2,670 research outputs found
Differential cell autonomous responses determine the outcome of coxsackievirus infections in murine pancreatic α and β cells
This is the final version of the article. Available from eLife Sciences Publications via the DOI in this record.Type 1 diabetes (T1D) is an autoimmune disease caused by loss of pancreatic β cells via apoptosis while neighboring α cells are preserved. Viral infections by coxsackieviruses (CVB) may contribute to trigger autoimmunity in T1D. Cellular permissiveness to viral infection is modulated by innate antiviral responses, which vary among different cell types. We presently describe that global gene expression is similar in cytokine-treated and virus-infected human islet cells, with up-regulation of gene networks involved in cell autonomous immune responses. Comparison between the responses of rat pancreatic α and β cells to infection by CVB5 and 4 indicate that α cells trigger a more efficient antiviral response than β cells, including higher basal and induced expression of STAT1-regulated genes, and are thus better able to clear viral infections than β cells. These differences may explain why pancreatic β cells, but not α cells, are targeted by an autoimmune response during T1D.Fonds De La Recherche Scientifique – FNRS: FNRS- F 5/4/5.MCF/KP. Project de secherche (PDR) T.0036.13; European Commission (EC): Projects Naimit and BetaBat, in the Framework Programme 7 of the European Community; Federation Wallonie- Bruxelles: the Communaute Franc¸ aise de BelgiqueActions de Recherche Concertees (ARC); Fonds De La Recherche Scientifique – FNRS: FNRS post-doctoral fellowship; Governo Brasil: PDE/CSF Pos-Doutorado no Exterior; Juvenile Diabetes Research Foundation International (JDRF): JDRF Career Development Award; European Commission (EC): European Union’s Seventh Framework Programme [FP7/2007-2013] under grant agreement 261441 PEVNE
Toxic Epidermal Necrolysis after Pemetrexed and Cisplatin for Non-Small Cell Lung Cancer in a Patient with Sharp Syndrome
Background: Pemetrexed is an antifolate drug approved for maintenance and second-line therapy, and, in combination with cisplatin, for first-line treatment of advanced nonsquamous non-small cell lung cancer. The side-effect profile includes fatigue, hematological and gastrointestinal toxicity, an increase in hepatic enzymes, sensory neuropathy, and pulmonary and cutaneous toxicity in various degrees. Case Report: We present the case of a 58-year-old woman with history of Sharp's syndrome and adenocarcinoma of the lung, who developed toxic epidermal necrolysis after the first cycle of pemetrexed, including erythema, bullae, extensive skin denudation, subsequent systemic inflammation and severe deterioration in general condition. The generalized skin lesions occurred primarily in the previous radiation field and responded to immunosuppressive treatment with prednisone. Conclusion: Although skin toxicity is a well-known side effect of pemetrexed, severe skin reactions after pemetrexed administration are rare. Caution should be applied in cases in which pemetrexed is given subsequent to radiation therapy, especially in patients with pre-existing skin diseases
Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile
<p>Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.</p>
<p>Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).</p>
<p>Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.</p>
<p>Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.</p>
Rationale and design of the Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA) trial.
BACKGROUND: Device-detected subclinical atrial fibrillation (AF) refers to infrequent, short-lasting, asymptomatic AF that is detected only with long-term continuous monitoring. Subclinical AF is common and associated with an increased risk of stroke; however, the risk of stroke with subclinical AF is lower than for clinical AF, and very few patients with subclinical AF alone have been included in large AF anticoagulation trials. The net benefit of anticoagulation in patients with subclinical AF is unknown. DESIGN: ARTESiA is a prospective, multicenter, double-blind, randomized controlled trial, recruiting patients with subclinical AF detected by an implanted pacemaker, defibrillator, or cardiac monitor, and who have additional risk factors for stroke. Patients with clinical AF documented by surface electrocardiogram will be excluded from the study. Participants will be randomized to receive either apixaban (according to standard AF dosing) or aspirin 81mg daily. The primary outcome is the composite of stroke, transient ischemic attack with diffusion-weighted magnetic resonance imaging evidence of cerebral infarction, and systemic embolism. Approximately 4,000 patients will be enrolled from around 230 clinical sites, with an anticipated mean follow-up of 36months until 248 adjudicated primary outcome events have occurred. SUMMARY: ARTESiA will determine whether oral anticoagulation therapy with apixaban compared with aspirin reduces the risk of stroke or systemic embolism in patients with subclinical AF and additional risk factors
The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1 : contributions of the pore domains
We have investigated the contribution to ionic
selectivity of residues in the selectivity filter and pore
helices of the P1 and P2 domains in the acid sensitive
potassium channel TASK-1. We used site directed mutagenesis
and electrophysiological studies, assisted by structural
models built through computational methods. We have
measured selectivity in channels expressed in Xenopus
oocytes, using voltage clamp to measure shifts in reversal
potential and current amplitudes when Rb+ or Na+ replaced
extracellular K+. Both P1 and P2 contribute to selectivity,
and most mutations, including mutation of residues in the
triplets GYG and GFG in P1 and P2, made channels nonselective.
We interpret the effects of these—and of other
mutations—in terms of the way the pore is likely to be
stabilised structurally. We show also that residues in the
outer pore mouth contribute to selectivity in TASK-1.
Mutations resulting in loss of selectivity (e.g. I94S, G95A)
were associated with slowing of the response of channels to
depolarisation. More important physiologically, pH sensitivity
is also lost or altered by such mutations. Mutations
that retained selectivity (e.g. I94L, I94V) also retained their
response to acidification. It is likely that responses both to
voltage and pH changes involve gating at the selectivity filter
Extremal Multicenter Black Holes: Nilpotent Orbits and Tits Satake Universality Classes
Four dimensional supergravity theories whose scalar manifold is a symmetric
coset manifold U[D=4]/Hc are arranged into a finite list of Tits Satake
universality classes. Stationary solutions of these theories, spherically
symmetric or not, are identified with those of an euclidian three-dimensional
sigma-model, whose target manifold is a Lorentzian coset U[D=3]/H* and the
extremal ones are associated with H* nilpotent orbits in the K* representation
emerging from the orthogonal decomposition of the algebra U[D=3] with respect
to H*. It is shown that the classification of such orbits can always be reduced
to the Tits-Satake projection and it is a class property of the Tits Satake
universality classes. The construction procedure of Bossard et al of extremal
multicenter solutions by means of a triangular hierarchy of integrable
equations is completed and converted into a closed algorithm by means of a
general formula that provides the transition from the symmetric to the solvable
gauge. The question of the relation between H* orbits and charge orbits W of
the corresponding black holes is addressed and also reduced to the
corresponding question within the Tits Satake projection. It is conjectured
that on the vanishing locus of the Taub-NUT current the relation between
H*-orbit and W-orbit is rigid and one-to-one. All black holes emerging from
multicenter solutions associated with a given H* orbit have the same W-type.
For the S^3 model we provide a complete survey of its multicenter solutions
associated with all of the previously classified nilpotent orbits of sl(2) x
sl(2) within g[2,2]. We find a new intrinsic classification of the W-orbits of
this model that might provide a paradigm for the analogous classification in
all the other Tits Satake universality classes.Comment: 83 pages, LaTeX; v2: few misprints corrected and references adde
A New Class of Four-Dimensional N=1 Supergravity with Non-minimal Derivative Couplings
In the N=1 four-dimensional new-minimal supergravity framework, we
supersymmetrise the coupling of the scalar kinetic term to the Einstein tensor.
This coupling, although introduces a non-minimal derivative interaction of
curvature to matter, it does not introduce harmful higher-derivatives. For this
construction, we employ off-shell chiral and real linear multiplets. Physical
scalars are accommodated in the chiral multiplet whereas curvature resides in a
linear one.Comment: 18 pages, version published at JHE
Heterotic Black Horizons
We show that the supersymmetric near horizon geometry of heterotic black
holes is either an AdS_3 fibration over a 7-dimensional manifold which admits a
G_2 structure compatible with a connection with skew-symmetric torsion, or it
is a product R^{1,1} * S^8, where S^8 is a holonomy Spin(7) manifold,
preserving 2 and 1 supersymmetries respectively. Moreover, we demonstrate that
the AdS_3 class of heterotic horizons can preserve 4, 6 and 8 supersymmetries
provided that the geometry of the base space is further restricted. Similarly
R^{1,1} * S^8 horizons with extended supersymmetry are products of R^{1,1} with
special holonomy manifolds. We have also found that the heterotic horizons with
8 supersymmetries are locally isometric to AdS_3 * S^3 * T^4, AdS_3 * S^3 * K_3
or R^{1,1} * T^4 * K_3, where the radii of AdS_3 and S^3 are equal and the
dilaton is constant.Comment: 35 pages, latex. Minor alterations to equation (3.11) and section
4.1, the conclusions are not affecte
Highlights from the Student Council Symposium 2011 at the International Conference on Intelligent Systems for Molecular Biology and European Conference on Computational Biology
The Student Council (SC) of the International Society for Computational Biology (ISCB) organized their annual symposium in conjunction with the Intelligent Systems for Molecular Biology (ISMB) conference
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