775 research outputs found
Diagnostic 'omics' for active tuberculosis
The decision to treat active tuberculosis (TB) is dependent on microbiological tests for the organism or evidence of disease compatible with TB in people with a high demographic risk of exposure. The tuberculin skin test and peripheral blood interferon-Îł release assays do not distinguish active TB from a cleared or latent infection. Microbiological culture of mycobacteria is slow. Moreover, the sensitivities of culture and microscopy for acid-fast bacilli and nucleic acid detection by PCR are often compromised by difficulty in obtaining samples from the site of disease. Consequently, we need sensitive and rapid tests for easily obtained clinical samples, which can be deployed to assess patients exposed to TB, discriminate TB from other infectious, inflammatory or autoimmune diseases, and to identify subclinical TB in HIV-1 infected patients prior to commencing antiretroviral therapy. We discuss the evaluation of peripheral blood transcriptomics, proteomics and metabolomics to develop the next generation of rapid diagnostics for active TB. We catalogue the studies published to date seeking to discriminate active TB from healthy volunteers, patients with latent infection and those with other diseases. We identify the limitations of these studies and the barriers to their adoption in clinical practice. In so doing, we aim to develop a framework to guide our approach to discovery and development of diagnostic biomarkers for active TB
Identification of Therapeutic Targets of Inflammatory Monocyte Recruitment to Modulate the Allogeneic Injury to Donor Cornea
Purpose: We sought to test the hypothesis that monocytes contribute to the immunopathogenesis of corneal allograft rejection and identify therapeutic targets to inhibit monocyte recruitment.
Methods: Monocytes and proinflammatory mediators within anterior chamber samples during corneal graft rejection were quantified by flow cytometry and multiplex protein assays. Lipopolysaccharide or IFN-Îł stimulation of monocyte-derived macrophages (MDMs) was used to generate inflammatory conditioned media (CoM). Corneal endothelial viability was tested by nuclear counting, connexin 43, and propidium iodide staining. Chemokine and chemokine receptor expression in monocytes and MDMs was assessed in microarray transcriptomic data. The role of chemokine pathways in monocyte migration across microvascular endothelium was tested in vitro by chemokine depletion or chemokine receptor inhibitors.
Results: Inflammatory monocytes were significantly enriched in anterior chamber samples within 1 week of the onset of symptoms of corneal graft rejection. The MDM inflammatory CoM was cytopathic to transformed human corneal endothelia. This effect was also evident in endothelium of excised human cornea and increased in the presence of monocytes. Gene expression microarrays identified monocyte chemokine receptors and cognate chemokines in MDM inflammatory responses, which were also enriched in anterior chamber samples. Depletion of selected chemokines in MDM inflammatory CoM had no effect on monocyte transmigration across an endothelial bloodâeye barrier, but selective chemokine receptor inhibition reduced monocyte recruitment significantly.
Conclusions: We propose a role for inflammatory monocytes in endothelial cytotoxicity in corneal graft rejection. Therefore, targeting monocyte recruitment offers a putative novel strategy to reduce donor endothelial cell injury in survival of human corneal allografts
Cell-type-specific modulation of innate immune signalling by vitamin D in human mononuclear phagocytes
Vitamin D is widely reported to inhibit innate immune signalling and dendritic cell (DC) maturation as a potential immunoregulatory mechanism. It is not known whether vitamin D has global or gene-specific effects on transcriptional responses downstream of innate immune stimulation, or whether vitamin D inhibition of innate immune signalling is common to different cells. We confirmed vitamin D inhibition of nuclear factor-ÎșB (NF-ÎșB) and p38 mitogen-activated protein kinase (MAPK) signalling in monocyte-derived DC (MDDC) stimulated with lipopolysaccharide (LPS). This was associated with global but modest attenuation of LPS-induced transcriptional changes at genome-wide level. Surprisingly, vitamin D did not inhibit innate immune NF-ÎșB activation in monocyte-derived macrophages. Consistent with our findings in MDDC, ex vivo vitamin D treatment of primary peripheral blood myeloid DC also led to significant inhibition of LPS-inducible NF-ÎșB activation. Unexpectedly, in the same samples, vitamin D enhanced activation of both NF-ÎșB and MAPK signalling in primary peripheral blood monocytes. In a cross-sectional clinical cohort, we found no relationship between peripheral blood vitamin D levels and LPS-inducible activation of NF-ÎșB and MAPK pathways in monocytes of myeloid DC. Remarkably, however, in vivo supplementation of people with vitamin D deficiency in this clinical cohort also enhanced LPS-inducible MAPK signalling in peripheral blood monocytes. Therefore, we report that vitamin D differentially modulates the molecular response to innate immune stimulation in monocytes, macrophages and dendritic cells. These results are of importance in the design of studies on vitamin D supplementation in infectious and immunological diseases
Reduction of T-Helper Cell Responses to Recall Antigen Medicated by Codelivery with Peptidoglycan via the Intestinal Nanomineral-Antigen Pathway
Naturally occurring intestinal nanomineral particles constituently form in the mammalian
gut and trap luminal protein and microbial components. These cargo loaded nanominerals are actively scavenged by M cells of intestinal immune follicles, such as Peyerâs
patches and are passed to antigen-presenting cells. Using peripheral blood mononuclear
cell populations as an in vitro model of nanomineral uptake and antigen presentation,
we show that monocytes avidly phagocytose nanomineral particles bearing antigen
and peptidoglycan (PGN), and that the presence of PGN within particles downregulates
their cell surface MHC class II and upregulates programmed death receptor ligand 1.
Nanomineral delivery of antigen suppresses antigen-specific CD4+ T cell responses,
an effect that is enhanced in the presence of PGN. Blocking the interleukin-10 receptor
restores CD4+ T cell responses to antigen codelivered with PGN in nanomineral form.
