Potent induction of antibody-secreting B-cells by human dermal-derived CD14+ dendritic cells triggered by dual toll-like receptor ligation

Targeting CD14(+) dermal-derived dendritic cells (DDCs) is a rational approach for vaccination strategies aimed at improving humoral immune responses, because of their natural ability to stimulate naïve B-cells. Here, we show that CD14(+) DDCs express mRNA for TLRs 1–9, but respond differentially to single or paired TLR ligands. Compared to single ligands, some combinations were particularly effective at activating CD14(+) DDCs, as shown by enhanced expression of B-cell stimulatory cytokines (IL-6, IL-10 and TNF-α) and more pronounced phenotypic maturation. These combinations were Resiquimod (R-848) plus Polyinosinic:polycytidylic acid (Poly(I:C)); R-848 plus LPS; Pam3CSK4 plus Poly(I:C); LPS plus Poly(I:C). We also found that selected TLR ligand pairs (R-848 plus either LPS or Poly(I:C)) were superior to individual agents at boosting the inherent capacity of CD14(+) DDCs to induce naïve B-cells to proliferate and differentiate into CD27(+) CD38(+) B-cells that secrete high levels of IgG and IgA. When treated with the same TLR ligand combinations, CD14(+) DDCs also promoted the differentiation of Th1 (IFN-γ-secreting) CD4(+) T-cells, but not of Th2 or Th17 CD4(+) T-cells. These observations may help to identify adjuvant strategies aimed at inducing protective immune responses to various pathogens, including but not limited to HIV-1

Atrial fibrillation epidemiology, disparity and healthcare contacts: a population-wide study of 5.6 million individuals

Background: We aimed to evaluate atrial fibrillation occurrence, reasons for healthcare visits, mortality, causes of death and examined patterns by relative deprivation in the UK. Methods: To study the atrial fibrillation (AF) incidence, mortality and case-fatality, we implemented a prospective cohort study with the linked electronic health records of 5.6 million population in the United Kingdom Clinical Practice Research Datalink from 1998 to 2016. A matched case-control study was used to investigate causes of hospitalisation and death comparing individuals with and without incident AF. Results: During a median follow-up of 10.3 years, 199,433(3.6%) patients developed incident AF. Increased risk of hospitalisation for heart failure, cardiovascular conditions and infection was present among patients who later developed AF. Following an AF diagnosis, patients were frequently admitted to the hospital for heart failure, lower respiratory tract infection, chronic obstructive pulmonary disease and ischemic heart disease. One in 5 AF patients died during the first year after diagnosis, and the mortality increased to 42.7% at the fifth year. The excess deaths in AF cases compared to controls may result from cardiovascular diseases, infection and metabolic disorders. Individuals from areas with higher deprivation in socioeconomic and living status had both higher AF incidence and fatality. Interpretation: We observed an elevated risk of hospitalisation for cardiovascular or respiratory diseases among incident AF patients, and the considerable disparity in AF burden by socioeconomic deprivation informs priorities for prevention and provision of patient care

Bino Dark Matter and Big Bang Nucleosynthesis in the Constrained E6SSM with Massless Inert Singlinos

We discuss a new variant of the E6 inspired supersymmetric standard model (E6SSM) in which the two inert singlinos are exactly massless and the dark matter candidate has a dominant bino component. A successful relic density is achieved via a novel mechanism in which the bino scatters inelastically into heavier inert Higgsinos during the time of thermal freeze-out. The two massless inert singlinos contribute to the effective number of neutrino species at the time of Big Bang Nucleosynthesis, where the precise contribution depends on the mass of the Z' which keeps them in equilibrium. For example for mZ' > 1300 GeV we find Neff \approx 3.2, where the smallness of the additional contribution is due to entropy dilution. We study a few benchmark points in the constrained E6SSM with massless inert singlinos to illustrate this new scenario.Comment: 24 pages, revised for publication in JHE

Experimental verification of electrostatic boundary conditions in gate-patterned quantum devices

In a model of a gate-patterned quantum device it is important to choose the correct electrostatic boundary conditions (BCs) in order to match experiment. In this study, we model gated-patterned devices in doped and undoped GaAs heterostructures for a variety of BCs. The best match is obtained for an unconstrained surface between the gates, with a dielectric region above it and a frozen layer of surface charge, together with a very deep back boundary. Experimentally, we find a 0.2V offset in pinch-off characteristics of one-dimensional channels in a doped heterostructure before and after etching off a ZnO overlayer, as predicted by the model. Also, we observe a clear quantised current driven by a surface acoustic wave through a lateral induced n-i-n junction in an undoped heterostructure. In the model, the ability to pump electrons in this type of device is highly sensitive to the back BC. Using the improved boundary conditions, it is straightforward to model quantum devices quite accurately using standard software

