Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity

Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. Here we devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; they recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models

Gluino Decay as a Probe of High Scale Supersymmetry Breaking

A supersymmetric standard model with heavier scalar supersymmetric particles has many attractive features. If the scalar mass scale is O(10 - 10^4) TeV, the standard model like Higgs boson with mass around 125 GeV, which is strongly favored by the LHC experiment, can be realized. However, in this scenario the scalar particles are too heavy to be produced at the LHC. In addition, if the scalar mass is much less than O(10^4) TeV, the lifetime of the gluino is too short to be measured. Therefore, it is hard to probe the scalar particles at a collider. However, a detailed study of the gluino decay reveals that two body decay of the gluino carries important information on the scalar scale. In this paper, we propose a test of this scenario by measuring the decay pattern of the gluino at the LHC.Comment: 29 pages, 9 figures; version published in JHE

Kinetic frustration and the nature of the magnetic and paramagnetic states in iron pnictides and iron chalcogenides

The iron pnictide and chalcogenide compounds are a subject of intensive investigations due to their high temperature superconductivity.\cite{a-LaFeAsO} They all share the same structure, but there is significant variation in their physical properties, such as magnetic ordered moments, effective masses, superconducting gaps and T$_c$. Many theoretical techniques have been applied to individual compounds but no consistent description of the trends is available \cite{np-review}. We carry out a comparative theoretical study of a large number of iron-based compounds in both their magnetic and paramagnetic states. We show that the nature of both states is well described by our method and the trends in all the calculated physical properties such as the ordered moments, effective masses and Fermi surfaces are in good agreement with experiments across the compounds. The variation of these properties can be traced to variations in the key structural parameters, rather than changes in the screening of the Coulomb interactions. Our results provide a natural explanation of the strongly Fermi surface dependent superconducting gaps observed in experiments\cite{Ding}. We propose a specific optimization of the crystal structure to look for higher T$_c$ superconductors.Comment: 5 pages, 3 figures with a 5-page supplementary materia

HGF Mediates the Anti-inflammatory Effects of PRP on Injured Tendons

Platelet-rich plasma (PRP) containing hepatocyte growth factor (HGF) and other growth factors are widely used in orthopaedic/sports medicine to repair injured tendons. While PRP treatment is reported to decrease pain in patients with tendon injury, the mechanism of this effect is not clear. Tendon pain is often associated with tendon inflammation, and HGF is known to protect tissues from inflammatory damages. Therefore, we hypothesized that HGF in PRP causes the anti-inflammatory effects. To test this hypothesis, we performed in vitro experiments on rabbit tendon cells and in vivo experiments on a mouse Achilles tendon injury model. We found that addition of PRP or HGF decreased gene expression of COX-1, COX-2, and mPGES-1, induced by the treatment of tendon cells in vitro with IL-1β. Further, the treatment of tendon cell cultures with HGF antibodies reduced the suppressive effects of PRP or HGF on IL-1β-induced COX-1, COX-2, and mPGES-1 gene expressions. Treatment with PRP or HGF almost completely blocked the cellular production of PGE2 and the expression of COX proteins. Finally, injection of PRP or HGF into wounded mouse Achilles tendons in vivo decreased PGE2 production in the tendinous tissues. Injection of platelet-poor plasma (PPP) however, did not reduce PGE2 levels in the wounded tendons, but the injection of HGF antibody inhibited the effects of PRP and HGF. Further, injection of PRP or HGF also decreased COX-1 and COX-2 proteins. These results indicate that PRP exerts anti-inflammatory effects on injured tendons through HGF. This study provides basic scientific evidence to support the use of PRP to treat injured tendons because PRP can reduce inflammation and thereby reduce the associated pain caused by high levels of PGE2. © 2013 Zhang et al

CtBP1/BARS is an activator of phospholipase D1 necessary for agonist-induced macropinocytosis

Vesicular trafficking such as macropinocytosis is a dynamic process that requires coordinated interactions between specialized proteins and lipids. A recent report suggests the involvement of CtBP1/BARS in epidermal growth factor (EGF)-induced macropinocytosis. Detailed mechanisms as to how lipid remodelling is regulated during macropinocytosis are still undefined. Here, we show that CtBP1/BARS is a physiological activator of PLD1 required in agonist-induced macropinocytosis. EGF-induced macropinocytosis was specifically blocked by 1-butanol but not by 2-butanol. In addition, stimulation of cells by serum or EGF resulted in the association of CtBP1/BARS with PLD1. Finally, CtBP1/BARS activated PLD1 in a synergistic manner with other PLD activators, including ADP-ribosylation factors as demonstrated by in vitro and intact cell systems. The present results shed light on the molecular basis of how the ‘fission protein' CtBP1/BARS controls vesicular trafficking events including macropinocytosis

