1,932 research outputs found
Oral tolerance to cancer can be abrogated by T regulatory cell inhibition
Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue – JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut
lp-Recovery of the Most Significant Subspace among Multiple Subspaces with Outliers
We assume data sampled from a mixture of d-dimensional linear subspaces with
spherically symmetric distributions within each subspace and an additional
outlier component with spherically symmetric distribution within the ambient
space (for simplicity we may assume that all distributions are uniform on their
corresponding unit spheres). We also assume mixture weights for the different
components. We say that one of the underlying subspaces of the model is most
significant if its mixture weight is higher than the sum of the mixture weights
of all other subspaces. We study the recovery of the most significant subspace
by minimizing the lp-averaged distances of data points from d-dimensional
subspaces, where p>0. Unlike other lp minimization problems, this minimization
is non-convex for all p>0 and thus requires different methods for its analysis.
We show that if 0<p<=1, then for any fraction of outliers the most significant
subspace can be recovered by lp minimization with overwhelming probability
(which depends on the generating distribution and its parameters). We show that
when adding small noise around the underlying subspaces the most significant
subspace can be nearly recovered by lp minimization for any 0<p<=1 with an
error proportional to the noise level. On the other hand, if p>1 and there is
more than one underlying subspace, then with overwhelming probability the most
significant subspace cannot be recovered or nearly recovered. This last result
does not require spherically symmetric outliers.Comment: This is a revised version of the part of 1002.1994 that deals with
single subspace recovery. V3: Improved estimates (in particular for Lemma 3.1
and for estimates relying on it), asymptotic dependence of probabilities and
constants on D and d and further clarifications; for simplicity it assumes
uniform distributions on spheres. V4: minor revision for the published
versio
The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology
Background/Aims: Evidence suggests that tyrosine-kinase inhibitors may attenuate lung inflammation and fibrosis in experimental acute respiratory distress syndrome (ARDS). We hypothesized that dasatinib, a tyrosine-kinase inhibitor, might act differently depending on the ARDS etiology and the dose. Methods: C57/BL6 mice were divided to be pre-treated with dasatinib (1mg/kg or 10mg/kg) or vehicle (1% dimethyl-sulfoxide) by oral gavage. Thirty-minutes after pre-treatment, mice were subdivided into control (C) or ARDS groups. ARDS animals received Escherichia coli lipopolysaccharide intratracheally (ARDSp) or intraperitoneally (ARDSexp). A new dose of dasatinib or vehicle was administered at 6 and 24h. Results: Forty-eight hours after ARDS induction, dasatinib 1mg/kg yielded: improved lung morphofunction and reduced cells expressing toll-like receptor (TLR)-4 in lung, independent of ARDS etiology; reduced neutrophil and levels of interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-β in ARDSp. The higher dose of dasatinib caused no changes in lung mechanics, diffuse alveolar damage, neutrophil, or cells expressing TLR4, but increased IL-6, vascular endothelial growth factor (VEGF), and cells expressing Fas receptor in lung in ARDSp. In ARDSexp, it improved lung morphofunction, increased VEGF, and reduced cells expressing TLR4. Conclusion: Dasatinib may have therapeutic potential in ARDS independent of etiology, but careful dose monitoring is required. © 2015 S. Karger AG, Basel
The Effects of Cocaine on Different Redox Forms of Cysteine and Homocysteine, and on Labile, Reduced Sulfur in the Rat Plasma Following Active versus Passive Drug Injections
Received: 28 November 2012 / Revised: 19 April 2013 / Accepted: 6 May 2013 / Published online: 16 May 2013
The Author(s) 2013. This article is published with open access at Springerlink.comThe aim of the present studies was to evaluate
cocaine-induced changes in the concentrations of different
redox forms of cysteine (Cys) and homocysteine (Hcy),
and products of anaerobic Cys metabolism, i.e., labile,
reduced sulfur (LS) in the rat plasma. The above-mentioned
parameters were determined after i.p. acute and
subchronic cocaine treatment as well as following i.v.
cocaine self-administration using the yoked procedure.
