing of his political party to the extent that there was barely any difference between his and Abbott’s prime ministership. You could argue he needed to do so, that his power was so weak he had to placate the rump who support Abbott, who believe the IPA makes some good points, who see welfare recipients as bludgers, and who think we need to protect our glorious western civilisation from Muslims and anyone who does not follow our “values”. But such a strategy has proved about as popular as the smallpox inflicted on indigenous populations by those glorious western civilisations. And so last week we saw signs of change, an embrace, to use one of Turnbull’s favourite phrases, of the “penetrating glimpse of the obvious”. Turnbull has seemingly realised that to cling to the 2014 budget is to cling to political death. Last week the government leaked that the zombie welfare cuts from that budget, such as a four-week waiting period for going on the dole, are to be dumped. It also looks set to unfreeze the Medicare rebate to doctors. And most crucially, it embraced the funding model proposed under the former ALP government by David Gonski. It appears Turnbull has grasped that despite what groups such as the IPA and the hard-right rump in his party would have us believe, Australians actually like well-funded and fairly provided government services. The schools funding reform package will result in a much better targeting of commonwealth funds than was ever proposed or considered by the Abbott government. Is it less money than the ALP would have provided? Yes – the ALP would say it’s lower by $22bn over 10 years, although that figure appears less than certain at this point. But there is no getting around the fact the funding will now be better targeted – a smaller share of the money to the schools in the wealthiest areas, and a bigger share going to the poorest areas. And it is 180 degrees away from Turnbull’s idiotic idea of last year for the commonwealth to pay for private schools and states to pay for public ones. Perhaps there needs to be a bigger total amount of money, but at least we are on the way to having a fair distribution – freed from the Gillard government’s foolish, but at the time politically necessary, promise that no school would be worse off. It certainly is not perfect, and as with any policy we need to await the details to see the full impact. As the Mitchell Institute’s Brownyn Hinz for example, notes, while it is all very well to talk about needs of schools, assessment of those needs “should also take into account the different starting points and learning growth of student populations in different schools”. There are those who will suggest Turnbull and Birmingham have wedged the ALP and also flummoxed the unions who campaigned for the Gonski funding model. Personally I couldn’t give a stuff. I really don’t care who enacts progressive policies, so long as they are enacted! But of course one policy doesn’t make a government progressive. Last week as well, the government announced cuts to higher education and changes that will have people earning less than $52,000 paying up to $1,290 more than they would have previously, and all students paying more for their degrees. Similarly, while the government is to spend more money than it would have on schools, we are yet to find out how it is to be paid – Birmingham only said “the budget will show clearly how that’s going to occur”. The cuts targeting welfare recipients remain, as does the ending of the 2% “deficit levy” for those earning more than $180,000. And there appears little sense of any moves on housing affordability that will affect capital gains tax or negative gearing. The weeks around the budget are always as much about media management as they are about policy. Last week, with the announcement on school funding coming straight after and thus somewhat burying the cuts to higher education, the government certainly was trying to create the impression of a good-news budget. But unless the government has decided that ongoing funding for schools is good debt, someone is going to have to pay, and who does and how they do will help determine whether this shift towards progressive policy is anything more than just a brief flirtation away from the rightwing rump of Turnbull’s party.
