1,484 research outputs found
Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells
It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions
Promoter polymorphisms of DNMT3B and the risk of colorectal cancer in Chinese: a case-control study
<p>Abstract</p> <p>Background</p> <p>DNA-methyltransferase-3B (DNMT3B), which plays a role in DNA methylation, is usually aberrant expression involved in carcinogenesis. Polymorphisms of the DNMT3B gene may influence DNMT3B activity on DNA methylation in several cancers, thereby modulating the susceptibility to cancer.</p> <p>Methods</p> <p>DNMT3B -579G>T genotypes and -149C>T were determined by PCR-RFLP and sequencing in 137 colorectal cancer patients and 308 controls matched for age and sex, who did not receive radiotherapy or chemotherapy for newly diagnosed and histopathologically confirmed colorectal cancer. The association between two SNPs of the <it>DNMT3B </it>promoter and the risk of the development of colorectal cancer was analyzed in a population of Chinese.</p> <p>Results</p> <p>The allele frequency of -149C >T among patients and controls was 0.73% versus 0.65%, respectively. The allele frequency of -597G>T for patients and controls was 6.57% versus 11.53%, respectively. Individuals with at least one -149C>T allele were no at a significantly increase risk of colorectal cancer compared with those having a -149TT genotype. However, Individuals with at least one 579G>T allele were decreased risk of colorectal cancer compared with those having a -579TT genotype.</p> <p>Conclusion</p> <p>The relative distribution of -149C>T <it>DNMT3B </it>SNPs among a Chinese population can not be used as a stratification marker to predict an individual's susceptibility to colorectal cancer. However, the DNMT3B -579G>T polymorphism may contribute to the genetic susceptibility to colorectal cancer.</p
A New Era in the Quest for Dark Matter
There is a growing sense of `crisis' in the dark matter community, due to the
absence of evidence for the most popular candidates such as weakly interacting
massive particles, axions, and sterile neutrinos, despite the enormous effort
that has gone into searching for these particles. Here, we discuss what we have
learned about the nature of dark matter from past experiments, and the
implications for planned dark matter searches in the next decade. We argue that
diversifying the experimental effort, incorporating astronomical surveys and
gravitational wave observations, is our best hope to make progress on the dark
matter problem.Comment: Published in Nature, online on 04 Oct 2018. 13 pages, 1 figur
Impact of facial conformation on canine health: Brachycephalic Obstructive Airway Syndrome
The domestic dog may be the most morphologically diverse terrestrial mammalian species known to man; pedigree dogs are artificially selected for extreme aesthetics dictated by formal Breed Standards, and breed-related disorders linked to conformation are ubiquitous and diverse. Brachycephaly–foreshortening of the facial skeleton–is a discrete mutation that has been selected for in many popular dog breeds e.g. the Bulldog, Pug, and French Bulldog. A chronic, debilitating respiratory syndrome, whereby soft tissue blocks the airways, predominantly affects dogs with this conformation, and thus is labelled Brachycephalic Obstructive Airway Syndrome (BOAS). Despite the name of the syndrome, scientific evidence quantitatively linking brachycephaly with BOAS is lacking, but it could aid efforts to select for healthier conformations. Here we show, in (1) an exploratory study of 700 dogs of diverse breeds and conformations, and (2) a confirmatory study of 154 brachycephalic dogs, that BOAS risk increases sharply in a non-linear manner as relative muzzle length shortens. BOAS only occurred in dogs whose muzzles comprised less than half their cranial lengths. Thicker neck girths also increased BOAS risk in both populations: a risk factor for human sleep apnoea and not previously realised in dogs; and obesity was found to further increase BOAS risk. This study provides evidence that breeding for brachycephaly leads to an increased risk of BOAS in dogs, with risk increasing as the morphology becomes more exaggerated. As such, dog breeders and buyers should be aware of this risk when selecting dogs, and breeding organisations should actively discourage exaggeration of this high-risk conformation in breed standards and the show ring
Regulation of rat intrapulmonary arterial tone by arachidonic acid and prostaglandin E2 during hypoxia
Aims Arachidonic acid (AA) and its metabolites, prostaglandins (PG) are known to be involved in regulation of vascular homeostasis including vascular tone and vessel wall tension, but their potential role in Hypoxic pulmonary vasoconstriction (HPV) remains unclear. In this study, we examined the effects of AA and PGE2 on the hypoxic response in isolated rat intrapulmonary arteries (IPAs). Methods and Results We carried out the investigation on IPAs by vessel tension measurement. Isotetrandrine (20 µM) significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. Both indomethacin (100 µM) and NS398 attenuated KPSS-induced vessel contraction and phase I, phase IIb and phase IIc of HPV, implying that COX-2 plays a primary role in the hypoxic response of rat IPAs. PGE2 alone caused a significant vasoconstriction in isolated rat IPAs. This constriction is mediated by EP4. Blockage of EP4 by L-161982 (1 µM) significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. However, AH6809 (3 µM), an antagonist of EP1, EP2, EP3 and DP1 receptors, exerted no effect on KPSS or hypoxia induced vessel contraction. Increase of cellular cAMP by forskolin could significantly reduce KPSS-induced vessel contraction and abolish phase I, phase II b and phase II c of HPV. Conclusion Our results demonstrated a vasoconstrictive effect of PGE2 on rat IPAs and this effect is via activation of EP4. Furthermore, our results suggest that intracellular cAMP plays dual roles in regulation of vascular tone, depending on the spatial distribution of cAMP and its coupling with EP receptor and Ca2+ channels
Tumor markers in breast cancer - European Group on Tumor Markers recommendations
Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel
Exploring the Universe with Metal-Poor Stars
The early chemical evolution of the Galaxy and the Universe is vital to our
understanding of a host of astrophysical phenomena. Since the most metal-poor
Galactic stars (with metallicities down to [Fe/H]\sim-5.5) are relics from the
high-redshift Universe, they probe the chemical and dynamical conditions of the
Milky Way and the origin and evolution of the elements through nucleosynthesis.
