648 research outputs found
The role of host PrP in Transmissible Spongiform Encephalopathies
AbstractPrP has a central role in the Transmissible Spongiform Encephalopathies (TSEs), and mutations and polymorphisms in host PrP can profoundly alter the host's susceptibility to a TSE agent. However, precisely how host PrP influences the outcome of disease has not been established. To investigate this we have produced by gene targeting a series of inbred lines of transgenic mice expressing different PrP genes. This allows us to study directly the influence of the host PrP gene in TSEs. We have examined the role of glycosylation, point mutations, polymorphisms and PrP from different species on host susceptibility and the disease process both within the murine species and across species barriers
METTL13 methylation of eEF1A increases translational output to promote tumorigenesis
Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.We thank Pal Falnes, Jerry Pelletier, and Julien Sage for helpful discussion, Lauren Brown and William Devine for SDS-1-021, and members of the Gozani and Mazur laboratories for critical reading of the manuscript. This work was supported in part by grants from the NIH to S.M.C. (K99CA190803), M.P.K. (5K08CA218690-02), J.A.P. (R35GM118173), M.C.B. (1DP2HD084069-01), J.S. (1R35GM119721), I.T. (R01CA202021), P.K.M. (R00CA197816, P50CA070907, and P30CA016672), and O.G. (R01GM079641). J.E.E. received support from Stanford ChEM-H, and A.M. was supported by the MD Anderson Moonshot Program. I.T. is a Junior 2 Research Scholar of the Fonds de Recherche du Quebec - Sante (FRQ-S). P.K.M. is supported by the Neuroendocrine Tumor Research Foundation and American Association for Cancer Research and is the Andrew Sabin Family Foundation Scientist and CPRIT scholar (RR160078). S.H. is supported by a Deutsche Forschungsgemeinschaft Postdoctoral Fellowship. J.W.F. is supported by 5T32GM007276. (K99CA190803 - NIH; 5K08CA218690-02 - NIH; R35GM118173 - NIH; 1DP2HD084069-01 - NIH; 1R35GM119721 - NIH; R01CA202021 - NIH; R00CA197816 - NIH; P50CA070907 - NIH; P30CA016672 - NIH; R01GM079641 - NIH; Stanford ChEM-H; MD Anderson Moonshot Program; Neuroendocrine Tumor Research Foundation; American Association for Cancer Research; Deutsche Forschungsgemeinschaft Postdoctoral Fellowship; 5T32GM007276)Supporting documentationAccepted manuscrip
Sediment Cores from White Pond, South Carolina, contain a Platinum Anomaly, Pyrogenic Carbon Peak, and Coprophilous Spore Decline at 12.8 ka
A widespread platinum (Pt) anomaly was recently documented in Greenland ice and 11 North American sedimentary sequences at the onset of the Younger Dryas (YD) event (~12,800 cal yr BP), consistent with the YD Impact Hypothesis. We report high-resolution analyses of a 1-meter section of a lake core from White Pond, South Carolina, USA. After developing a Bayesian age-depth model that brackets the late Pleistocene through early Holocene, we analyzed and quantified the following: (1) Pt and palladium (Pd) abundance, (2) geochemistry of 58 elements, (3) coprophilous spores, (4) sedimentary organic matter (OC and sedaDNA), (5) stable isotopes of C (δ13C) and N (δ15N), (6) soot, (7) aciniform carbon, (8) cryptotephra, (9) mercury (Hg), and (10) magnetic susceptibility. We identified large Pt and Pt/Pd anomalies within a 2-cm section dated to the YD onset (12,785 ± 58 cal yr BP). These anomalies precede a decline in coprophilous spores and correlate with an abrupt peak in soot and C/OC ratios, indicative of large-scale regional biomass burning. We also observed a relatively large excursion in δ15N values, indicating rapid climatic and environmental/hydrological changes at the YD onset. Our results are consistent with the YD Impact Hypothesis and impact-related environmental and ecological changes
Upper ocean ecosystem dynamics and iron cycling in a global three-dimensional model
Author Posting. © American Geophysical Union, 2004. 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 18 (2004): GB4028, doi:10.1029/2004GB002220.A global three-dimensional marine ecosystem model with several key phytoplankton functional groups, multiple limiting nutrients, explicit iron cycling, and a mineral ballast/organic matter parameterization is run within a global ocean circulation model. The coupled biogeochemistry/ecosystem/circulation (BEC) model reproduces known basin-scale patterns of primary and export production, biogenic silica production, calcification, chlorophyll, macronutrient and dissolved iron concentrations. The model captures observed high nitrate, low chlorophyll (HNLC) conditions in the Southern Ocean, subarctic and equatorial Pacific. Spatial distributions of nitrogen fixation are in general agreement with field data, with total N-fixation of 55 Tg N. Diazotrophs directly account for a small fraction of primary production (0.5%) but indirectly support 10% of primary production and 8% of sinking particulate organic carbon (POC) export. Diatoms disproportionately contribute to export of POC out of surface waters, but CaCO3 from the coccolithophores is the key driver of POC flux to the deep ocean in the model. An iron source from shallow ocean sediments is found critical in preventing iron limitation in shelf regions, most notably in the Arctic Ocean, but has a relatively localized impact. In contrast, global-scale primary production, export production, and nitrogen fixation are all sensitive to variations in atmospheric mineral dust inputs. The residence time for dissolved iron in the upper ocean is estimated to be a few years to a decade. Most of the iron utilized by phytoplankton is from subsurface sources supplied by mixing, entrainment, and ocean circulation. However, owing to the short residence time of iron in the upper ocean, this subsurface iron pool is critically dependent on continual replenishment from atmospheric dust deposition and, to a lesser extent, lateral transport from shelf regions.This work was funded
by NSF grant OCE-0222033 and the National Center for Atmospheric
Research
Earthquakes: from chemical alteration to mechanical rupture