News Article | December 19, 2016
Papovich notes that large disk galaxies like our own Milky Way were not always the well-ordered, pinwheel-like, spiral structures we see in the universe today. On the contrary, he and other international experts who specialize in galaxy formation and evolution believe that about 8-to-10 billion years ago, progenitors of the Milky Way and similar disk/spiral galaxies were smaller and less organized, yet highly active in their youth. In previous NASA and National Science Foundation-funded research, Papovich and his collaborators showed that these younger versions of such galaxies were churning out new stars faster than at any other point in their lifespans, suggesting that they must be amazingly rich in star-forming material. And now, they have compelling evidence—the galactic equivalent of a smoking gun. Using the National Radio Astronomy Observatory's Atacama Large Millimeter/submillimeter Array (ALMA)—a huge, highly sophisticated radio telescope array situated at 16,500 feet altitude in the high desert of Chile—a Papovich-led team of astronomers studied four very young versions of galaxies like the Milky Way that are 9 billion light-years distant, meaning the team could see them as they looked approximately 9 billion years ago. They discovered that each galaxy was incredibly rich in carbon monoxide—a well-known tracer of molecular gas, which is the fuel for star formation. The team's findings are reported in a paper posted to arXiv and set to be published in the inaugural issue of Nature Astronomy in January. "We used ALMA to detect adolescent versions of the Milky Way and found that such galaxies do indeed have much higher amounts of molecular gas, which would fuel rapid star formation," said Papovich, lead author on the paper and a member of the George P. and Cynthia Woods Mitchell Institute for Fundamental Physics and Astronomy. "I liken these galaxies to an adolescent human who consumes prodigious amounts of food to fuel their own growth during their teenage years." In addition to Papovich, the research team also includes fellow Texas A&M astronomers Ryan Quadri and Kim-Vy Tran, as well as astronomers from Leiden Observatory in Holland, Swinburne University and Macquarie University in Australia, the National Optical Astronomy Observatory (NOAO), the University of Texas at Austin, Lyon Observatory in France and the Max Plank Institute for Astronomy in Germany. Though the relative abundance of star-forming gas is extreme in these galaxies, Papovich says they are not yet fully formed and rather small compared to the Milky Way as we see it today. The new ALMA data indicate that the vast majority of the mass in these galaxies is in cold molecular gas rather than in stars—a situation that Papovich says is reversed at present in our Milky Way, where the mass in stars outweighs that in gas by a factor of 10 to 1. These observations, he notes, are helping build a complete picture of how matter in Milky-Way-size galaxies evolved and how our own galaxy formed. "Most stars today exist in galaxies like the Milky Way, so by studying how galaxies like our own formed, we've come to understand the most typical locations of stars in the universe," said Papovich, a member since 2008 of the Texas A&M Department of Physics and Astronomy, where he is a co-holder of the Marsha L. '69 and Ralph F. Schilling '68 Chair in Experimental Physics. "Our current research shows that Milky Way-mass galaxies appear to accumulate most of their gas during their first few billion years of history. At that stage, they have most of the fuel they need to produce the stars they currently encompass in the present." The presence of extensive gas reservoirs backs up the team's previous observations that provided the first tangible pictures showcasing the unprecedented life story of Milky Way galaxy evolution. Among other details, their prior study revealed a stellar birth rate 30 times higher than it is in the Milky Way today—roughly one per year, compared to about 30 each year 9.5 billion years ago. "Thanks to ALMA and other innovative instruments that allow us to peer 9 billion years into the past to analyze galaxies that are likely similar to the progenitor of our own Milky Way galaxy, we can actually prove what our observations show," Papovich said. Papovich and his team recently have been awarded more highly competitive time with ALMA to study the temperature and density of the star-forming gas, allowing them to measure and map its transitions and phases and ideally the related impacts within the galaxies. "This will begin to tell us how these galaxies formed stars at such a rapid pace, compared to conditions at present," he said. Papovich, Quadri and Tran are among roughly two dozen astronomers around the world who have spent years studying carefully selected distant galaxies similar in mass to the progenitor of our own Milky Way that were found in two deep-sky program surveys of the universe, the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS) and the FourStar Galaxy Evolution Survey (ZFOURGE). Beyond ALMA, the team's research has used observations from NASA's Hubble and Spitzer Space Telescopes and the European Space Agency's Herschel Space Observatory. The Hubble images from the CANDELS survey also provided structural information about galaxy sizes and how they evolved. Far-infrared light observations from Spitzer and Herschel helped the astronomers trace the star-formation rate. The team's paper, Large Molecular Gas Reservoirs in Ancestors of Milky Way-Mass Galaxies 9 Billion Years Ago, can be viewed online along with related images and captions. Explore further: Our Sun came late to the Milky Way's star-birth party More information: C. Papovich et al. Large molecular gas reservoirs in ancestors of Milky Way-mass galaxies nine billion years ago, Nature Astronomy (2016). DOI: 10.1038/s41550-016-0003
Jansson J.K.,Lawrence Berkeley National Laboratory |
Jansson J.K.,Mitchell Institute |
Jansson J.K.,Joint BioEnergy Institute |
Jansson J.K.,Copenhagen University |
And 2 more authors.
