55 research outputs found
Yukawa hierarchies at the point of in F-theory
We analyse the structure of Yukawa couplings in local SU(5) F-theory models
with enhancement. In this setting the symmetry is broken down to
SU(5) by a 7-brane configuration described by T-branes, all the Yukawa
couplings are generated in the vicinity of a point and only one family of
quarks and leptons is massive at tree-level. The other two families obtain
their masses when non-perturbative effects are taken into account, being
hierarchically lighter than the third family. However, and contrary to previous
results, we find that this hierarchy of fermion masses is not always
appropriate to reproduce measured data. We find instead that different T-brane
configurations breaking to SU(5) give rise to distinct hierarchical
patterns for the holomorphic Yukawa couplings. Only some of these patterns
allow to fit the observed fermion masses with reasonable local model parameter
values, adding further constraints to the construction of F-theory GUTs. We
consider an model where such appropriate hierarchy is realised and
compute its physical Yukawas, showing that realistic charged fermions masses
can indeed be obtained in this case.Comment: 46 pages + appendices, 5 figures. v2, added references and typos
corrected, version accepted on JHEP. v3, typos correcte
Wavefunctions and the Point of E8 in F-theory
In F-theory GUTs interactions between fields are typically localised at
points of enhanced symmetry in the internal dimensions implying that the
coefficient of the associated operator can be studied using a local
wavefunctions overlap calculation. Some F-theory SU(5) GUT theories may exhibit
a maximum symmetry enhancement at a point to E8, and in this case all the
operators of the theory can be associated to the same point. We take initial
steps towards the study of operators in such theories. We calculate
wavefunctions and their overlaps around a general point of enhancement and
establish constraints on the local form of the fluxes. We then apply the
general results to a simple model at a point of E8 enhancement and calculate
some example operators such as Yukawa couplings and dimension-five couplings
that can lead to proton decay.Comment: 46 page
Building SO(10) models from F-theory
We revisit local F-theory SO(10) and SU(5) GUTs and analyze their properties
within the framework of the maximal underlying E_8 symmetry in the elliptic
fibration. We consider the symmetry enhancements along the intersections of
seven-branes with the GUT surface and study in detail the embedding of the
abelian factors undergoing monodromies in the covering gauge groups. We combine
flux data from the successive breaking of SO(10) to SU(5) gauge symmetry and
subsequently to the Standard Model one, and further constrain the parameters
determining the models' particle spectra. In order to eliminate dangerous
baryon number violating operators we propose ways to construct matter parity
like symmetries from intrinsic geometric origin. We study implementations of
the resulting constrained scenario in specific examples obtained for a variety
of monodromies.Comment: 53 page
Propagation of an Earth-directed coronal mass ejection in three dimensions
Solar coronal mass ejections (CMEs) are the most significant drivers of
adverse space weather at Earth, but the physics governing their propagation
through the heliosphere is not well understood. While stereoscopic imaging of
CMEs with the Solar Terrestrial Relations Observatory (STEREO) has provided
some insight into their three-dimensional (3D) propagation, the mechanisms
governing their evolution remain unclear due to difficulties in reconstructing
their true 3D structure. Here we use a new elliptical tie-pointing technique to
reconstruct a full CME front in 3D, enabling us to quantify its deflected
trajectory from high latitudes along the ecliptic, and measure its increasing
angular width and propagation from 2-46 solar radii (approximately 0.2 AU).
