143 research outputs found
Essential role for CD103 in the T cell–mediated regulation of experimental colitis
The integrin CD103 is highly expressed at mucosal sites, but its role in mucosal immune regulation remains poorly understood. We have analyzed the functional role of CD103 in intestinal immune regulation using the T cell transfer model of colitis. Our results show no mandatory role for CD103 expression on T cells for either the development or CD4+CD25+ regulatory T (T reg) cell–mediated control of colitis. However, wild-type CD4+CD25+ T cells were unable to prevent colitis in immune-deficient recipients lacking CD103, demonstrating a nonredundant functional role for CD103 on host cells in T reg cell–mediated intestinal immune regulation. Non–T cell expression of CD103 is restricted primarily to CD11chighMHC class IIhigh dendritic cells (DCs). This DC population is present at a high frequency in the gut-associated lymphoid tissue and appears to mediate a distinct functional role. Thus, CD103+ DCs, but not their CD103− counterparts, promoted expression of the gut-homing receptor CCR9 on T cells. Conversely, CD103− DCs promoted the differentiation of IFN-γ–producing T cells. Collectively, these data suggest that CD103+ and CD103− DCs represent functionally distinct subsets and that CD103 expression on DCs influences the balance between effector and regulatory T cell activity in the intestine
How do public perceptions affect the security of connected places? A systematic literature review
This systematic literature review explores the scholarly debate around public perceptions and behaviors in the context of cybersecurity in connected places. It reveals that, while many articles highlight the importance of public perceptions and behaviors during a cyberattack, there is no unified consensus on how to influence them in order to minimize the attack’s impact and expedite recovery. Public perceptions can affect the success and sustainability of connected places; however, exactly how and to what extent remains unknown. We argue that more research is needed on the mechanisms to assess the influence of public perceptions and associated behaviors on threats to security in connected places. Furthermore, there is a need to investigate the models and tools currently being deployed by connected place design and management to understand and influence public perceptions and behaviors. Lastly, we identify the requirements to investigate the complex relationship between the public and connected place managers, define all stakeholders clearly, and explore the patterns between specific connected place cybersecurity incidents and the methods used to transform public perceptions
LOFAR/H-ATLAS: The low-frequency radio luminosity - star-formation rate relation
Radio emission is a key indicator of star-formation activity in galaxies, but
the radio luminosity-star formation relation has to date been studied almost
exclusively at frequencies of 1.4 GHz or above. At lower radio frequencies the
effects of thermal radio emission are greatly reduced, and so we would expect
the radio emission observed to be completely dominated by synchrotron radiation
from supernova-generated cosmic rays. As part of the LOFAR Surveys Key Science
project, the Herschel-ATLAS NGP field has been surveyed with LOFAR at an
effective frequency of 150 MHz. We select a sample from the MPA-JHU catalogue
of SDSS galaxies in this area: the combination of Herschel, optical and
mid-infrared data enable us to derive star-formation rates (SFRs) for our
sources using spectral energy distribution fitting, allowing a detailed study
of the low-frequency radio luminosity--star-formation relation in the nearby
Universe. For those objects selected as star-forming galaxies (SFGs) using
optical emission line diagnostics, we find a tight relationship between the 150
MHz radio luminosity () and SFR. Interestingly, we find that a single
power-law relationship between and SFR is not a good description of
all SFGs: a broken power law model provides a better fit. This may indicate an
additional mechanism for the generation of radio-emitting cosmic rays. Also, at
given SFR, the radio luminosity depends on the stellar mass of the galaxy.