Nature Reviews Microbiology | Year: 2014
Permafrost constitutes a major portion of the terrestrial cryosphere of the Earth and is a unique ecological niche for cold-adapted microorganisms. There is a relatively high microbial diversity in permafrost, although there is some variation in community composition across different permafrost features and between sites. Some microorganisms are even active at subzero temperatures in permafrost. An emerging concern is the impact of climate change and the possibility of subsequent permafrost thaw promoting microbial activity in permafrost, resulting in increased potential for greenhouse-gas emissions. This Review describes new data on the microbial ecology of permafrost and provides a platform for understanding microbial life strategies in frozen soil as well as the impact of climate change on permafrost microorganisms and their functional roles. © 2014 Macmillan Publishers Limited. All rights reserved.
Silke J.,Walter and Eliza Hall Institute of Medical Research |
Meier P.,Mitchell Institute
Cold Spring Harbor Perspectives in Biology | Year: 2013
Misregulated innate immune signaling and cell death form the basis of much human disease pathogenesis. Inhibitor of apoptosis (IAP) protein family members are frequently overex- pressed in cancer and contribute to tumor cell survival, chemo-resistance, disease progres- sion, and poor prognosis. Although best known for theirabilitytoregulate caspases, IAPs also influence ubiquitin (Ub)-dependent pathways that modulate innate immune signaling via activation of nuclear factor kB (NF-kB). Recent research into IAP biology has unearthed unexpected roles for this group of proteins. In addition, the advances in our understanding of the molecular mechanisms that IAPs use to regulate cell death and innate immune re- sponses have provided new insights into disease states and suggested novel intervention strategies. Here we review the functions assigned to those IAP proteins that act at the inter- section of cell death regulation and inflammatory signaling. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.
Lowe C.J.,Stanford University |
Clarke D.N.,Stanford University |
Medeiros D.M.,University of Colorado at Boulder |
Rokhsar D.S.,University of California at Berkeley |
And 3 more authors.
Nature | Year: 2015
Our understanding of vertebrate origins is powerfully informed by comparative morphology, embryology and genomics of chordates, hemichordates and echinoderms, which together make up the deuterostome clade. Striking body-plan differences among these phyla have historically hindered the identification of ancestral morphological features, but recent progress in molecular genetics and embryology has revealed deep similarities in body-axis formation and organization across deuterostomes, at stages before morphological differences develop. These developmental genetic features, along with robust support of pharyngeal gill slits as a shared deuterostome character, provide the foundation for the emergence of chordates. © 2015 Macmillan Publishers Limited. All rights reserved.
Darding M.,Mitchell Institute |
Meier P.,Mitchell Institute
Cell Death and Differentiation | Year: 2012
Deregulation of innate immune signalling and cell death form the basis of most human disease pathogenesis. Inhibitor of APoptosis (IAP) protein-family members are frequently overexpressed in cancer and contribute to tumour cell survival, chemo-resistance, disease progression and poor prognosis. Although best known for their ability to regulate caspases, IAPs also influence ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-κB. Recent advances in our understanding of the molecular mechanisms through which IAPs influence cell death and innate immune responses have provided new insights into novel strategies for treatment of cancer. In this review we discuss our current understanding of IAP-mediated NF-κB signalling, as well as elaborate on unexpected insights into the involvement of IAPs in regulating the Ripoptosome, a novel intrinsic cell death-inducing platform. We propose an evolutionarily conserved concept whereby IAPs function as guardians of killer platforms such as the apoptosome in Drosophila and the Ripoptosome in mammals. © 2012 Macmillan Publishers Limited All rights reserved.