They also provide constraints on the nature of the first stars, their
associated supernovae and initial mass function, and early star and galaxy
formation. The Milky Way's dwarf satellites contain a large fraction (~30%) of
the known most metal-poor stars that have chemical abundances that closely
resemble those of equivalent halo stars. This suggests that chemical evolution
may be universal, at least at early times, and that it is driven by massive,
energetic SNe. Some of these surviving, ultra-faint systems may show the
signature of just one such PopIII star; they may even be surviving first
galaxies. Early analogs of the surviving dwarfs may thus have played an
important role in the assembly of the old Galactic halo whose formation can now
be studied with stellar chemistry. Following the cosmic evolution of small
halos in simulations of structure formation enables tracing the cosmological
origin of the most metal-poor stars in the halo and dwarf galaxies. Together
with future observations and additional modeling, many of these issues,
including the reionization history of the Milky Way, may be constrained this
way. The chapter concludes with an outlook about upcoming observational
challenges and ways forward is to use metal-poor stars to constrain theoretical
studies.Comment: 34 pages, 11 figures. Book chapter to appear in "The First Galaxies -
Theoretical Predictions and Observational Clues", 2012 by Springer, eds. V.
Bromm, B. Mobasher, T. Wiklin
Application of Two-Part Statistics for Comparison of Sequence Variant Counts
Investigation of microbial communities, particularly human associated communities, is significantly enhanced by the vast amounts of sequence data produced by high throughput sequencing technologies. However, these data create high-dimensional complex data sets that consist of a large proportion of zeros, non-negative skewed counts, and frequently, limited number of samples. These features distinguish sequence data from other forms of high-dimensional data, and are not adequately addressed by statistical approaches in common use. Ultimately, medical studies may identify targeted interventions or treatments, but lack of analytic tools for feature selection and identification of taxa responsible for differences between groups, is hindering advancement. The objective of this paper is to examine the application of a two-part statistic to identify taxa that differ between two groups. The advantages of the two-part statistic over common statistical tests applied to sequence count datasets are discussed. Results from the t-test, the Wilcoxon test, and the two-part test are compared using sequence counts from microbial ecology studies in cystic fibrosis and from cenote samples. We show superior performance of the two-part statistic for analysis of sequence data. The improved performance in microbial ecology studies was independent of study type and sequence technology used
Radio Emission from Ultra-Cool Dwarfs
The 2001 discovery of radio emission from ultra-cool dwarfs (UCDs), the very
low-mass stars and brown dwarfs with spectral types of ~M7 and later, revealed
that these objects can generate and dissipate powerful magnetic fields. Radio
observations provide unparalleled insight into UCD magnetism: detections extend
to brown dwarfs with temperatures <1000 K, where no other observational probes
are effective. The data reveal that UCDs can generate strong (kG) fields,
sometimes with a stable dipolar structure; that they can produce and retain
nonthermal plasmas with electron acceleration extending to MeV energies; and
that they can drive auroral current systems resulting in significant
atmospheric energy deposition and powerful, coherent radio bursts. Still to be
understood are the underlying dynamo processes, the precise means by which
particles are accelerated around these objects, the observed diversity of
magnetic phenomenologies, and how all of these factors change as the mass of
the central object approaches that of Jupiter. The answers to these questions
are doubly important because UCDs are both potential exoplanet hosts, as in the
TRAPPIST-1 system, and analogues of extrasolar giant planets themselves.Comment: 19 pages; submitted chapter to the Handbook of Exoplanets, eds. Hans
J. Deeg and Juan Antonio Belmonte (Springer-Verlag
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