253 research outputs found
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Epitope Specificity Appears To Be an Important Determinant of In Vivo Killing Ability of Simian Immunodeficiency Virus (SIV)-Specific CD8+ T Cells
Quantification of lactoyl-CoA (lactyl-CoA) by liquid chromatography mass spectrometry in mammalian cells and tissues.
Lysine lactoylation is a recently described protein post-translational modification (PTM). However, the biochemical pathways responsible for this acylation remain unclear. Two metabolite-dependent mechanisms have been proposed: enzymatic histone lysine lactoylation derived from lactoyl-coenzyme A (lactoyl-CoA, also termed lactyl-CoA), and non-enzymatic lysine lactoylation resulting from acyl-transfer via lactoyl-glutathione. While the former has precedent in the form of enzyme-catalysed lysine acylation, the lactoyl-CoA metabolite has not been previously quantified in mammalian systems. Here, we use liquid chromatography-high-resolution mass spectrometry (LC-HRMS) together with a synthetic standard to detect and validate the presence of lactoyl-CoA in cell and tissue samples. Conducting a retrospective analysis of data from previously analysed samples revealed the presence of lactoyl-CoA in diverse cell and tissue contexts. In addition, we describe a biosynthetic route to generate 13C315N1-isotopically labelled lactoyl-CoA, providing a co-eluting internal standard for analysis of this metabolite. We estimate lactoyl-CoA concentrations of 1.14 Ă 10-8 pmol per cell in cell culture and 0.0172 pmol mg-1 tissue wet weight in mouse heart. These levels are similar to crotonyl-CoA, but between 20 and 350 times lower than predominant acyl-CoAs such as acetyl-, propionyl- and succinyl-CoA. Overall our studies provide the first quantitative measurements of lactoyl-CoA in metazoans, and provide a methodological foundation for the interrogation of this novel metabolite in biology and disease
Examining the role of transfer coupling in sub-barrier fusion of âŽâ¶,â”â°Ti+ÂčÂČâŽSn
Background: The presence of neutron transfer channels with positive Q values can enhance sub-barrier fusion
cross sections. Recent measurements of the fusion excitation functions for 58Ni +132,124Sn found that the fusion
enhancement due to the influence of neutron transfer is smaller than that in 40Ca +132,124Sn although the Q values
for multineutron transfer are comparable.
Purpose: To investigate the differences observed between the fusion of Sn + Ni and Sn + Ca.
Methods: Fusion excitation functions for 46,50Ti +124Sn have been measured at energies near the Coulomb barrier.
Results: A comparison of the barrier distributions for 46Ti +124Sn and 40Ca +124Sn shows that the 40Ca +124Sn
system has a barrier strength resulting from the coupling to the very collective octupole state in 40Ca at an energy
significantly lower than the uncoupled barrier.
Conclusions: The large sub-barrier fusion enhancement in 40Ca induced reactions is attributed to both couplings
to neutron transfer and inelastic excitation, with the octupole vibration of 40Ca playing a major role.Research at ANU was supported by the Australian Research Council Grants DP130101569, FT120100760, DP140101337,
FL110100098, DE140100784 and by National Collaborative
Research Infrastructure Strategy (NCRIS) for the operation of
the Heavy Ion Accelerator Facility
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Soil Respiration in a Northeastern US Temperate Forest: A 22-Year Synthesis
To better understand how forest management, phenology, vegetation type, and actual and simulated climatic change affect seasonal and inter-annual variations in soil respiration (R), we analyzed more than 100,000 individual measurements of soil respiration from 23 studies conducted over 22 years at the Harvard Forest in Petersham, Massachusetts, USA. We also used 24 site-years of eddy-covariance measurements from two Harvard Forest sites to examine the relationship between soil and ecosystem respiration (R).