Using human intestinal specimens, we have shown that the in vivo nanomineral pathway
operates in an interleukin-10 rich environment. Consequently, the delivery of a dual
antigenâPGN cargo by endogenous nanomineral in vivo is likely to be important in the
establishment of intestinal tolerance, while their synthetic mimetics present a potential
delivery system for therapeutic applications targeting the modulation of Peyerâs patch
T cell responses
Membership nominations in international scientific assessments
International scientific assessments are transnational knowledge-based expert networks with a mandate to advise policymakers. A well-known example is the Millennium Ecosystem Assessment (MA), which synthesized research on ecosystem services between 2001 and 2005, utilizing the knowledge of 1,360 expert members. Little, however, is known about the membership composition and the driving forces behind membership nominations in the MA and similar organizations. Here we introduce a survey data set on recruitment in the MA and analyse nomination patterns among experts as a complex network. The results indicate that membership recruitment was governed by prior contacts in other transnational elite organizations and a range of other factors related to personal affinity. Network analysis demonstrates how some core individuals were particularly influential in shaping the overall membership composition of the group. These findings add to recently noted concerns about the lack of diversity of views represented in international scientific assessments
Spatio-temporal Models of Lymphangiogenesis in Wound Healing
Several studies suggest that one possible cause of impaired wound healing is
failed or insufficient lymphangiogenesis, that is the formation of new
lymphatic capillaries. Although many mathematical models have been developed to
describe the formation of blood capillaries (angiogenesis), very few have been
proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a
markedly different process from angiogenesis, occurring at different times and
in response to different chemical stimuli. Two main hypotheses have been
proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the
edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic
endothelial cells first pool in the wound region following the lymph flow and
then, once sufficiently populated, start to form a network. Here we present two
PDE models describing lymphangiogenesis according to these two different
hypotheses. Further, we include the effect of advection due to interstitial
flow and lymph flow coming from open capillaries. The variables represent
different cell densities and growth factor concentrations, and where possible
the parameters are estimated from biological data. The models are then solved
numerically and the results are compared with the available biological
literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total
Stochastically Gating Ion Channels Enable Patterned Spike Firing through Activity-Dependent Modulation of Spike Probability
The transformation of synaptic input into patterns of spike output is a
fundamental operation that is determined by the particular complement of ion
channels that a neuron expresses. Although it is well established that
individual ion channel proteins make stochastic transitions between conducting
and non-conducting states, most models of synaptic integration are
deterministic, and relatively little is known about the functional consequences
of interactions between stochastically gating ion channels. Here, we show that a
model of stellate neurons from layer II of the medial entorhinal cortex
implemented with either stochastic or deterministically gating ion channels can
reproduce the resting membrane properties of stellate neurons, but only the
stochastic version of the model can fully account for perithreshold membrane
potential fluctuations and clustered patterns of spike output that are recorded
from stellate neurons during depolarized states. We demonstrate that the
stochastic model implements an example of a general mechanism for patterning of
neuronal output through activity-dependent changes in the probability of spike
firing. Unlike deterministic mechanisms that generate spike patterns through
slow changes in the state of model parameters, this general stochastic mechanism
does not require retention of information beyond the duration of a single spike
and its associated afterhyperpolarization. Instead, clustered patterns of spikes
emerge in the stochastic model of stellate neurons as a result of a transient
increase in firing probability driven by activation of HCN channels during
recovery from the spike afterhyperpolarization. Using this model, we infer
conditions in which stochastic ion channel gating may influence firing patterns
in vivo and predict consequences of modifications of HCN
channel function for in vivo firing patterns
Search for anomalous t t-bar production in the highly-boosted all-hadronic final state
A search is presented for a massive particle, generically referred to as a
Z', decaying into a t t-bar pair. The search focuses on Z' resonances that are
sufficiently massive to produce highly Lorentz-boosted top quarks, which yield
collimated decay products that are partially or fully merged into single jets.
The analysis uses new methods to analyze jet substructure, providing
suppression of the non-top multijet backgrounds. The analysis is based on a
data sample of proton-proton collisions at a center-of-mass energy of 7 TeV,
corresponding to an integrated luminosity of 5 inverse femtobarns. Upper limits
in the range of 1 pb are set on the product of the production cross section and
branching fraction for a topcolor Z' modeled for several widths, as well as for
a Randall--Sundrum Kaluza--Klein gluon. In addition, the results constrain any
enhancement in t t-bar production beyond expectations of the standard model for
t t-bar invariant masses larger than 1 TeV.Comment: Submitted to the Journal of High Energy Physics; this version
includes a minor typo correction that will be submitted as an erratu
Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV
The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of âs = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pTâ„20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60â€pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2â€{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration
Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector
The inclusive and dijet production cross-sections have been measured for jets
containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass
energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The
measurements use data corresponding to an integrated luminosity of 34 pb^-1.
The b-jets are identified using either a lifetime-based method, where secondary
decay vertices of b-hadrons in jets are reconstructed using information from
the tracking detectors, or a muon-based method where the presence of a muon is
used to identify semileptonic decays of b-hadrons inside jets. The inclusive
b-jet cross-section is measured as a function of transverse momentum in the
range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet
cross-section is measured as a function of the dijet invariant mass in the
range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets
and the angular variable chi in two dijet mass regions. The results are
compared with next-to-leading-order QCD predictions. Good agreement is observed
between the measured cross-sections and the predictions obtained using POWHEG +
Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet
cross-section. However, it does not reproduce the measured inclusive
cross-section well, particularly for central b-jets with large transverse
momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final
version published in European Physical Journal
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