Harris L.G.,Mitchell Institute |
Samant R.S.,Mitchell Institute |
Shevde L.A.,Mitchell Institute
Molecular Cancer Research | Year: 2011
In addition to its role in embryonic development, the Hedgehog pathway has been shown to be an active participant in cancer development, progression, and metastasis. Although this pathway is activated by autocrine signaling by Hedgehog ligands, it can also initiate paracrine signaling with cells in the microenvironment. This creates a network of Hedgehog signaling that determines the malignant behavior of the tumor cells. As a result of paracrine signal transmission, the effects of Hedgehog signaling most profoundly influence the stromal cells that constitute the tumor microenvironment. The stromal cells in turn produce factors that nurture the tumor. Thus, such a resonating cross-talk can amplify Hedgehog signaling, resulting in molecular chatter that overall promotes tumor progression. Inhibitors of Hedgehog signaling have been the subject of intense research. Several of these inhibitors are currently being evaluated in clinical trials. Here, we review the role of the Hedgehog pathway in the signature characteristics of cancer cells that determine tumor development, progression, and metastasis. This review condenses the latest findings on the signaling pathways that are activated and/or regulated by molecules generated from Hedgehog signaling in cancer and cites promising clinical interventions. Finally, we discuss future directions for identifying the appropriate patients for therapy, developing reliable markers of efficacy of treatment, and combating resistance to Hedgehog pathway inhibitors. ©2011 AACR.
Kudo K.,Mitchell Institute
Nucleic acids research | Year: 2010
We have developed a new approach to systematically study post-transcriptional regulation in a small number of cells. Actively translating mRNAs are associated with polysomes and the newly synthesized peptide chains are closely associated with molecular chaperones such as hsp70s, which assist in the proper folding of nascent polypeptides into higher ordered structures. These chaperones provide an anchor with which to separate actively translating mRNAs associated with polysomes from free mRNAs. Affinity capture beads were developed to capture hsp70 chaperones associated with the polysome complexes. The isolated actively translating mRNAs were used for high-throughput expression profiling analysis. Feasibility was demonstrated using an in vitro translation system with known translationally regulated mRNA transcript thymidylate synthase (TS). We further developed the approach using HCT-116 colon cancer cells with both TS and p53 as positive controls. The steady-state levels of TS and p53 mRNAs were unaltered after 5-fluorouracil treatment as assessed by real-time qRT-PCR analysis. In contrast, the protein expression and polysome-associated mRNA levels of both genes were increased. These differences in translational rate were revealed with our new approach from 500 cells. This technology has the potential to make investigation of translational control feasible with limited quantities of clinical specimens.
Lopez J.,Mitchell Institute |
Meier P.,Mitchell Institute
Current Opinion in Cell Biology | Year: 2010
The processes of dying are as tightly regulated as those of growth and proliferation, and together they establish a finely tuned balance that ensures proper organ size and function. Failure in the regulation of these responses lies at the heart of many human diseases. Certain members of the inhibitor of apoptosis (IAP) protein family function as important gatekeepers of cell death and survival. While IAPs can regulate cell death by controlling caspases, they also modulate other signalling processes that impact on cell viability. Probably the most important contribution of IAPs to cell survival and tumorigenesis resides in the ability of a number of IAPs to act as ubiquitin-E3 ligases regulating NF-κB signalling. Here, we discuss the latest insights into the ubiquitin-related roles of IAPs and how this contributes to the survival of cells and the organism. © 2010 Elsevier Ltd.