2,695 research outputs found
Targeting Macrophages and Synoviocytes Intracellular Milieu to Augment Anti-Inflammatory Drug Potency
Using a preclinical in vivo model of arthritis and the gold standard disease-modifying anti-rheumatic drug, methotrexate, pH-responsive phosphorylcholine polymersomes, elicit both anti-inflammatory and anti-arthritic therapeutic efficacy, while drastically minimizing off-target toxicity. First, the selective accumulation of polymersomes within synovium of inflamed joints. Second, the polymersomes targeting ability toward activated macrophages and synoviocytes, via scavenger receptors, allow their uptake via endocytosis. And third, the polymersomes pH-responsiveness enables the drug escape from early endosomes and hence its intracellular milieu delivery. On-site augment of methotrexate loaded polymersomes enable the complete abrogation of synovial inflammation and prevent the disease progression and severity. Overall, in vitro and in vivo investigations reveal the potential of polymersomes as a promising nanotherapy for treating arthritic inflammation
Chitosan inhibits septinâmediated plant infection by the rice blast fungus Magnaporthe oryzae in a protein kinase C and Nox1 NADPH oxidaseâdependent manner
Summary
Chitosan is a partially deacetylated linear polysaccharide composed of βâ1,4âlinked units of dâglucosamine and Nâacetyl glucosamine. As well as a structural component of fungal cell walls, chitosan is a potent antifungal agent. However, the mode of action of chitosan is poorly understood.
Here, we report that chitosan is effective for control of rice blast disease. Chitosan application impairs growth of the blast fungus Magnaporthe oryzae and has a pronounced effect on appressoriumâmediated plant infection. Chitosan inhibits septinâmediated Fâactin remodelling at the appressorium pore, thereby preventing repolarization of the infection cell.
Chitosan causes plasma membrane permeabilization of M. oryzae and affects NADPH oxidaseâdependent synthesis of reactive oxygen species, essential for septin ring formation and fungal pathogenicity. We further show that toxicity of chitosan to M. oryzae requires the protein kinase Câdependent cell wall integrity pathway, the Mps1 mitogenâactivated protein kinase and the Nox1 NADPH oxidase. A conditionally lethal, analogue (PP1)âsensitive mutant of Pkc1 is partially remediated for growth in the presence of chitosan, while ânox1 mutants increase their glucan : chitin cell wall ratio, rendering them resistant to chitosan.
Taken together, our data show that chitosan is a potent fungicide which requires the cell integrity pathway, disrupts plasma membrane function and inhibits septinâmediated plant infection.
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The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis
Acknowledgements We wish to thank Jorge GalĂĄn, Gregory Pazour, Derek Toomre, Giuliano Callaini, Joel Rosenbaum, Alessandra Boletta and Francesco Blasi for generously providing reagents and for productive discussions, and Sonia Grassini for technical assistance. The work was carried out with the financial support of Telethon (GGP11021) and AIRC.Peer reviewedPostprin
Charged-Higgs phenomenology in the Aligned two-Higgs-doublet model
The alignment in flavour space of the Yukawa matrices of a general
two-Higgs-doublet model results in the absence of tree-level flavour-changing
neutral currents. In addition to the usual fermion masses and mixings, the
aligned Yukawa structure only contains three complex parameters, which are
potential new sources of CP violation. For particular values of these three
parameters all known specific implementations of the model based on discrete
Z_2 symmetries are recovered. One of the most distinctive features of the
two-Higgs-doublet model is the presence of a charged scalar. In this work, we
discuss its main phenomenological consequences in flavour-changing processes at
low energies and derive the corresponding constraints on the parameters of the
aligned two-Higgs-doublet model.Comment: 46 pages, 19 figures. Version accepted for publication in JHEP.
References added. Discussion slightly extended. Conclusions unchange
NKG2A inhibits TH2 cell effector function in vitro
This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens
Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis
Thyroid hormones (THs) are essential for embryonic brain development but the genetic mechanisms involved in the action of maternal THs (MTHs) are still largely unknown. As the basis for understanding the underlying genetic mechanisms of MTHs regulation we used an established zebrafish monocarboxylic acid transporter 8 (MCT8) knock-down model and characterised the transcriptome in 25hpf zebrafish embryos. Subsequent mapping of differentially expressed genes using Reactome pathway analysis together with in situ expression analysis and immunohistochemistry revealed the genetic networks and cells under MTHs regulation during zebrafish embryogenesis. We found 4,343 differentially expressed genes and the Reactome pathway analysis revealed that TH is involved in 1681 of these pathways. MTHs regulated the expression of core developmental pathways, such as NOTCH and WNT in a cell specific context. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. Taken together our data show that MTHs have a role in zebrafish neurogenesis and suggest they may be involved in cross talk between key pathways in neural development. Given that the observed MCT8 zebrafish knockdown phenotype resembles the symptoms in human patients with Allan-Herndon-Dudley syndrome our data open a window into understanding the genetics of this human congenital condition.Portuguese Fundacao para Ciencia e Tecnologia (FCT) [PTDC/EXPL/MARBIO/0430/2013]; CCMAR FCT Plurianual financing [UID/Multi/04326/2013]; FCT [SFRH/BD/111226/2015, SFRH/BD/108842/2015, SFRH/BPD/89889/2012]; FCT-IF Starting Grant [IF/01274/2014]info:eu-repo/semantics/publishedVersio
Light hadron, Charmonium(-like) and Bottomonium(-like) states
Hadron physics represents the study of strongly interacting matter in all its
manifestations and the understanding of its properties and interactions. The
interest on this field has been revitalized by the discovery of new light
hadrons, charmonium- and bottomonium-like states. I review the most recent
experimental results from different experiments.Comment: Presented at Lepton-Photon 2011, Mumbai, India; 21 pages, 18 figures;
add more references; some correctio
Collider signatures of goldstini in gauge mediation
We investigate the collider signatures of the multiple goldstini scenario in
the framework of gauge mediation. This class of models is characterized by a
visible sector (e.g. the MSSM or any extension) coupled by gauge interactions
to more than one SUSY breaking sector. The spectrum consists of a light
gravitino LSP, behaving as a goldstino, and a number of neutral fermions (the
pseudo-goldstini) with a mass between that of the LSP and that of the lightest
particle of the observable sector (LOSP). We consider the two situations where
the LOSP is either a gaugino-like neutralino or a stau and we assume only one
pseudo-goldstino of a mass of O(100) GeV. The coupling of the LOSP to the
pseudo-goldstino can be enhanced with respect to those of the gravitino giving
rise to characteristic signatures. We show that the decay modes of the LOSP
into a SM particle and a pseudo-goldstino can be significant. For both LOSP
scenarios we analyze (pseudo)-goldstini production at colliders. Compared to
standard gauge mediation the final state spectrum is softer and more
structured.Comment: v2: analysis of the stau LOSP scenario added, sections rearranged,
and Introduction and Conclusions rewritten to include the added scenario.
Version to appear in JHE
Native American Children and Their Reports of Hope: Construct Validation of the Children's Hope Scale
Child reports of hope continue to be utilized as predictors of positive adjustment; however, the utilization of the hope construct has not been assessed within the culturally diverse Native American child group. The present study investigated the applicability of the Hope theory among 96 Native American children in the Midwest. Measures included the Childrenâs Hope Scale and a Hope Interview. Native American children in the current sample appear to conceptualize hope as a way to reach goals as did the children in the normative sample. Results from the factor analysis demonstrate that the factor structure found in the current study was similar to the factor structure found in the standardization sample. Because of the similar Hope theory conceptualization and factor structure, interventions focused on the positive psychology construct of hope may be applicable within a Native American child population
Effective Dark Matter Model: Relic density, CDMS II, Fermi LAT and LHC
The Cryogenic Dark Matter Search recently announced the observation of two
signal events with a 77% confidence level. Although statistically inconclusive,
it is nevertheless suggestive. In this work we present a model-independent
analysis on the implication of a positive signal in dark matter scattering off
nuclei. Assuming the interaction between (scalar, fermion or vector) dark
matter and the standard model induced by unknown new physics at the scale
, we examine various dimension-6 tree-level induced operators and
constrain them using the current experimental data, e.g. the WMAP data of the
relic abundance, CDMS II direct detection of the spin-independent scattering,
and indirect detection data (Fermi LAT cosmic gamma-ray), etc. Finally, the LHC
reach is also explored
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