R was highly variable at all spatial (respiration collar to forest stand) and temporal (minutes to years) scales of measurement. The response of R to experimental manipulations mimicking aspects of global change or aimed at partitioning R into component fluxes ranged from â70% to +52%. The response appears to arise from variations in substrate availability induced by changes in the size of soil C pools and of belowground C fluxes or in environmental conditions. In some cases (e.g., logging, warming), the effect of experimental manipulations on R was transient, but in other cases the time series were not long enough to rule out long-term changes in respiration rates. Inter-annual variations in weather and phenology induced variation among annual R estimates of a magnitude similar to that of other drivers of global change (i.e., invasive insects, forest management practices, N deposition). At both eddy-covariance sites, aboveground respiration dominated R early in the growing season, whereas belowground respiration dominated later. Unusual aboveground respiration patternsâhigh apparent rates of respiration during winter and very low rates in mid-to-late summerâat the Environmental Measurement Site suggest either bias in R and R estimates caused by differences in the spatial scale of processes influencing fluxes, or that additional research on the hard-to-measure fluxes (e.g., wintertime R, unaccounted losses of CO from eddy covariance sites), daytime and nighttime canopy respiration and its impacts on estimates of R, and independent measurements of flux partitioning (e.g., aboveground plant respiration, isotopic partitioning) may yield insight into the unusually high and low fluxes. Overall, however, this data-rich analysis identifies important seasonal and experimental variations in R and R and in the partitioning of R above- vs. belowground.Organismic and Evolutionary Biolog
The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe
The preponderance of matter over antimatter in the early Universe, the
dynamics of the supernova bursts that produced the heavy elements necessary for
life and whether protons eventually decay --- these mysteries at the forefront
of particle physics and astrophysics are key to understanding the early
evolution of our Universe, its current state and its eventual fate. The
Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed
plan for a world-class experiment dedicated to addressing these questions. LBNE
is conceived around three central components: (1) a new, high-intensity
neutrino source generated from a megawatt-class proton accelerator at Fermi
National Accelerator Laboratory, (2) a near neutrino detector just downstream
of the source, and (3) a massive liquid argon time-projection chamber deployed
as a far detector deep underground at the Sanford Underground Research
Facility. This facility, located at the site of the former Homestake Mine in
Lead, South Dakota, is approximately 1,300 km from the neutrino source at
Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino
charge-parity symmetry violation and mass ordering effects. This ambitious yet
cost-effective design incorporates scalability and flexibility and can
accommodate a variety of upgrades and contributions. With its exceptional
combination of experimental configuration, technical capabilities, and
potential for transformative discoveries, LBNE promises to be a vital facility
for the field of particle physics worldwide, providing physicists from around
the globe with opportunities to collaborate in a twenty to thirty year program
of exciting science. In this document we provide a comprehensive overview of
LBNE's scientific objectives, its place in the landscape of neutrino physics
worldwide, the technologies it will incorporate and the capabilities it will
possess.Comment: Major update of previous version. This is the reference document for
LBNE science program and current status. Chapters 1, 3, and 9 provide a
comprehensive overview of LBNE's scientific objectives, its place in the
landscape of neutrino physics worldwide, the technologies it will incorporate
and the capabilities it will possess. 288 pages, 116 figure
Integrin CD11b activation drives anti-tumor innate immunity
Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth. CD11b activation promotes pro-inflammatory macrophage polarization by stimulating expression of microRNA Let7a. In contrast, inhibition of CD11b prevents Let7a expression and induces cMyc expression, leading to immune suppressive macrophage polarization, vascular maturation, and accelerated tumor growth. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy
Tumor-specific expression of αvÎČ3 integrin promotes spontaneous metastasis of breast cancer to bone
INTRODUCTION: Studies in xenograft models and experimental models of metastasis have implicated several ÎČ3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific αvÎČ3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. METHODS: We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of αvÎČ3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of αvÎČ3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. RESULTS: The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. αvÎČ3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, αvÎČ3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, αvÎČ3 increased 66cl4 tumor cell adhesion and αvÎČ3-dependent haptotactic migration towards bone matrix proteins, as well as their chemotactic response to bone-derived soluble factors in vitro. CONCLUSION: These results demonstrate for the first time that tumor-specific αvÎČ3 contributes to spontaneous metastasis of breast tumors to bone and suggest a critical role for this receptor in mediating chemotactic and haptotactic migration towards bone factors
COSORE: A community database for continuous soil respiration and other soilâatmosphere greenhouse gas flux data
Globally, soils store two to three times as much carbon as currently resides in the atmosphere, and it is critical to understand how soil greenhouse gas (GHG) emissions and uptake will respond to ongoing climate change. In particular, the soilâtoâatmosphere CO2 flux, commonly though imprecisely termed soil respiration (RS), is one of the largest carbon fluxes in the Earth system. An increasing number of highâfrequency RS measurements (typically, from an automated system with hourly sampling) have been made over the last two decades; an increasing number of methane measurements are being made with such systems as well. Such high frequency data are an invaluable resource for understanding GHG fluxes, but lack a central database or repository. Here we describe the lightweight, openâsource COSORE (COntinuous SOil REspiration) database and software, that focuses on automated, continuous and longâterm GHG flux datasets, and is intended to serve as a community resource for earth sciences, climate change syntheses and model evaluation. Contributed datasets are mapped to a single, consistent standard, with metadata on contributors, geographic location, measurement conditions and ancillary data. The design emphasizes the importance of reproducibility, scientific transparency and open access to data. While being oriented towards continuously measured RS, the database design accommodates other soilâatmosphere measurements (e.g. ecosystem respiration, chamberâmeasured net ecosystem exchange, methane fluxes) as well as experimental treatments (heterotrophic only, etc.). We give brief examples of the types of analyses possible using this new community resource and describe its accompanying R software package
Low exposure long-baseline neutrino oscillation sensitivity of the DUNE experiment
The Deep Underground Neutrino Experiment (DUNE) will produce world-leading
neutrino oscillation measurements over the lifetime of the experiment. In this
work, we explore DUNE's sensitivity to observe charge-parity violation (CPV) in
the neutrino sector, and to resolve the mass ordering, for exposures of up to
100 kiloton-megawatt-years (kt-MW-yr). The analysis includes detailed
uncertainties on the flux prediction, the neutrino interaction model, and
detector effects. We demonstrate that DUNE will be able to unambiguously
resolve the neutrino mass ordering at a 3 (5) level, with a 66
(100) kt-MW-yr far detector exposure, and has the ability to make strong
statements at significantly shorter exposures depending on the true value of
other oscillation parameters. We also show that DUNE has the potential to make
a robust measurement of CPV at a 3 level with a 100 kt-MW-yr exposure
for the maximally CP-violating values \delta_{\rm CP}} = \pm\pi/2.
Additionally, the dependence of DUNE's sensitivity on the exposure taken in
neutrino-enhanced and antineutrino-enhanced running is discussed. An equal
fraction of exposure taken in each beam mode is found to be close to optimal
when considered over the entire space of interest
Identification and reconstruction of low-energy electrons in the ProtoDUNE-SP detector
Measurements of electrons from interactions are crucial for the Deep
Underground Neutrino Experiment (DUNE) neutrino oscillation program, as well as
searches for physics beyond the standard model, supernova neutrino detection,
and solar neutrino measurements. This article describes the selection and
reconstruction of low-energy (Michel) electrons in the ProtoDUNE-SP detector.
ProtoDUNE-SP is one of the prototypes for the DUNE far detector, built and
operated at CERN as a charged particle test beam experiment. A sample of
low-energy electrons produced by the decay of cosmic muons is selected with a
purity of 95%. This sample is used to calibrate the low-energy electron energy
scale with two techniques. An electron energy calibration based on a cosmic ray
muon sample uses calibration constants derived from measured and simulated
cosmic ray muon events. Another calibration technique makes use of the
theoretically well-understood Michel electron energy spectrum to convert
reconstructed charge to electron energy. In addition, the effects of detector
response to low-energy electron energy scale and its resolution including
readout electronics threshold effects are quantified. Finally, the relation
between the theoretical and reconstructed low-energy electron energy spectrum
is derived and the energy resolution is characterized. The low-energy electron
selection presented here accounts for about 75% of the total electron deposited
energy. After the addition of lost energy using a Monte Carlo simulation, the
energy resolution improves from about 40% to 25% at 50~MeV. These results are
used to validate the expected capabilities of the DUNE far detector to
reconstruct low-energy electrons.Comment: 19 pages, 10 figure
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