Beyond 7 solar radii, we show that its motion is determined by an aerodynamic
drag in the solar wind and, using our reconstruction as input for a 3D
magnetohydrodynamic simulation, we determine an accurate arrival time at the
Lagrangian L1 point near Earth.Comment: 5 figures, 2 supplementary movie
Intestinal strongyloidiasis and hyperinfection syndrome
In spite of recent advances with experiments on animal models, strongyloidiasis, an infection caused by the nematode parasite Strongyloides stercoralis, has still been an elusive disease. Though endemic in some developing countries, strongyloidiasis still poses a threat to the developed world. Due to the peculiar but characteristic features of autoinfection, hyperinfection syndrome involving only pulmonary and gastrointestinal systems, and disseminated infection with involvement of other organs, strongyloidiasis needs special attention by the physician, especially one serving patients in areas endemic for strongyloidiasis. Strongyloidiasis can occur without any symptoms, or as a potentially fatal hyperinfection or disseminated infection. Th(2 )cell-mediated immunity, humoral immunity and mucosal immunity have been shown to have protective effects against this parasitic infection especially in animal models. Any factors that suppress these mechanisms (such as intercurrent immune suppression or glucocorticoid therapy) could potentially trigger hyperinfection or disseminated infection which could be fatal. Even with the recent advances in laboratory tests, strongyloidiasis is still difficult to diagnose. But once diagnosed, the disease can be treated effectively with antihelminthic drugs like Ivermectin. This review article summarizes a case of strongyloidiasis and various aspects of strongyloidiasis, with emphasis on epidemiology, life cycle of Strongyloides stercoralis, clinical manifestations of the disease, corticosteroids and strongyloidiasis, diagnostic aspects of the disease, various host defense pathways against strongyloidiasis, and available treatment options
Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers
Characterization of small oligomers formed at an early stage of amyloid formation is critical to
understanding molecular mechanism of pathogenic aggregation process. Here we identifed and
characterized cytotoxic oligomeric intermediates populated during transthyretin (TTR) aggregation
process. Under the amyloid-forming conditions, TTR initially forms a dimer through interactions
between outer strands. The dimers are then associated to form a hexamer with a spherical shape, which
serves as a building block to self-assemble into cytotoxic oligomers. Notably, wild-type (WT) TTR tends
to form linear oligomers, while aTTR variant(G53A) prefers forming annular oligomers with pore-like
structures. Structural analyses of the amyloidogenic intermediates using circular dichroism (CD) and
solid-state NMR revealthatthe dimer and oligomers have a signifcant degree of native-like β-sheet
structures (35–38%), but with more disordered regions (~60%)than those of nativeTTR.TheTTR variant
oligomers are also less structured than WT oligomers. The partially folded nature of the oligomeric
intermediates might be a common structural property of cytotoxic oligomers.The higher fexibility of
the dimer and oligomers may also compensate for the entropic loss due to the oligomerization of the
monomers
Using enhanced number and brightness to measure protein oligomerization dynamics in live cells
Protein dimerization and oligomerization are essential to most cellular functions, yet measurement of the size of these oligomers in live cells, especially when their size changes over time and space, remains a challenge. A commonly used approach for studying protein aggregates in cells is number and brightness (N&B), a fluorescence microscopy method that is capable of measuring the apparent average number of molecules and their oligomerization (brightness) in each pixel from a series of fluorescence microscopy images. We have recently expanded this approach in order to allow resampling of the raw data to resolve the statistical weighting of coexisting species within each pixel. This feature makes enhanced N&B (eN&B) optimal for capturing the temporal aspects of protein oligomerization when a distribution of oligomers shifts toward a larger central size over time. In this protocol, we demonstrate the application of eN&B by quantifying receptor clustering dynamics using electron-multiplying charge-coupled device (EMCCD)-based total internal reflection microscopy (TIRF) imaging. TIRF provides a superior signal-to-noise ratio, but we also provide guidelines for implementing eN&B in confocal microscopes. For each time point, eN&B requires the acquisition of 200 frames, and it takes a few seconds up to 2 min to complete a single time point. We provide an eN&B (and standard N&B) MATLAB software package amenable to any standard confocal or TIRF microscope. The software requires a high-RAM computer (64 Gb) to run and includes a photobleaching detrending algorithm, which allows extension of the live imaging for more than an hour
Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP)
Background
Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment.
Methods
The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15–20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18–24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial.
Discussion
If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy.
Trial registration
ISRCTN Registry, ISRCTN92634082. Registered on 31 March 2016
Evaluation of appendicitis risk prediction models in adults with suspected appendicitis
Background
Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis.
Methods
A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis).
Results
Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent).
Conclusion
Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified
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