Postural loads during walking after an imbalance of occlusion created with unilateral cotton rolls

<p>Abstract</p> <p>Background</p> <p>It was showed that stomatognathic functions correlate with alterations in locomotion, that are detectable through the analysis of loading during walking. For example, subjects with symptoms of Temporomandibular disorders (TMDs) showed a significant higher load pressure on the two feet, respect to health subjects, when cotton rolls were inserted. This previous study appeared to suggest that the alteration of postural loads associated to a particular alteration of stomatognathic condition (in this case, the cotton rolls inserted between the two dental arches) is detectable only in TMD's subjects, while it resulted not detectable in health subjects, because in that study, health subjects did not show any significant alteration of postural loads related to the different stomatognathic tested conditions. In other words, in that previous study, in the group of health subjects, no significant difference in postural loads was observed among the different test conditions; while TMD subjects showed a significant higher load pressure on the two feet when cotton rolls were inserted, respect to all the other tested conditions. Thus, the aim of this study was to better investigate these correlations in health subjects without TMD's symptoms, testing other different intra-oral conditions, and to verifywhether an experimentally induced imbalance of occlusion, obtained putting an unilateral cotton roll, could cause an alteration of postural loading on feet during walking.</p> <p>Findings</p> <p>In a sample of thirty Caucasian adult females (mean age 28.5 ± 4.5), asymptomatic for TMDs, when a cotton roll was positioned on the left or the right sides of dental arches, so causing a lateral shift of the mandible, the percentage of loading and the loading surface of the ipsi-lateral foot, left or right, were found to be significantly lower than in habitual occlusion (p < 0.05). Males were not included because of their different postural attitude respect to females. Further studies in a sample of males will be presented.</p> <p>Conclusions</p> <p>This study showed that in health subjects without TMD's symptoms, an experimentally induced imbalance of the occlusion, obtained through an unilateral cotton roll, is associated to detectable alterations in the distribution of loading on feet surface, during walking.</p

On Global Flipped SU(5) GUTs in F-theory

We construct an SU(4) spectral divisor and its factorization of types (3,1) and (2,2) based on the construction proposed in [1]. We calculate the chiral spectra of flipped SU(5) GUTs by using the spectral divisor construction. The results agree with those from the analysis of semi-local spectral covers. Our computations provide an example for the validity of the spectral divisor construction and suggest that the standard heterotic formulae are applicable to the case of F-theory on an elliptically fibered Calabi-Yau fourfold with no heterotic dual.Comment: 45 pages, 12 tables, 1 figure; typos corrected, footnotes added, and a reference adde

Optimized T1- and T2-weighted volumetric brain imaging as a diagnostic tool in very preterm neonates.

BACKGROUND: T1- and T2-W MR sequences used for obtaining diagnostic information and morphometric measurements in the neonatal brain are frequently acquired using different imaging protocols. Optimizing one protocol for obtaining both kinds of information is valuable. OBJECTIVE: To determine whether high-resolution T1- and T2-W volumetric sequences optimized for preterm brain imaging could provide both diagnostic and morphometric value. MATERIALS AND METHODS: Thirty preterm neonates born between 24 and 32 weeks' gestational age were scanned during the first 2 weeks after birth. T1- and T2-W high-resolution sequences were optimized in terms of signal-to-noise ratio, contrast-to-noise ratio and scan time and compared to conventional spin-echo-based sequences. RESULTS: No differences were found between conventional and high-resolution T1-W sequences for diagnostic confidence, image quality and motion artifacts. A preference for conventional over high-resolution T2-W sequences for image quality was observed. High-resolution T1 images provided better delineation of thalamic myelination and the superior temporal sulcus. No differences were found for detection of myelination and sulcation using conventional and high-resolution T2-W images. CONCLUSION: High-resolution T1- and T2-W volumetric sequences can be used in clinical MRI in the very preterm brain to provide both diagnostic and morphometric information

Flipped SU(5) GUTs from E_8 Singularities in F-theory

In this paper we construct supersymmetric flipped SU(5) GUTs from E_8 singularities in F-theory. We start from an SO(10) singularity unfolded from an E_8 singularity by using an SU(4) spectral cover. To obtain realistic models, we consider (3,1) and (2,2) factorizations of the SU(4) cover. After turning on the massless U(1)_X gauge flux, we obtain the SU(5) X U(1)_X gauge group. Based on the well-studied geometric backgrounds in the literature, we demonstrate several models and discuss their phenomenology.Comment: 46 pages, 23 tables, 1 figure, typos corrected, references added, and new examples presente