Novel Influenza Virus NS1 Antagonists Block Replication and Restore Innate Immune Function

The innate immune system guards against virus infection through a variety of mechanisms including mobilization of the host interferon system, which attacks viral products mainly at a posttranscriptional level. The influenza virus NS1 protein is a multifunctional facilitator of virus replication, one of whose actions is to antagonize the interferon response. Since NS1 is required for efficient virus replication, it was reasoned that chemical inhibitors of this protein could be used to further understand virus-host interactions and also serve as potential new antiviral agents. A yeast-based assay was developed to identify compounds that phenotypically suppress NS1 function. Several such compounds exhibited significant activity specifically against influenza A virus in cell culture but had no effect on the replication of another RNA virus, respiratory syncytial virus. Interestingly, cells lacking an interferon response were drug resistant, suggesting that the compounds block interactions between NS1 and the interferon system. Accordingly, the compounds reversed the inhibition of beta interferon mRNA induction during infection, which is known to be caused by NS1. In addition, the compounds blocked the ability of NS1 protein to inhibit double-stranded RNA-dependent activation of a transfected beta interferon promoter construct. The effects of the compounds were specific to NS1, because they had no effect on the ability of the severe acute respiratory syndrome coronavirus papainlike protease protein to block beta interferon promoter activation. These data demonstrate that the function of NS1 can be modulated by chemical inhibitors and that such inhibitors will be useful as probes of biological function and as starting points for clinical drug development

Implications of heavy-ion-induced satellite x-ray emission. II. Production of K and L x rays by 0. 9 to 2. 6 MeV/u Ar ions in thick targets of V, Cu, Nb, Ta, and Pt

Cross sections are reported for x-ray production in targets of /sup 23/V, /sup 29/Cu, /sup 41/Nb, /sup 73/Ta, and /sup 78/Pt by /sup 40/Ar ions of 36.0, 56.4, 76.6, and 103 MeV. Because the targets were relatively thick, approx. 1 mg/cm/sup 2/, the data were corrected, using a novel approach, for projectile energy loss and x-ray attenuation in the targets. The cross sections so analyzed are compared with the predictions of the first Born approximation as well as with those of a more extensive treatment which includes energy loss, Coulomb deflection, perturbed stationary-state, and relativistic effects. The significant discrepancies between the data and this latter theory are atrributed primarily to the influence of multiple ionization on the x-ray emission probabilities

Electromagnetic Decay of Giant Resonances

Coincidence experiments were done to investigate the photon and neutron emission from the giant resonance regions of /sup 208/Pb and /sup 90/Zr using the ORNL Spin Spectrometer, a 72-segment NaI detector system. We have determined the total gamma-decay probability, the ground-state gamma branching ratio, and the branching ratios to a number of low-lying states as a function of excitation energy in /sup 208/Pb to approx.15 MeV. Similar data were also obtained on /sup 90/Zr. The total yield of ground-state E2 gamma radiation in /sup 208/Pb and the comparative absence of such radiation in /sup 90/Zr can only be understood if decay of compound (damped) states is considered. Other observations in /sup 208/Pb include the absence of a significant branch from the giant quadrupole resonance (GQR) to the 3/sup -/ state at 2.6 MeV, a strong branch to a 3/sup -/ state at 4.97 MeV from the same region, and transitions to various 1/sup -/ states between 5 to 7 MeV from the E* approx. 14 MeV region (EO resonance)

Surface Energy Budgets of Arctic Tundra During Growing Season

This study analyzed summer observations of diurnal and seasonal surface energy budgets across several monitoring sites within the Arctic tundra underlain by permafrost. In these areas, latent and sensible heat fluxes have comparable magnitudes, and ground heat flux enters the subsurface during short summer intervals of the growing period, leading to seasonal thaw. The maximum entropy production (MEP) model was tested as an input and parameter parsimonious model of surface heat fluxes for the simulation of energy budgets of these permafrost‐underlain environments. Using net radiation, surface temperature, and a single parameter characterizing the thermal inertia of the heat exchanging surface, the MEP model estimates latent, sensible, and ground heat fluxes that agree closely with observations at five sites for which detailed flux data are available. The MEP potential evapotranspiration model reproduces estimates of the Penman‐Monteith potential evapotranspiration model that requires at least five input meteorological variables (net radiation, ground heat flux, air temperature, air humidity, and wind speed) and empirical parameters of surface resistance. The potential and challenges of MEP model application in sparsely monitored areas of the Arctic are discussed, highlighting the need for accurate measurements and constraints of ground heat flux.Plain Language SummaryGrowing season latent and sensible heat fluxes are nearly equal over the Arctic permafrost tundra regions. Persistent ground heat flux into the subsurface layer leads to seasonal thaw of the top permafrost layer. The maximum energy production model accurately estimates the latent, sensible, and ground heat flux of the surface energy budget of the Arctic permafrost regions.Key PointThe MEP model is parsimonious and well suited to modeling surface energy budget in data‐sparse permafrost environmentsPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150560/1/jgrd55584.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150560/2/jgrd55584_am.pd

