3,550 research outputs found
Combining semantic web technologies with evolving fuzzy classifier eClass for EHR-based phenotyping : a feasibility study
In parallel to nation-wide efforts for setting up shared electronic health records (EHRs) across healthcare settings, several large-scale national and international projects are developing, validating, and deploying electronic EHR oriented phenotype algorithms that aim at large-scale use of EHRs data for genomic studies. A current bottleneck in using EHRs data for obtaining computable phenotypes is to transform the raw EHR data into clinically relevant features. The research study presented here proposes a novel combination of Semantic Web technologies with the on-line evolving fuzzy classifier eClass to
obtain and validate EHR-driven computable phenotypes derived from 1956 clinical statements from EHRs. The evaluation performed with clinicians demonstrates the feasibility and practical acceptability of the approach proposed
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Sustained release silk fibroin discs: Antibody and protein delivery for HIV prevention
With almost 2 million new HIV infections worldwide each year, the prevention of HIV infection is critical for stopping the pandemic. The only approved form of pre-exposure prophylaxis is a costly daily pill, and it is recognized that several options will be needed to provide protection to the various affected communities around the world. In particular, many at-risk people would benefit from a prevention method that is simple to use and does not require medical intervention or a strict daily regimen. We show that silk fibroin protein can be formulated into insertable discs that encapsulate either an antibody (IgG) or the potent HIV inhibitor 5P12-RANTES. Several formulations were studied, including silk layering, water vapor annealing and methanol treatment to stabilize the protein cargo and impact the release kinetics over weeks. In the case of IgG, high concentrations were released over a short time using methanol treatment, with more sustained results with the use of water vapor annealing and layering during device fabrication. For 5P12-RANTES, sustained release was obtained for 31 days using water vapor annealing. Further, we show that the released inhibitor 5P12-RANTES was functional both in vitro and in ex vivo colorectal tissue. This work shows that silk fibroin discs can be developed into formidable tools to prevent HIV infection
Dirac Gauginos, Negative Supertraces and Gauge Mediation
In an attempt to maximize General Gauge Mediated parameter space, I propose
simple models in which gauginos and scalars are generated from disconnected
mechanisms. In my models Dirac gauginos are generated through the supersoft
mechanism, while independent R-symmetric scalar masses are generated through
operators involving non-zero messenger supertrace. I propose several new
methods for generating negative messenger supertraces which result in viable
positive mass squareds for MSSM scalars. The resultant spectra are novel,
compressed and may contain light fermionic SM adjoint fields.Comment: 16 pages 3 figure
Closing in on Asymmetric Dark Matter I: Model independent limits for interactions with quarks
It is argued that experimental constraints on theories of asymmetric dark
matter (ADM) almost certainly require that the DM be part of a richer hidden
sector of interacting states of comparable mass or lighter. A general requisite
of models of ADM is that the vast majority of the symmetric component of the DM
number density must be removed in order to explain the observed relationship
via the DM asymmetry. Demanding the efficient
annihilation of the symmetric component leads to a tension with experimental
limits if the annihilation is directly to Standard Model (SM) degrees of
freedom. A comprehensive effective operator analysis of the model independent
constraints on ADM from direct detection experiments and LHC monojet searches
is presented. Notably, the limits obtained essentially exclude models of ADM
with mass 1GeV 100GeV annihilating to SM quarks via
heavy mediator states. This motivates the study of portal interactions between
the dark and SM sectors mediated by light states. Resonances and threshold
effects involving the new light states are shown to be important for
determining the exclusion limits.Comment: 18+6 pages, 18 figures. v2: version accepted for publicatio
Ascaroside Expression in Caenorhabditis elegans Is Strongly Dependent on Diet and Developmental Stage
Background:
The ascarosides form a family of small molecules that have been isolated from cultures of the nematode Caenorhabditis elegans. They are often referred to as “dauer pheromones” because most of them induce formation of long-lived and highly stress resistant dauer larvae. More recent studies have shown that ascarosides serve additional functions as social signals and mating pheromones. Thus, ascarosides have multiple functions. Until now, it has been generally assumed that ascarosides are constitutively expressed during nematode development.
Methodology/Principal Findings:
Cultures of C. elegans were developmentally synchronized on controlled diets. Ascarosides released into the media, as well as stored internally, were quantified by LC/MS. We found that ascaroside biosynthesis and release were strongly dependent on developmental stage and diet. The male attracting pheromone was verified to be a blend of at least four ascarosides, and peak production of the two most potent mating pheromone components, ascr#3 and asc#8 immediately preceded or coincided with the temporal window for mating. The concentration of ascr#2 increased under starvation conditions and peaked during dauer formation, strongly supporting ascr#2 as the main population density signal (dauer pheromone). After dauer formation, ascaroside production largely ceased and dauer larvae did not release any ascarosides. These findings show that both total ascaroside production and the relative proportions of individual ascarosides strongly correlate with these compounds' stage-specific biological functions.
