Epstein-Barr virus IL-10 gene expression by a recombinant murine gammaherpesvirus in vivo enhances acute pathogenicity but does not affect latency or reactivation.

BackgroundMany viral genes affect cytokine function within infected hosts, with interleukin 10 (IL-10) as a commonly targeted mediator. Epstein-Barr virus (EBV) encodes an IL-10 homologue (vIL-10) expressed during productive (lytic) infection and induces expression of cellular IL-10 (cIL-10) during latency. This study explored the role of vIL-10 in a murine gammaherpesvirus (MHV) model of viral infection.MethodsThe EBV vIL-10 gene was inserted into MHV-76, a strain which lacks the ability to induce cIL-10, by recombination in transfected mouse cells. Mice were infected intranasally with the recombinant, vIL-10-containing MHV-76 or control virus strains and assayed at various days post infection for lung virus titer, spleen cell number, percentage of latently infected spleen cells and ability to reactivate virus from spleen cells.ResultsRecombinant murine gammaherpesvirus expressing EBV vIL-10 rose to significantly higher titers in lungs and promoted an increase in spleen cell number in infected mice in comparison to MHV strains lacking the vIL-10 gene. However, vIL-10 expression did not alter the quantity of latent virus in the spleen or its ability to reactivate.ConclusionsIn this mouse model of gammaherpesvirus infection, EBV vIL-10 appears to influence acute-phase pathogenicity. Given that EBV and MHV wild-type strains contain other genes that induce cIL-10 expression in latency (e.g. LMP-1 and M2, respectively), vIL-10 may have evolved to serve the specific role in acute infection of enlarging the permissive host cell population, perhaps to facilitate initial survival and dissemination of viral-infected cells

Cooperative action in eukaryotic gene regulation: physical properties of a viral example

The Epstein-Barr virus (EBV) infects more than 90% of the human population, and is the cause of several both serious and mild diseases. It is a tumorivirus, and has been widely studied as a model system for gene (de)regulation in human. A central feature of the EBV life cycle is its ability to persist in human B cells in states denoted latency I, II and III. In latency III the host cell is driven to cell proliferation and hence expansion of the viral population, but does not enter the lytic pathway, and no new virions are produced, while the latency I state is almost completely dormant. In this paper we study a physico-chemical model of the switch between latency I and latency III in EBV. We show that the unusually large number of binding sites of two competing transcription factors, one viral and one from the host, serves to make the switch sharper (higher Hill coefficient), either by cooperative binding between molecules of the same species when they bind, or by competition between the two species if there is sufficient steric hindrance.Comment: 7 pages, 6 figures, 1 tabl

In Defense of the Epistemic Imperative

Sample (2015) argues that scientists ought not to believe that their theories are true because they cannot fulfill the epistemic obligation to take the diachronic perspective on their theories. I reply that Sample’s argument imposes an inordinately heavy epistemic obligation on scientists, and that it spells doom not only for scientific theories but also for observational beliefs and philosophical ideas that Samples endorses. I also delineate what I take to be a reasonable epistemic obligation for scientists. In sum, philosophers ought to impose on scientists only an epistemic standard that they are willing to impose on themselves

VerdictDB: Universalizing Approximate Query Processing

Despite 25 years of research in academia, approximate query processing (AQP) has had little industrial adoption. One of the major causes of this slow adoption is the reluctance of traditional vendors to make radical changes to their legacy codebases, and the preoccupation of newer vendors (e.g., SQL-on-Hadoop products) with implementing standard features. Additionally, the few AQP engines that are available are each tied to a specific platform and require users to completely abandon their existing databases---an unrealistic expectation given the infancy of the AQP technology. Therefore, we argue that a universal solution is needed: a database-agnostic approximation engine that will widen the reach of this emerging technology across various platforms. Our proposal, called VerdictDB, uses a middleware architecture that requires no changes to the backend database, and thus, can work with all off-the-shelf engines. Operating at the driver-level, VerdictDB intercepts analytical queries issued to the database and rewrites them into another query that, if executed by any standard relational engine, will yield sufficient information for computing an approximate answer. VerdictDB uses the returned result set to compute an approximate answer and error estimates, which are then passed on to the user or application. However, lack of access to the query execution layer introduces significant challenges in terms of generality, correctness, and efficiency. This paper shows how VerdictDB overcomes these challenges and delivers up to 171$\times$ speedup (18.45$\times$ on average) for a variety of existing engines, such as Impala, Spark SQL, and Amazon Redshift, while incurring less than 2.6% relative error. VerdictDB is open-sourced under Apache License.Comment: Extended technical report of the paper that appeared in Proceedings of the 2018 International Conference on Management of Data, pp. 1461-1476. ACM, 201

Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis

BACKGROUND: Pain and impaired mobility because of osteoarthritis (OA) is common in dogs and humans. Efficacy studies of analgesic drug treatment of dogs with naturally occurring OA may be challenging, as a caregiver placebo effect is typically evident. However, little is known about effect sizes of common outcome-measures in canine clinical trials evaluating treatment of OA pain. Forty-nine client-owned dogs with hip OA were enrolled in a randomized, double-blinded placebo-controlled prospective trial. After a 1 week baseline period, dogs were randomly assigned to a treatment (ABT-116 – transient receptor potential vanilloid 1 (TRPV1) antagonist, Carprofen – non-steroidal anti-inflammatory drug (NSAID), Tramadol - synthetic opiate, or Placebo) for 2 weeks. Outcome-measures included physical examination parameters, owner questionnaire, activity monitoring, gait analysis, and use of rescue medication. RESULTS: Acute hyperthermia developed after ABT-116 treatment (P < 0.001). Treatment with carprofen (P ≤ 0.01) and tramadol (P ≤ 0.001) led to improved mobility assessed by owner questionnaire. Nighttime activity was increased after ABT-116 treatment (P = 0.01). Kinetic gait analysis did not reveal significant treatment effects. Use of rescue treatment decreased with treatment in the ABT-116 and Carprofen groups (P < 0.001). Questionnaire score and activity count at the end of treatment were correlated with age, clinical severity at trial entry, and outcome measure baseline status (S(R) ≥ ±0.40, P ≤ 0.005). Placebo treatment effects were evident with all variables studied. CONCLUSION: Treatment of hip OA in client-owned dogs is associated with a placebo effect for all variables that are commonly used for efficacy studies of analgesic drugs. This likely reflects caregiver bias or the phenomenon of regression to the mean. In the present study, outcome measures with significant effects also varied between groups, highlighting the value of using multiple outcome measures, as well as an a priori analysis of effect size associated with each measure. Effect size data from the present study could be used to inform design of future trials studying analgesic treatment of canine OA. Our results suggest that analgesic treatment with ABT-116 is not as effective as carprofen or tramadol for treatment of hip arthritis pain in client-owned dogs

Parity-violating Electron Deuteron Scattering and the Proton's Neutral Weak Axial Vector Form Factor

We report on a new measurement of the parity-violating asymmetry in quasielastic electron scattering from the deuteron at backward angles at Q2= 0.038 (GeV/c)2. This quantity provides a determination of the neutral weak axial vector form factor of the nucleon, which can potentially receive large electroweak corrections. The measured asymmetry A=-3.51 +/- 0.57(stat) +/- 0.58(sys)ppm is consistent with theoretical predictions. We also report on updated results of the previous experiment at Q2=0.091 (GeV/c)2, which are also consistent with theoretical predictions.Comment: 4 pages, 2 figures, submitted to Phys. Rev. Let

Radiative Muon Capture on Hydrogen and the Induced Pseudoscalar Coupling

The first measurement of the elementary process $\mu^- p \rightarrow \nu_{\mu} n \gamma$ is reported. A photon pair spectrometer was used to measure the partial branching ratio ($2.10 \pm 0.22) \times 10^{-8}$ for photons of k > 60 MeV. The value of the weak pseudoscalar coupling constant determined from the partial branching ratio is $g_p(q^{2}=-0.88m_{\mu}^2) = (9.8 \pm 0.7 \pm 0.3) \cdot g_a(0)$, where the first error is the quadrature sum of statistical and systematic uncertainties and the second error is due to the uncertainty in $\lambda_{op}$, the decay rate of the ortho to para $p \mu p$ molecule. This value of g_p is $\sim$1.5 times the prediction of PCAC and pion-pole dominance.Comment: 13 pages, RevTeX type, 3 figures (encapsulated postscript), submitted to Phys. Rev. Let

Jamming and Fluctuations in Granular Drag

We investigate the dynamic evolution of jamming in granular media through fluctuations in the granular drag force. The successive collapse and formation of jammed states give a stick-slip nature to the fluctuations which is independent of the contact surface between the grains and the dragged object -- thus implying that the stress-induced collapse is nucleated in the bulk of the granular sample. We also find that while the fluctuations are periodic at small depths, they become "stepped" at large depths, a transition which we interpret as a consequence of the long-range nature of the force chains.Comment: 7 pages, 4 figures, RevTe

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM