121 research outputs found
Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G
Background:
The activating immunoreceptor NKG2D is expressed on Natural Killer (NK) cells and subsets of T cells. NKG2D contributes to anti-tumour and anti-viral immune responses in vitro and in vivo. The ligands for NKG2D in humans are diverse proteins of the MIC and ULBP/RAET families that are upregulated on the surface of virally infected cells and tumours. Two splicing variants of ULBP5/RAET1G have been cloned previously, but not extensively characterised.
Methodology/Principal Findings:
We pursue a number of approaches to characterise the expression, trafficking, and function of the two isoforms of ULBP5/RAET1G. We show that both transcripts are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers. The full-length transcript, RAET1G1, is predicted to encode a molecule with transmembrane and cytoplasmic domains that are unique amongst NKG2D ligands. Using specific anti-RAET1G1 antiserum to stain tissue microarrays we show that RAET1G1 expression is highly restricted in normal tissues. RAET1G1 was expressed at a low level in normal gastrointestinal epithelial cells in a similar pattern to MICA. Both RAET1G1 and MICA showed increased expression in the gut of patients with celiac disease. In contrast to healthy tissues the RAET1G1 antiserum stained a wide variety or different primary tumour sections. Both endogenously expressed and transfected RAET1G1 was mainly found inside the cell, with a minority of the protein reaching the cell surface. Conversely the truncated splicing variant of RAET1G2 was shown to encode a soluble molecule that could be secreted from cells. Secreted RAET1G2 was shown to downregulate NKG2D receptor expression on NK cells and hence may represent a novel tumour immune evasion strategy.
Conclusions/Significance:
We demonstrate that the expression patterns of ULBP5RAET1G are very similar to the well-characterised NKG2D ligand, MICA. However the two isoforms of ULBP5/RAET1G have very different cellular localisations that are likely to reflect unique functionality
NK Cell Terminal Differentiation: Correlated Stepwise Decrease of NKG2A and Acquisition of KIRs
BACKGROUND: Terminal differentiation of NK cells is crucial in maintaining broad responsiveness to pathogens and discriminating normal cells from cells in distress. Although it is well established that KIRs, in conjunction with NKG2A, play a major role in the NK cell education that determines whether cells will end up competent or hyporesponsive, the events underlying the differentiation are still debated. METHODOLOGY/PRINCIPAL FINDINGS: A combination of complementary approaches to assess the kinetics of the appearance of each subset during development allowed us to obtain new insights into these terminal stages of differentiation, characterising their gene expression profiles at a pan-genomic level, their distinct surface receptor patterns and their prototypic effector functions. The present study supports the hypothesis that CD56dim cells derive from the CD56bright subset and suggests that NK cell responsiveness is determined by persistent inhibitory signals received during their education. We report here the inverse correlation of NKG2A expression with KIR expression and explore whether this correlation bestows functional competence on NK cells. We show that CD56dimNKG2A-KIR+ cells display the most differentiated phenotype associated to their unique ability to respond against HLA-E+ target cells. Importantly, after IL-12+IL-18 stimulation, reacquisition of NKG2A strongly correlates with IFN-gamma production in CD56dimNKG2A- NK cells. CONCLUSIONS/SIGNIFICANCE: Together, these findings call for the reclassification of mature human NK cells into distinct subsets and support a new model, in which the NK cell differentiation and functional fate are based on a stepwise decrease of NKG2A and acquisition of KIRs
Exceptional Diversity, Non-Random Distribution, and Rapid Evolution of Retroelements in the B73 Maize Genome
Recent comprehensive sequence analysis of the maize genome now permits detailed discovery and description of all transposable elements (TEs) in this complex nuclear environment. Reiteratively optimized structural and homology criteria were used in the computer-assisted search for retroelements, TEs that transpose by reverse transcription of an RNA intermediate, with the final results verified by manual inspection. Retroelements were found to occupy the majority (>75%) of the nuclear genome in maize inbred B73. Unprecedented genetic diversity was discovered in the long terminal repeat (LTR) retrotransposon class of retroelements, with >400 families (>350 newly discovered) contributing >31,000 intact elements. The two other classes of retroelements, SINEs (four families) and LINEs (at least 30 families), were observed to contribute 1,991 and ∼35,000 copies, respectively, or a combined ∼1% of the B73 nuclear genome. With regard to fully intact elements, median copy numbers for all retroelement families in maize was 2 because >250 LTR retrotransposon families contained only one or two intact members that could be detected in the B73 draft sequence. The majority, perhaps all, of the investigated retroelement families exhibited non-random dispersal across the maize genome, with LINEs, SINEs, and many low-copy-number LTR retrotransposons exhibiting a bias for accumulation in gene-rich regions. In contrast, most (but not all) medium- and high-copy-number LTR retrotransposons were found to preferentially accumulate in gene-poor regions like pericentromeric heterochromatin, while a few high-copy-number families exhibited the opposite bias. Regions of the genome with the highest LTR retrotransposon density contained the lowest LTR retrotransposon diversity. These results indicate that the maize genome provides a great number of different niches for the survival and procreation of a great variety of retroelements that have evolved to differentially occupy and exploit this genomic diversity
Searches for Neutrinos from Large High Altitude Air Shower Observatory Ultra-high-energy γ-Ray Sources Using the IceCube Neutrino Observatory
Measurement of atmospheric neutrino mixing with improved IceCube DeepCore calibration and data processing
We describe a new data sample of IceCube DeepCore and report on the latest measurement of atmospheric neutrino oscillations obtained with data recorded between 2011–2019. The sample includes significant improvements in data calibration, detector simulation, and data processing, and the analysis benefits from a sophisticated treatment of systematic uncertainties, with significantly greater level of detail since our last study. By measuring the relative fluxes of neutrino flavors as a function of their reconstructed energies and arrival directions we constrain the atmospheric neutrino mixing parameters to be sin2θ23=0.51±0.05 and Δm232=2.41±0.07×10−3 eV2, assuming a normal mass ordering. The errors include both statistical and systematic uncertainties. The resulting 40% reduction in the error of both parameters with respect to our previous result makes this the most precise measurement of oscillation parameters using atmospheric neutrinos. Our results are also compatible and complementary to those obtained using neutrino beams from accelerators, which are obtained at lower neutrino energies and are subject to different sources of uncertainties
Searches for Neutrinos from LHAASO ultra-high-energy {\gamma}-ray sources using the IceCube Neutrino Observatory
Galactic PeVatrons are Galactic sources theorized to accelerate cosmic rays
up to PeV in energy. The accelerated cosmic rays are expected to interact
hadronically with nearby ambient gas or the interstellar medium, resulting in
{\gamma}-rays and neutrinos. Recently, the Large High Altitude Air Shower
Observatory (LHAASO) identified 12 {\gamma}-ray sources with emissions above
100 TeV, making them candidates for PeV cosmic-ray accelerators (PeVatrons).
While at these high energies the Klein-Nishina effect suppresses exponentially
leptonic emission from Galactic sources, evidence for neutrino emission would
unequivocally confirm hadronic acceleration. Here, we present the results of a
search for neutrinos from these {\gamma}-ray sources and stacking searches
testing for excess neutrino emission from all 12 sources as well as their
subcatalogs of supernova remnants and pulsar wind nebulae with 11 years of
track events from the IceCube Neutrino Observatory. No significant emissions
were found. Based on the resulting limits, we place constraints on the fraction
of {\gamma}-ray flux originating from the hadronic processes in the Crab Nebula
and LHAASOJ2226+6057
A Search for Coincident Neutrino Emission from Fast Radio Bursts with Seven Years of IceCube Cascade Events
This paper presents the results of a search for neutrinos that are spatially
and temporally coincident with 22 unique, non-repeating Fast Radio Bursts
(FRBs) and one repeating FRB (FRB121102). FRBs are a rapidly growing class of
Galactic and extragalactic astrophysical objects that are considered a
potential source of high-energy neutrinos. The IceCube Neutrino Observatory's
previous FRB analyses have solely used track events. This search utilizes seven
years of IceCube's cascade events which are statistically independent of the
track events. This event selection allows probing of a longer range of extended
timescales due to the low background rate. No statistically significant
clustering of neutrinos was observed. Upper limits are set on the
time-integrated neutrino flux emitted by FRBs for a range of extended
time-windows
Limits on Neutrino Emission from GRB 221009A from MeV to PeV using the IceCube Neutrino Observatory
Gamma-ray bursts (GRBs) have long been considered a possible source of
high-energy neutrinos. While no correlations have yet been detected between
high-energy neutrinos and GRBs, the recent observation of GRB 221009A - the
brightest GRB observed by Fermi-GBM to date and the first one to be observed
above an energy of 10 TeV - provides a unique opportunity to test for hadronic
emission. In this paper, we leverage the wide energy range of the IceCube
Neutrino Observatory to search for neutrinos from GRB 221009A. We find no
significant deviation from background expectation across event samples ranging
from MeV to PeV energies, placing stringent upper limits on the neutrino
emission from this source.Comment: Version in ApJ Letters Focus on the Ultra-luminous Gamma-Ray Burst
GRB 221009
Measurement of Atmospheric Neutrino Mixing with Improved IceCube DeepCore Calibration and Data Processing
We describe a new data sample of IceCube DeepCore and report on the latest
measurement of atmospheric neutrino oscillations obtained with data recorded
between 2011-2019. The sample includes significant improvements in data
calibration, detector simulation, and data processing, and the analysis
benefits from a detailed treatment of systematic uncertainties, with
significantly higher level of detail since our last study. By measuring the
relative fluxes of neutrino flavors as a function of their reconstructed
energies and arrival directions we constrain the atmospheric neutrino mixing
parameters to be and , assuming a normal mass ordering. The
resulting 40\% reduction in the error of both parameters with respect to our
previous result makes this the most precise measurement of oscillation
parameters using atmospheric neutrinos. Our results are also compatible and
complementary to those obtained using neutrino beams from accelerators, which
are obtained at lower neutrino energies and are subject to different sources of
uncertainties
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