An Image-Based Genetic Assay Identifies Genes in T1D Susceptibility Loci Controlling Cellular Antiviral Immunity in Mouse

The pathogenesis of complex diseases, such as type 1 diabetes (T1D), derives from interactions between host genetics and environmental factors. Previous studies have suggested that viral infection plays a significant role in initiation of T1D in genetically predisposed individuals. T1D susceptibility loci may therefore be enriched in previously uncharacterized genes functioning in antiviral defense pathways. To identify genes involved in antiviral immunity, we performed an image-based high-throughput genetic screen using short hairpin RNAs (shRNAs) against 161 genes within T1D susceptibility loci. RAW 264.7 cells transduced with shRNAs were infected with GFP-expressing herpes simplex virus type 1 (HSV-1) and fluorescent microscopy was performed to assess the viral infectivity by fluorescence reporter activity. Of the 14 candidates identified with high confidence, two candidates were selected for further investigation, Il27 and Tagap. Administration of recombinant IL-27 during viral infection was found to act synergistically with interferon gamma (IFN-γ) to activate expression of type I IFNs and proinflammatory cytokines, and to enhance the activities of interferon regulatory factor 3 (IRF3). Consistent with a role in antiviral immunity, Tagap-deficient macrophages demonstrated increased viral replication, reduced expression of proinflammatory chemokines and cytokines, and decreased production of IFN-β. Taken together, our unbiased loss-of-function genetic screen identifies genes that play a role in host antiviral immunity and delineates roles for IL-27 and Tagap in the production of antiviral cytokines

Routine Pediatric Enterovirus 71 Vaccination in China: a Cost-Effectiveness Analysis.

BACKGROUND: China accounted for 87% (9.8 million/11.3 million) of all hand, foot, and mouth disease (HFMD) cases reported to WHO during 2010-2014. Enterovirus 71 (EV71) is responsible for most of the severe HFMD cases. Three EV71 vaccines recently demonstrated good efficacy in children aged 6-71 mo. Here we assessed the cost-effectiveness of routine pediatric EV71 vaccination in China. METHODS AND FINDINGS: We characterized the economic and health burden of EV71-associated HFMD (EV71-HFMD) in China using (i) the national surveillance database, (ii) virological surveillance records from all provinces, and (iii) a caregiver survey on the household costs and health utility loss for 1,787 laboratory-confirmed pediatric cases. Using a static model parameterized with these data, we estimated the effective vaccine cost (EVC, defined as cost/efficacy or simply the cost of a 100% efficacious vaccine) below which routine pediatric vaccination would be considered cost-effective. We performed the base-case analysis from the societal perspective with a willingness-to-pay threshold of one times the gross domestic product per capita (GDPpc) and an annual discount rate of 3%. We performed uncertainty analysis by (i) accounting for the uncertainty in the risk of EV71-HFMD due to missing laboratory data in the national database, (ii) excluding productivity loss of parents and caregivers, (iii) increasing the willingness-to-pay threshold to three times GDPpc, (iv) increasing the discount rate to 6%, and (v) accounting for the proportion of EV71-HFMD cases not registered by national surveillance. In each of these scenarios, we performed probabilistic sensitivity analysis to account for parametric uncertainty in our estimates of the risk of EV71-HFMD and the expected costs and health utility loss due to EV71-HFMD. Routine pediatric EV71 vaccination would be cost-saving if the all-inclusive EVC is below US$10.6 (95$9.7-US$11.5) and would remain cost-effective if EVC is below US$17.9 (95% CI US$16.9-US$18.8) in the base case, but these ceilings could be up to 66% higher if all the test-negative cases with missing laboratory data are EV71-HFMD. The EVC ceiling is (i) 10%-14% lower if productivity loss of parents/caregivers is excluded, (ii) 58%-84% higher if the willingness-to-pay threshold is increased to three times GDPpc, (iii) 14%-19% lower if the discount rate is increased to 6%, and (iv) 36% (95% CI 23%-50%) higher if the proportion of EV71-HFMD registered by national surveillance is the same as that observed in the three EV71 vaccine phase III trials. The validity of our results relies on the following assumptions: (i) self-reported hospital charges are a good proxy for the opportunity cost of care, (ii) the cost and health utility loss estimates based on laboratory-confirmed EV71-HFMD cases are representative of all EV71-HFMD cases, and (iii) the long-term average risk of EV71-HFMD in the future is similar to that registered by national surveillance during 2010-2013. CONCLUSIONS: Compared to no vaccination, routine pediatric EV71 vaccination would be very cost-effective in China if the cost of immunization (including all logistical, procurement, and administration costs needed to confer 5 y of vaccine protection) is below US$12.0-US$18.3, depending on the choice of vaccine among the three candidates. Given that the annual number of births in China has been around 16 million in recent years, the annual costs for routine pediatric EV71 vaccination at this cost range should not exceed US$192-US$293 million. Our results can be used to determine the optimal vaccine when the prices of the three vaccines are known