Singlet-doublet Higgs mixing and its implications on the Higgs mass in the PQ-NMSSM

We examine the implications of singlet-doublet Higgs mixing on the properties of a Standard Model (SM)-like Higgs boson within the Peccei-Quinn invariant extension of the NMSSM (PQ-NMSSM). The SM singlet added to the Higgs sector connects the PQ and visible sectors through a PQ-invariant non-renormalizable K\"ahler potential term, making the model free from the tadpole and domain-wall problems. For the case that the lightest Higgs boson is dominated by the singlet scalar, the Higgs mixing increases the mass of a SM-like Higgs boson while reducing its signal rate at collider experiments compared to the SM case. The Higgs mixing is important also in the region of parameter space where the NMSSM contribution to the Higgs mass is small, but its size is limited by the experimental constraints on the singlet-like Higgs boson and on the lightest neutralino constituted mainly by the singlino whose Majorana mass term is forbidden by the PQ symmetry. Nonetheless the Higgs mixing can increase the SM-like Higgs boson mass by a few GeV or more even when the Higgs signal rate is close to the SM prediction, and thus may be crucial for achieving a 125 GeV Higgs mass, as hinted by the recent ATLAS and CMS data. Such an effect can reduce the role of stop mixing.Comment: 26 pages, 3 figures; published in JHE

Sexuality throughout all the stages of pregnancy: experiences of expectant mothers

Objective: To explore and understand the sexual experiences of expectant mothers during their pregnancy. Methods: The study was carried out in two healthcare centers in the Almería Health District, in southern Spain. The participants included pregnant women who received prenatal care and/or maternity education. The inclusion criteria were being pregnant, maintaining sexual activity and agreeing to participate in the study. The exclusion criteria were having limitations on sexual activity by medical prescription. The sample consisted of 15 expectant women selected using a convenience sample, of which 5 took part in a focus group (FG) and 10 in in-depth interviews (IDI). Data was collected between the months of June and December 2016. Participants were contacted by the main researcher and an appointment was made to carry out the FGs or the IDIs. Results: Three main categories emerged: False beliefs and a holistic approach to sexuality during pregnancy, which is related to the concept of sexuality, false beliefs, and limited sexual counseling during pregnancy. Limitations: From fear at the beginning to physical diffi culty at the end, referring to the fluctuations in sexual desire as well as the physical changes that limit sexual activity. Adapting to changes: safe practices and satisfaction with one’s body image, which encompasses concerns about the risks and the relationship between body image and self-esteem. Conclusion: A lack of sexual counseling during pregnancy leads to the creation of false beliefs, which, together with physical changes, concerns about the risk, and fl uctuations in sexual desire and interest, bring about a decrease in sexual activity. But sexuality remains an important aspect of pregnancy, toward which the participants must adopt a broader approach, not limited to intercourse, and adopt sexual practices that are adapted to the physical and emotional changes that happen during this time

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Developing a digital intervention for cancer survivors: an evidence-, theory- and person-based approach

This paper illustrates a rigorous approach to developing digital interventions using an evidence-, theory- and person-based approach. Intervention planning included a rapid scoping review which identified cancer survivors’ needs, including barriers and facilitators to intervention success. Review evidence (N=49 papers) informed the intervention’s Guiding Principles, theory-based behavioural analysis and logic model. The intervention was optimised based on feedback on a prototype intervention through interviews (N=96) with cancer survivors and focus groups with NHS staff and cancer charity workers (N=31). Interviews with cancer survivors highlighted barriers to engagement, such as concerns about physical activity worsening fatigue. Focus groups highlighted concerns about support appointment length and how to support distressed participants. Feedback informed intervention modifications, to maximise acceptability, feasibility and likelihood of behaviour change. Our systematic method for understanding user views enabled us to anticipate and address important barriers to engagement. This methodology may be useful to others developing digital interventions

Kothe dual of Banach lattices generated by vector measures

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