Conclusions/Significance:
Ascaroside expression changes with development and environmental conditions. This is consistent with multiple functions of these signaling molecules. Knowledge of such differential regulation will make it possible to associate ascaroside production to gene expression profiles (transcript, protein or enzyme activity) and help to determine genetic pathways that control ascaroside biosynthesis. In conjunction with findings from previous studies, our results show that the pheromone system of C. elegans mimics that of insects in many ways, suggesting that pheromone signaling in C. elegans may exhibit functional homology also at the sensory level. In addition, our results provide a strong foundation for future behavioral modeling studies
Diboson-Jets and the Search for Resonant Zh Production
New particles at the TeV-scale may have sizeable decay rates into boosted
Higgs bosons or other heavy scalars. Here, we investigate the possibility of
identifying such processes when the Higgs/scalar subsequently decays into a
pair of W bosons, constituting a highly distinctive "diboson-jet." These can
appear as a simple dilepton (plus MET) configuration, as a two-prong jet with
an embedded lepton, or as a four-prong jet. We study jet substructure methods
to discriminate these objects from their dominant backgrounds. We then
demonstrate the use of these techniques in the search for a heavy spin-one Z'
boson, such as may arise from strong dynamics or an extended gauge sector,
utilizing the decay chain Z' -> Zh -> Z(WW^(*)). We find that modes with
multiple boosted hadronic Zs and Ws tend to offer the best prospects for the
highest accessible masses. For 100/fb luminosity at the 14 TeV LHC, Z' decays
into a standard 125 GeV Higgs can be observed with 5-sigma significance for
masses of 1.5-2.5 TeV for a range of models. For a 200 GeV Higgs (requiring
nonstandard couplings, such as fermiophobic), the reach may improve to up to
2.5-3.0 TeV.Comment: 23 pages plus appendices, 9 figure
Testing many treatments within a single protocol over 10 years at MRC Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket protocols
There is real need to change how we do some of our clinical trials, as currently the testing and development process is too slow, too costly and too failure-prone often we find that a new treatment is no better than the current standard. Much of the focus on the development and testing pathway has been in improving the design of phase I and II trials. In this article, we present examples of new methods for improving the design of phase III trials (and the necessary lead up to them) as they are the most time-consuming and expensive part of the pathway. Key to all these methods is the aim to test many treatments and/or pose many therapeutic questions within one protocol
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Stabilization and Sustained Release of HIV Inhibitors by Encapsulation in Silk Fibroin Disks
Topical microbicides have the potential to provide effective protection against sexual transmission of HIV. Challenges in developing microbicides include their application in resource-poor settings with high temperatures and a lack of refrigeration, and low user adherence to a rigorous daily regimen. Several protein-based HIV inhibitors show great promise as microbicides, being highly specific and not expected to lead to resistance that would affect the efficacy of current antiretroviral treatments. We show that four potent protein HIV inhibitors, 5P12-RANTES, 5P12-RANTES-L-C37, Grft, and Grft-L-C37 can be formulated into silk fibroin (SF) disks and remain functional for 14 months at 25, 37, and 50 °C. These HIV inhibitor-encapsulated SF disks show excellent inhibition properties in PBMC and in human colorectal and cervical tissue explants, and do not induce inflammatory cytokine secretion. Further, the SF provides a mechanically robust matrix with versatile material formats for this type of application. Finally, a formulation was developed to allow sustained release of functional Grft for 4 weeks at levels sufficient to inhibit HIV transmission. This work establishes the suitability of HIV inhibitor-encapsulated SF disks as topical HIV microbicides that can be further developed to allow easy insertion for extended protection
Electroweak Baryogenesis and Dark Matter with an approximate R-symmetry
It is well known that R-symmetric models dramatically alleviate the SUSY
flavor and CP problems. We study particular modifications of existing
R-symmetric models which share the solution to the above problems, and have
interesting consequences for electroweak baryogenesis and the Dark Matter (DM)
content of the universe. In particular, we find that it is naturally possible
to have a strongly first-order electroweak phase transition while
simultaneously relaxing the tension with EDM experiments. The R-symmetry (and
its small breaking) implies that the gauginos (and the neutralino LSP) are
pseudo-Dirac fermions, which is relevant for both baryogenesis and DM. The
singlet superpartner of the U(1)_Y pseudo-Dirac gaugino plays a prominent role
in making the electroweak phase transition strongly first-order. The
pseudo-Dirac nature of the LSP allows it to behave similarly to a Dirac
particle during freeze-out, but like a Majorana particle for annihilation today
and in scattering against nuclei, thus being consistent with current
constraints. Assuming a standard cosmology, it is possible to simultaneously
have a strongly first-order phase transition conducive to baryogenesis and have
the LSP provide the full DM relic abundance, in part of the allowed parameter
space. However, other possibilities for DM also exist, which are discussed. It
is expected that upcoming direct DM searches as well as neutrino signals from
DM annihilation in the Sun will be sensitive to this class of models.
Interesting collider and Gravity-wave signals are also briefly discussed.Comment: 50 pages, 10 figure
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