Is distortion of the bioprosthesis ring a risk factor for early calcification ?

<p>Abstract</p> <p>Background</p> <p>As the population ages, bioprosthesis are increasingly being used in cardiac valve replacement. Pericardial bioprosthesis combine an excellent hemodynamic performance with low thrombogenicity, but valve failure associated with calcification remains a concern with these valves. We describe distortion of the bioprosthesis ring as a risk factor for early calcification.</p> <p>Methods</p> <p>A total of 510 patients over the age of 70 years underwent isolated aortic valve replacement with the Mitroflow (A12) pericardial bioprosthesis. Thirty two patients (6,2%) have undergone a second aortic valve replacement due to structural valve dysfunction resulting from valve calcification. In all patients a chest radiography and coronary angiography was performed before reoperation. A 64 Multidetector Computed Tomography (MDCT) with retrospective ECG gating study was performed in four patients to evaluate the aortic bioprosthesis.</p> <p>Results</p> <p>Chest radiography showed in all patients an irregular bioprosthesis ring. At preoperative coronary angiography a distorted bioprosthesis ring was detected in all patients. Macroscopic findings of the explanted bioprostheses included extensive calcification in all specimens.</p> <p>Conclusion</p> <p>There was a possible relationship between early bioprosthetic calcification and radiologic distortion of the bioprosthesis ring.</p

Glycine Potentiates AMPA Receptor Function through Metabotropic Activation of GIuN2A-Containing NMDA Receptors

NMDA receptors are Ca2+.-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor -mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GIuN2A-containing NMDA receptors (GIuN2ARs), but not GIuN2B-containing NMDA receptors (GIuN2BRs), to enhance ERK1/2 phosphorylation independent of the channel activity of GIuN2ARs. Without requiring the channel activity of GIuN2ARs, glycine increases AMPA receptor -mediated currents through GIuN2ARs. Thus, these results reveal a metabotropic function of GIuN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation

A novel hypoxia gene signature indicates prognosis and immune microenvironments characters in patients with hepatocellular carcinoma

Due to the lack of a suitable gene signature, it is difficult to assess the hypoxic exposure of HCC tissues. The clinical value of assessing hypoxia in HCC is short of tissue-level evidence. We tried to establish a robust and HCC-suitable hypoxia signature using microarray analysis and a robust rank aggregation algorithm. Based on the hypoxia signature, we obtained a hypoxia-associated HCC subtypes system using unsupervised hierarchical clustering and a hypoxia score system was provided using gene set variation analysis. A novel signature containing 21 stable hypoxia-related genes was constructed to effectively indicate the exposure of hypoxia in HCC tissues. The signature was validated by qRT-PCR and compared with other published hypoxia signatures in multiple large-size HCC cohorts. The subtype of HCC derived from this signature had different prognosis and other clinical characteristics. The hypoxia score obtained from the signature could be used to indicate clinical characteristics and predict prognoses of HCC patients. Moreover, we reveal a landscape of immune microenvironments in patients with different hypoxia score. In conclusion, we identified a novel HCC-suitable 21-gene hypoxia signature that could be used to estimate the hypoxia exposure in HCC tissues and indicated prognosis and a series of important clinical features in HCCs. It may enable the development of personalized counselling or treatment strategies for HCC patients with different levels of hypoxia exposure

A Multi-Institutional Approach to Delivering Shared Curricula for Developing a Next-Generation Energy Workforce

