1,413 research outputs found
The Financial Valuation of the Return to Capital
macroeconomics, financial valuation
The interferon-induced exonuclease ISG20 exerts antiviral activity through upregulation of type I interferon response proteins
The host immune responses to infection lead to the production of type I interferon (IFN), and the upregulation of interferon-stimulated genes (ISGs) reduces virus replication and virus dissemination within a host. Ectopic expression of the interferon-induced 20-kDa exonuclease ISG20 suppressed replication of chikungunya virus and Venezuelan equine encephalitis virus, two mosquito-vectored RNA alphaviruses. Since the replication of alphavirus genomes occurs exclusively in the cytoplasm, the mechanism of nucleus-localized ISG20 inhibition of replication is unclear. In this study, we determined that ISG20 acts as a master regulator of over 100 genes, many of which are ISGs. Specifically, ISG20 upregulated IFIT1 genes and inhibited translation of the alphavirus genome. Furthermore, IFIT1-sensitive alphavirus replication was increased in Isg20−/− mice compared to the replication of wild-type viruses but not in cells ectopically expressing ISG20. We propose that ISG20 acts as an indirect regulator of RNA virus replication in the cytoplasm through the upregulation of many other ISGs.Type I interferon (IFN)-stimulated genes (ISGs) have critical roles in inhibiting virus replication and dissemination. Despite advances in understanding the molecular basis of ISG restriction, the antiviral mechanisms of many remain unclear. The 20-kDa ISG ISG20 is a nuclear 3′–5′ exonuclease with preference for single-stranded RNA (ssRNA) and has been implicated in the IFN-mediated restriction of several RNA viruses. Although the exonuclease activity of ISG20 has been shown to degrade viral RNA in vitro, evidence has yet to be presented that virus inhibition in cells requires this activity. Here, we utilized a combination of an inducible, ectopic expression system and newly generated Isg20−/− mice to investigate mechanisms and consequences of ISG20-mediated restriction. Ectopically expressed ISG20 localized primarily to Cajal bodies in the nucleus and restricted replication of chikungunya and Venezuelan equine encephalitis viruses. Although restriction by ISG20 was associated with inhibition of translation of infecting genomic RNA, degradation of viral RNAs was not observed. Instead, translation inhibition of viral RNA was associated with ISG20-induced upregulation of over 100 other genes, many of which encode known antiviral effectors. ISG20 modulated the production of IFIT1, an ISG that suppresses translation of alphavirus RNAs. Consistent with this observation, the pathogenicity of IFIT1-sensitive alphaviruses was increased in Isg20−/− mice compared to that of wild-type viruses but not in cells ectopically expressing ISG20. Our findings establish an indirect role for ISG20 in the early restriction of RNA virus replication by regulating expression of other ISGs that inhibit translation and possibly other activities in the replication cycle
Hydrodynamics of polar liquid crystals
Starting from a microscopic definition of an alignment vector proportional to
the polarization, we discuss the hydrodynamics of polar liquid crystals with
local -symmetry. The free energy for polar liquid crystals
differs from that of nematic liquid crystals () in that it
contains terms violating the symmetry. First we show
that these -odd terms induce a general splay instability of a
uniform polarized state in a range of parameters. Next we use the general
Poisson-bracket formalism to derive the hydrodynamic equations of the system in
the polarized state. The structure of the linear hydrodynamic modes confirms
the existence of the splay instability.Comment: 9 pages, corrected typos, added references, revised content, to
appear in PR
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Mortality Rate in Veterans with Multiple Chronic Conditions
Background: Among patients with multiple chronic conditions, there is increasing appreciation of the complex interrelatedness of diseases. Previous studies have focused on the prevalence and economic burden associated with multiple chronic conditions, much less is known about the mortality rate associated with specific combinations of multiple diseases. Objective: Measure the mortality rate in combinations of 11 chronic conditions. Design: Cohort study of veteran health care users. Participants Veterans between 55 and 64 years that used Veterans Health Administration health care services between October 1999 and September 2000. Measurements: Patients were identified as having one or more of the following: COPD, diabetes, hypertension, rheumatoid arthritis, osteoarthritis, asthma, depression, ischemic heart disease, dementia, stroke, and cancer. Mutually exclusive combinations of disease based on these conditions were created, and 5-year mortality rates were determined. Results: There were 741,847 persons included. The number in each group by a count of conditions was: none = 217,944 (29.34%); 1 = 221,111 (29.8%); 2 = 175,228 (23.6%); 3 = 86,447 (11.7%); and 4+ = 41,117 (5.5%). The 5-year mortality rate by the number of conditions was: none = 4.1%; 1 = 6.0%; 2 = 7.8%; 3 = 11.2%; 4+ = 16.7%. Among combinations with the same number of conditions, there was significant variability in mortality rates. Conclusions: Patients with multiple chronic conditions have higher mortality rates. Because there was significant variation in mortality across clusters with the same number of conditions, when studying patients with multiple coexisting illnesses, it is important to understand not only that several conditions may be present but that specific conditions can differentially impact the risk of mortality
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