Additionally, Cys, Hcy, and LS levels were measured
during the 10-day extinction training in rats that underwent
i.v. cocaine administration. Acute i.p. cocaine treatment
increased the total and protein-bound Hcy contents,
decreased LS, and did not change the concentrations of Cys
fractions in the rat plasma. In turn, subchronic i.p. cocaine administration significantly increased free Hcy and lowered
the total and protein-bound Cys concentrations while
LS level was unchanged. Cocaine self-administration
enhanced the total and protein-bound Hcy levels, decreased
LS content, and did not affect the Cys fractions. On the
other hand, yoked cocaine infusions did not alter the concentration
of Hcy fractions while decreased the total and
protein-bound Cys and LS content. This extinction training
resulted in the lack of changes in the examined parameters
in rats with a history of cocaine self-administration while in
the yoked cocaine group an increase in the plasma free Cys
fraction and LS was seen. Our results demonstrate for the
first time that cocaine does evoke significant changes in
homeostasis of thiol amino acids Cys and Hcy, and in some
products of anaerobic Cys metabolism, which are dependent
on the way of cocaine administration
Control and Characterization of Individual Grains and Grain Boundaries in Graphene Grown by Chemical Vapor Deposition
The strong interest in graphene has motivated the scalable production of high
quality graphene and graphene devices. Since large-scale graphene films
synthesized to date are typically polycrystalline, it is important to
characterize and control grain boundaries, generally believed to degrade
graphene quality. Here we study single-crystal graphene grains synthesized by
ambient CVD on polycrystalline Cu, and show how individual boundaries between
coalescing grains affect graphene's electronic properties. The graphene grains
show no definite epitaxial relationship with the Cu substrate, and can cross Cu
grain boundaries. The edges of these grains are found to be predominantly
parallel to zigzag directions. We show that grain boundaries give a significant
Raman "D" peak, impede electrical transport, and induce prominent weak
localization indicative of intervalley scattering in graphene. Finally, we
demonstrate an approach using pre-patterned growth seeds to control graphene
nucleation, opening a route towards scalable fabrication of single-crystal
graphene devices without grain boundaries.Comment: New version with additional data. Accepted by Nature Material
Citalopram reduces aggregation of ATXN3 in a YAC transgenic mouse model of Machado-Joseph disease
Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is a fatal polyglutamine disease with no disease-modifying treatment. The selective serotonin reuptake inhibitor citalopram was shown in nematode and mouse models to be a compelling repurposing candidate for Machado-Joseph disease therapeutics. We sought to confirm the efficacy of citalopram to decrease ATXN3 aggregation in an unrelated mouse model of Machado-Joseph disease. Four-week-old YACMJD84.2 mice and non-transgenic littermates were given citalopram 8 mg/kg in drinking water or water for 10 weeks. At the end of treatment, brains were collected for biochemical and pathological analyses. Brains of citalopram-treated YACMJD84.2 mice showed an approximate 50% decrease in the percentage of cells containing ATXN3-positive inclusions in the substantia nigra and three examined brainstem nuclei compared to controls. No differences in ATXN3 inclusion load were observed in deep cerebellar nuclei of mice. Citalopram effect on ATXN3 aggregate burden was corroborated by immunoblotting analysis. While lysates from the brainstem and cervical spinal cord of citalopram-treated mice showed a decrease in all soluble forms of ATXN3 and a trend toward reduction of insoluble ATXN3, no differences in ATXN3 levels were found between cerebella of citalopram-treated and vehicle-treated mice. Citalopram treatment altered levels of select components of the cellular protein homeostatic machinery that may be expected to enhance the capacity to refold and/or degrade mutant ATXN3. The results here obtained in a second independent mouse model of Machado-Joseph disease further support citalopram as a potential drug to be repurposed for this fatal disorder.This work was funded by Becky Babcox Research
Fund/pilot research award G015617, University of Michigan to M.C.C.
and NINDS/NIH R01NS038712 to H.L.P. The work performed at the
University of Minho was funded by the European Regional
Development Funds (FEDER), through the Competitiveness Factors
Operational Programme (COMPETE), and by National funds, through
the Foundation for Science and Technology (FCT), under the scope of the
project POCI-01-0145-FEDER-007038. This article was developed under the scope of the project NORTE-01-0145-FEDER-000013, supported
by the Northern Portugal Regional Operational Program (NORTE 2020),
under the Portugal 2020 Partnership Agreement, through the FEDER.
This work was also supported by FCT and COMPETE through the projects [PTDC/SAU-GMG/112617/2009] (to P.M.) and [EXPL/BIM-MEC/
0239/2012] (to A.T.C.); by FCT through the project [POCI-01-0145-
FEDER-016818 (PTDC/NEU-NMC/3648/2014)] (to P.M.); by National
Ataxia Foundation (to P.M. and to A.T.C.); and by Ataxia UK (to P.M.).
S.D.S. and A.T.C. were supported by fellowships from FCT, SFRH/BD/
78388/2011 and SFRH/BPD/102317/2014, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República
Portuguesa and EU/FSE
Review for the generalist: evaluation of anterior knee pain
Anterior knee pain is common in children and adolescents. Evaluation and management is challenging and requires a thorough history and physical exam, and understanding of the pediatric skeleton. This article will review common causes of chronic anterior knee pain in the pediatric population with a focus on patellofemoral pain
Characterization of a membrane-bound C-glucosyltransferase responsible for carminic acid biosynthesis in Dactylopius coccus Costa
Carminic acid is a widely applied red colorant that is still harvested from insects because its biosynthesis is not fully understood. Here, the authors identify and characterize a membrane-bound C-glucosyltransferase catalyzing the final step during carminic acid biosynthesis
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