283 research outputs found
Theory Summary and Future Directions
Summary talk at the Lepton-Photon Symposium, Cornell University, Aug. 10-15,
1993.Comment: (Talk presented at the Lepton-Photon Symposium, Cornell University,
Aug. 10-15, 1993.) 19 page
Arrays of MEMS-based actuators for control of supersonic jet screech
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76460/1/AIAA-1997-1963-653.pd
Intrinsic function of the peptidylarginine deiminase PADI4 is dispensable for normal haematopoiesis.
Peptidylarginine deiminases (PADIs) are strongly associated with the development of autoimmunity, neurodegeneration and cancer but their physiological roles are ill-defined. The nuclear deiminase PADI4 regulates pluripotency in the mammalian pre-implantation embryo but its function in tissue development is unknown. PADI4 is primarily expressed in the bone marrow, as part of a self-renewal-associated gene signature. It has been shown to regulate the proliferation of multipotent haematopoietic progenitors and proposed to impact on the differentiation of haematopoietic stem cells (HSCs), suggesting that it controls haematopoietic development or regeneration. Using conditional in vivo models of steady state and acute Padi4 ablation, we examined the role of PADI4 in the development and function of the haematopoietic system. We found that PADI4 loss does not significantly affect HSC self-renewal or differentiation potential upon injury or serial transplantation, nor does it lead to HSC exhaustion or premature ageing. Thus PADI4 is dispensable for cell-autonomous HSC maintenance, differentiation and haematopoietic regeneration. This work represents the first study of PADI4 in tissue development and indicates that pharmacological PADI4 inhibition may be tolerated without adverse effects
Background Rejection in the DMTPC Dark Matter Search Using Charge Signals
The Dark Matter Time Projection Chamber (DMTPC) collaboration is developing
low-pressure gas TPC detectors for measuring WIMP-nucleon interactions. Optical
readout with CCD cameras allows for the detection for the daily modulation in
the direction of the dark matter wind, while several charge readout channels
allow for the measurement of additional recoil properties. In this article, we
show that the addition of the charge readout analysis to the CCD allows us too
obtain a statistics-limited 90% C.L. upper limit on the rejection factor
of for recoils with energies between 40 and 200
keV. In addition, requiring coincidence between charge signals
and light in the CCD reduces CCD-specific backgrounds by more than two orders
of magnitude.Comment: 8 pages, 6 figures. For proceedings of DPF 2011 conferenc
Positron-molecule interactions: resonant attachment, annihilation, and bound states
This article presents an overview of current understanding of the interaction
of low-energy positrons with molecules with emphasis on resonances, positron
attachment and annihilation. Annihilation rates measured as a function of
positron energy reveal the presence of vibrational Feshbach resonances (VFR)
for many polyatomic molecules. These resonances lead to strong enhancement of
the annihilation rates. They also provide evidence that positrons bind to many
molecular species. A quantitative theory of VFR-mediated attachment to small
molecules is presented. It is tested successfully for selected molecules (e.g.,
methyl halides and methanol) where all modes couple to the positron continuum.
Combination and overtone resonances are observed and their role is elucidated.
In larger molecules, annihilation rates from VFR far exceed those explicable on
the basis of single-mode resonances. These enhancements increase rapidly with
the number of vibrational degrees of freedom. While the details are as yet
unclear, intramolecular vibrational energy redistribution to states that do not
couple directly to the positron continuum appears to be responsible for these
enhanced annihilation rates. Downshifts of the VFR from the vibrational mode
energies have provided binding energies for thirty species. Their dependence
upon molecular parameters and their relationship to positron-atom and
positron-molecule binding energy calculations are discussed. Feshbach
resonances and positron binding to molecules are compared with the analogous
electron-molecule (negative ion) cases. The relationship of VFR-mediated
annihilation to other phenomena such as Doppler-broadening of the gamma-ray
annihilation spectra, annihilation of thermalized positrons in gases, and
annihilation-induced fragmentation of molecules is discussed.Comment: 50 pages, 40 figure
Gaseous Dark Matter Detectors
Dark Matter detectors with directional sensitivity have the potential of
yielding an unambiguous positive observation of WIMPs as well as discriminating
between galactic Dark Matter halo models. In this article, we introduce the
motivation for directional detectors, discuss the experimental techniques that
make directional detection possible, and review the status of the experimental
effort in this field.Comment: 19 pages, review on gaseous directional dark matter detectors
submitted to New Journal of Physic
Photoelectric Emission from Interstellar Dust: Grain Charging and Gas Heating
We model the photoelectric emission from and charging of interstellar dust
and obtain photoelectric gas heating efficiencies as a function of grain size
and the relevant ambient conditions. Using realistic grain size distributions,
we evaluate the net gas heating rate for various interstellar environments, and
find less heating for dense regions characterized by R_V=5.5 than for diffuse
regions with R_V=3.1. We provide fitting functions which reproduce our
numerical results for photoelectric heating and recombination cooling for a
wide range of interstellar conditions. In a separate paper we will examine the
implications of these results for the thermal structure of the interstellar
medium. Finally, we investigate the potential importance of photoelectric
heating in H II regions, including the warm ionized medium. We find that
photoelectric heating could be comparable to or exceed heating due to
photoionization of H for high ratios of the radiation intensity to the gas
density. We also find that photoelectric heating by dust can account for the
observed variation of temperature with distance from the galactic midplane in
the warm ionized medium.Comment: 50 pages, including 18 figures; corrected title and abstract field
Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities.
The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) > 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.We thank T. Jacks (Kras^LSL-G12D), A. Berns (p53^Fx) and the NIH Mouse repository for mice. We also thank Sam Kleeman and Patricia Ogger for assistance with redox cell profiling and cell viability assays, respectively. We are very thankful to CRUK CI BRU staff for support with in vivo work and all the members of the Martins lab for critical comments and advice. This work was supported by the Medical Research Council.This is the author accepted manuscript. The final version is available at http://www.nature.com/nature/journal/v531/n7592/full/nature16967.html
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence(1,2). Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies(3). To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma(4,5). We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth
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