In this paper, we consider collaborative power systems education through the FEEDER consortium. To increase students\u27 access to power engineering educational content, the consortium of seven universities was formed. A framework is presented to characterize different collaborative education activities among the universities. Three of these approaches of collaborative educational activities are presented and discussed. These include 1) cross-institutional blended courses (“MS-MD”); 2) cross-institutional distance courses (“SS-MD”); and 3) single-site special experiential courses and concentrated on-site programs available to students across consortium institutions (“MS-SD”). This paper presents the advantages and disadvantages of each approach

Unparticle Effects on Top Quark Pair Production at Photon Collider

The unparticle effects on $t\bar t$ production at the future photon collider are investigated. Distributions of $t\bar t$ invariant mass and that for transverse momentum of top quark with respect to Standard Model and unparticle production are predicted. An odd valley with scalar unparticle contribution appears for some values of d_{\U}, which is due to the big cancellation between the contribution from SM and that from unparticle. This character may be used to study the properties of scalar unparticle. Our investigations also show that scalar unparticle may play a significant role in $t \bar t$ production at photon collider if it exists.Comment: 13 pages, 5figure

Synergies and Prospects for Early Resolution of the Neutrino Mass Ordering

The measurement of neutrino Mass Ordering (MO) is a fundamental element for the understanding of leptonic flavour sector of the Standard Model of Particle Physics. Its determination relies on the precise measurement of $\Delta m^2_{31}$ and $\Delta m^2_{32}$ using either neutrino vacuum oscillations, such as the ones studied by medium baseline reactor experiments, or matter effect modified oscillations such as those manifesting in long-baseline neutrino beams (LB$\nu$B) or atmospheric neutrino experiments. Despite existing MO indication today, a fully resolved MO measurement ($\geq$5$\sigma$) is most likely to await for the next generation of neutrino experiments: JUNO, whose stand-alone sensitivity is $\sim$3$\sigma$, or LB$\nu$B experiments (DUNE and Hyper-Kamiokande). Upcoming atmospheric neutrino experiments are also expected to provide precious information. In this work, we study the possible context for the earliest full MO resolution. A firm resolution is possible even before 2028, exploiting mainly vacuum oscillation, upon the combination of JUNO and the current generation of LB$\nu$B experiments (NOvA and T2K). This opportunity is possible thanks to a powerful synergy boosting the overall sensitivity where the sub-percent precision of $\Delta m^2_{32}$ by LB$\nu$B experiments is found to be the leading order term for the MO earliest discovery. We also found that the comparison between matter and vacuum driven oscillation results enables unique discovery potential for physics beyond the Standard Model.Comment: Entitled in arXiv:2008.11280v1 as "Earliest Resolution to the Neutrino Mass Ordering?

Decellularization of pericardial tissue and its impact on tensile viscoelasticity and glycosaminoglycan content

Bovine pericardium is a collagenous tissue commonly used as a natural biomaterial in the fabrication of cardiovascular devices. For tissue engineering purposes, this xenogeneic biomaterial must be decellularized to remove cellular antigens. With this in mind, three decellularization protocols were compared in terms of their effectiveness to extract cellular materials, their effect on glycosaminoglycan (GAG) content and, finally, their effect on tensile biomechanical behavior. The tissue decellularization was achieved by treatment with t-octyl phenoxy polyethoxy ethanol (Triton X-100), tridecyl polyethoxy ethanol (ATE) and alkaline treatment and subsequent treatment with nucleases (DNase/RNase). The quantified residual DNA content (3.0 ± 0.4%, 4.4 ± 0.6% and 5.6 ± 0.7% for Triton X-100, ATE and alkaline treatment, respectively) and the absence of nuclear structures (hematoxylin and eosin staining) were indicators of effective cell removal. In the same way, it was found that the native tissue GAG content decreased to 61.6 ± 0.6%, 62.7 ± 1.1% and 88.6 ± 0.2% for Triton X-100, ATE and alkaline treatment, respectively. In addition, an alteration in the tissue stress relaxation characteristics was observed after alkaline treatment. We can conclude that the three decellularization agents preserved the collagen structural network, anisotropy and the tensile modulus, tensile strength and maximum strain at failure of native tissue