In the standard rebound theory of earthquakes, elastic deformation energy is
progressively stored in the crust until a threshold is reached at which it is
suddenly released in an earthquake. We review three important paradoxes, the
strain paradox, the stress paradox and the heat flow paradox, that are
difficult to account for in this picture, either individually or when taken
together. Resolutions of these paradoxes usually call for additional
assumptions on the nature of the rupture process (such as novel modes of
deformations and ruptures) prior to and/or during an earthquake, on the nature
of the fault and on the effect of trapped fluids within the crust at
seismogenic depths. We review the evidence for the essential importance of
water and its interaction with the modes of deformations. Water is usually seen
to have mainly the mechanical effect of decreasing the normal lithostatic
stress in the fault core on one hand and to weaken rock materials via
hydrolytic weakening and stress corrosion on the other hand. We also review the
evidences that water plays a major role in the alteration of minerals subjected
to finite strains into other structures in out-of-equilibrium conditions. This
suggests novel exciting routes to understand what is an earthquake, that
requires to develop a truly multidisciplinary approach involving mineral
chemistry, geology, rupture mechanics and statistical physics.Comment: 44 pages, 1 figures, submitted to Physics Report
ATHENA: A knowledge-based hybrid backpropagation-grammatical evolution neural network algorithm for discovering epistasis among quantitative trait Loci
<p>Abstract</p> <p>Background</p> <p>Growing interest and burgeoning technology for discovering genetic mechanisms that influence disease processes have ushered in a flood of genetic association studies over the last decade, yet little heritability in highly studied complex traits has been explained by genetic variation. Non-additive gene-gene interactions, which are not often explored, are thought to be one source of this "missing" heritability.</p> <p>Methods</p> <p>Stochastic methods employing evolutionary algorithms have demonstrated promise in being able to detect and model gene-gene and gene-environment interactions that influence human traits. Here we demonstrate modifications to a neural network algorithm in ATHENA (the Analysis Tool for Heritable and Environmental Network Associations) resulting in clear performance improvements for discovering gene-gene interactions that influence human traits. We employed an alternative tree-based crossover, backpropagation for locally fitting neural network weights, and incorporation of domain knowledge obtainable from publicly accessible biological databases for initializing the search for gene-gene interactions. We tested these modifications <it>in silico </it>using simulated datasets.</p> <p>Results</p> <p>We show that the alternative tree-based crossover modification resulted in a modest increase in the sensitivity of the ATHENA algorithm for discovering gene-gene interactions. The performance increase was highly statistically significant when backpropagation was used to locally fit NN weights. We also demonstrate that using domain knowledge to initialize the search for gene-gene interactions results in a large performance increase, especially when the search space is larger than the search coverage.</p> <p>Conclusions</p> <p>We show that a hybrid optimization procedure, alternative crossover strategies, and incorporation of domain knowledge from publicly available biological databases can result in marked increases in sensitivity and performance of the ATHENA algorithm for detecting and modelling gene-gene interactions that influence a complex human trait.</p
Diffractive Dijet Production at sqrt(s)=630 and 1800 GeV at the Fermilab Tevatron
We report a measurement of the diffractive structure function of
the antiproton obtained from a study of dijet events produced in association
with a leading antiproton in collisions at GeV at the
Fermilab Tevatron. The ratio of at GeV to
obtained from a similar measurement at GeV is compared with
expectations from QCD factorization and with theoretical predictions. We also
report a measurement of the (-Pomeron) and ( of parton in
Pomeron) dependence of at GeV. In the region
, GeV and , is
found to be of the form , which obeys
- factorization.Comment: LaTeX, 9 pages, Submitted to Phys. Rev. Letter
Measurement of the B0 anti-B0 oscillation frequency using l- D*+ pairs and lepton flavor tags
The oscillation frequency Delta-md of B0 anti-B0 mixing is measured using the
partially reconstructed semileptonic decay anti-B0 -> l- nubar D*+ X. The data
sample was collected with the CDF detector at the Fermilab Tevatron collider
during 1992 - 1995 by triggering on the existence of two lepton candidates in
an event, and corresponds to about 110 pb-1 of pbar p collisions at sqrt(s) =
1.8 TeV. We estimate the proper decay time of the anti-B0 meson from the
measured decay length and reconstructed momentum of the l- D*+ system. The
charge of the lepton in the final state identifies the flavor of the anti-B0
meson at its decay. The second lepton in the event is used to infer the flavor
of the anti-B0 meson at production. We measure the oscillation frequency to be
Delta-md = 0.516 +/- 0.099 +0.029 -0.035 ps-1, where the first uncertainty is
statistical and the second is systematic.Comment: 30 pages, 7 figures. Submitted to Physical Review
Search for New Particles Decaying to top-antitop in proton-antiproton collisions at squareroot(s)=1.8 TeV
We use 106 \ipb of data collected with the Collider Detector at Fermilab to
search for narrow-width, vector particles decaying to a top and an anti-top
quark. Model independent upper limits on the cross section for narrow, vector
resonances decaying to \ttbar are presented. At the 95% confidence level, we
exclude the existence of a leptophobic \zpr boson in a model of
topcolor-assisted technicolor with mass M_{\zpr} 480 \gev for natural
width = 0.012 M_{\zpr}, and M_{\zpr} 780 \gev for =
0.04 M_{\zpr}.Comment: The CDF Collaboration, submitted to PRL 25-Feb-200
- …