Pediatric appendicitis rupture rate: a national indicator of disparities in healthcare access

BACKGROUND: The U.S. National Healthcare Disparities Report is a recent effort to measure and monitor racial and ethnic disparities in health and healthcare. The Report is a work in progress and includes few indicators specific to children. An indicator worthy of consideration is racial/ethnic differences in the rate of bad outcomes for pediatric acute appendicitis. Bad outcomes for this condition are indicative of poor access to healthcare, which is amenable to social and healthcare policy changes. METHODS: We analyzed the KID Inpatient Database, a nationally representative sample of pediatric hospitalization, to compare rates of appendicitis rupture between white, African American, Hispanic and Asian children. We ran weighted logistic regression models to obtain national estimates of relative odds of rupture rate for the four groups, adjusted for developmental, biological, socioeconomic, health services and hospital factors that might influence disease outcome. RESULTS: Rupture was a much more burdensome outcome than timely surgery and rupture avoidance. Rupture cases had 97% higher hospital charges and 175% longer hospital stays than non-rupture cases on average. These burdens disproportionately affected minority children, who had 24% – 38% higher odds of appendicitis rupture than white children, adjusting for age and gender. These differences were reduced, but remained significant after adjusting for other factors. CONCLUSION: The racial/ethnic disparities in pediatric appendicitis outcome are large and are preventable with timely diagnosis and surgery for all children. Furthermore, estimating this disparity using the KID survey is a relatively straightforward process. Therefore pediatric appendicitis rupture rate is a good candidate for inclusion in the National Healthcare Disparities Report. As with most other health and healthcare disparities, efforts to reduce disparities in income, wealth and access to care will most likely improve the odds of favorable outcome for this condition as well

Deconstructing Insight: EEG Correlates of Insightful Problem Solving

Background: Cognitive insight phenomenon lies at the core of numerous discoveries. Behavioral research indicates four salient features of insightful problem solving: (i) mental impasse, followed by (ii) restructuring of the problem representation, which leads to (iii) a deeper understanding of the problem, and finally culminates in (iv) an “Aha!” feeling of suddenness and obviousness of the solution. However, until now no efforts have been made to investigate the neural mechanisms of these constituent features of insight in a unified framework. Methodology/Principal Findings: In an electroencephalographic study using verbal remote associate problems, we identified neural correlates of these four features of insightful problem solving. Hints were provided for unsolved problems or after mental impasse. Subjective ratings of the restructuring process and the feeling of suddenness were obtained on trial-by-trial basis. A negative correlation was found between these two ratings indicating that sudden insightful solutions, where restructuring is a key feature, involve automatic, subconscious recombination of information. Electroencephalogram signals were analyzed in the space×time×frequency domain with a nonparametric cluster randomization test. First, we found strong gamma band responses at parieto-occipital regions which we interpreted as (i) an adjustment of selective attention (leading to a mental impasse or to a correct solution depending on the gamma band power level) and (ii) encoding and retrieval processes for the emergence of spontaneous new solutions. Secondly, we observed an increased upper alpha band response in right temporal regions (suggesting active suppression of weakly activated solution relevant information) for initially unsuccessful trials that after hint presentation led to a correct solution. Finally, for trials with high restructuring, decreased alpha power (suggesting greater cortical excitation) was observed in right prefrontal area. Conclusions/Significance: Our results provide a first account of cognitive insight by dissociating its constituent components and potential neural correlates

Robust image analysis with sparse representation on quantized visual features

10.1109/TIP.2012.2219543IEEE Transactions on Image Processing223860-871IIPR

Differential regulation of collagenase gene expression by retinoic acid receptors--alpha, beta and gamma.

The mechanisms involved in retinoic acid (RA)-mediated regulation of the collagenase gene in a rabbit synovial fibroblast cell line (HIG82) were investigated. When HIG82 cells are cotransfected with expression vectors containing cDNAs for retinoic acid receptor (RAR) alpha 1, beta 2, or gamma 1 and collagenase promoter-driven CAT reporter constructs, only RAR-gamma 1 represses basal CAT expression upon RA treatment, while RAR-alpha 1, beta 2, and gamma 1 all suppress phorbol-induced CAT expression. Thus, transcriptional regulation of collagenase by RA is mediated by RARs in an RAR-type specific manner. Using mutational and deletional analysis, we find that interaction between elements within 182 bp collagenase promoter plays an important role in this process. In addition, cotreatment with RA results in a decrease of phorbol-induced mRNA levels of fos and jun, and binding of nuclear proteins to an AP-1 oligonucleotide. Furthermore, RA-induced nuclear protein(s) specifically bind to a 22 bp sequence (-182 to -161) of the collagenase promoter. We propose that RA-mediated regulation of the collagenase gene depends on the availability and interaction of specific RARs with multiple DNA elements within the promoter and with transcription factors, including AP-1 related proteins