Objects which were not classified as SFGs have higher 150-MHz radio luminosity
than would be expected given their SFR, implying an important role for
low-level active galactic nucleus activity.Comment: 21 pages, 12 figures, accepted for publication in MNRA
C-ME: A 3D Community-Based, Real-Time Collaboration Tool for Scientific Research and Training
The need for effective collaboration tools is growing as multidisciplinary proteome-wide projects and distributed research teams become more common. The resulting data is often quite disparate, stored in separate locations, and not contextually related. Collaborative Molecular Modeling Environment (C-ME) is an interactive community-based collaboration system that allows researchers to organize information, visualize data on a two-dimensional (2-D) or three-dimensional (3-D) basis, and share and manage that information with collaborators in real time. C-ME stores the information in industry-standard databases that are immediately accessible by appropriate permission within the computer network directory service or anonymously across the internet through the C-ME application or through a web browser. The system addresses two important aspects of collaboration: context and information management. C-ME allows a researcher to use a 3-D atomic structure model or a 2-D image as a contextual basis on which to attach and share annotations to specific atoms or molecules or to specific regions of a 2-D image. These annotations provide additional information about the atomic structure or image data that can then be evaluated, amended or added to by other project members
Structural Insights Into the Disruption of Tnf-tnfr1 Signalling by Small Molecules Stabilising a Distorted Tnf
Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF trimer forms a complex with a dimer of TNFR1 molecules. This observation, along with data from a solution-based network assembly assay, leads us to suggest a model for TNF signalling based on TNF-TNFR1 clusters, which are disrupted by small molecule inhibitors
Small Molecules That Inhibit Tnf Signalling by Stabilising an Asymmetric Form of the Trimer
Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn\u27s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions
Collagen II antibody-induced arthritis in Tg1278TNFko mice: optimization of a novel model to assess treatments targeting human TNFα in rheumatoid arthritis
SPL7013 Gel (VivaGel®) Retains Potent HIV-1 and HSV-2 Inhibitory Activity following Vaginal Administration in Humans
SPL7013 Gel (VivaGel®) is a microbicide in development for prevention of HIV and HSV. This clinical study assessed retention and duration of antiviral activity following vaginal administration of 3% SPL7013 Gel in healthy women. Participants received 5 single doses of product with ≥5 days between doses. A cervicovaginal fluid (CVF) sample was collected using a SoftCup™ pre-dose, and immediately, or 1, 3, 12 or 24 h post-dose. HIV-1 and HSV-2 antiviral activities of CVF samples were determined in cell culture assays. Antiviral activity in the presence of seminal plasma was also tested. Mass and concentration of SPL7013 in CVF samples was determined. Safety was assessed by reporting of adverse events. Statistical analysis was performed using the Wilcoxon signed-rank test with Bonferroni adjustment; p≤0.003 was significant. Eleven participants completed the study. Inhibition of HIV-1 and HSV-2 by pre-dose CVF samples was negligible. CVF samples obtained immediately after dosing almost completely inhibited (median, interquartile range) HIV-1 [96% (95,97)] and HSV-2 [86% (85,94)], and activity was maintained in all women at 3 h (HIV-1 [96% (95,98), p = 0.9]; HSV-2 [94% (91,97), p = 0.005]). At 24 h, >90% of initial HIV-1 and HSV-2 inhibition was maintained in 6/11 women. SPL7013 was recovered in CVF samples obtained at baseline (46% of 105 mg dose). At 3 and 24 h, 22 mg and 4 mg SPL7013, respectively, were recovered. More than 70% inhibition of HIV-1 and HSV-2 was observed if there was >0.5 mg SPL7013 in CVF samples. High levels of antiviral activity were retained in the presence of seminal plasma. VivaGel was well tolerated with no signs or symptoms of vaginal, vulvar or cervical irritation reported. Potent antiviral activity was observed against HIV-1 and HSV-2 immediately following vaginal administration of VivaGel, with activity maintained for at least 3 h post-dose. The data provide evidence of antiviral activity in a clinical setting, and suggest VivaGel could be administered up to 3 h before coitus
The FAIR Guiding Principles for scientific data management and stewardship
There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders—representing academia, industry, funding agencies, and scholarly publishers—have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community
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