Increased immunogenicity and protective efficacy of influenza M2e fused to a tetramerizing protein

The ectodomain of the matrix 2 protein (M2e) of influenza A virus represents an attractive target for developing a universal influenza A vaccine, with its sequence being highly conserved amongst human variants of this virus. With the aim of targeting conformational epitopes presumably shared by diverse influenza A viruses, a vaccine (M2e-NSP4) was constructed linking M2e (in its consensus sequence) to the rotavirus fragment NSP4(98-135); due to its coiled-coil region this fragment is known to form tetramers in aqueous solution and in this manner we hoped to mimick the natural configuration of M2e as presented in membranes. M2e-NSP4 was then evaluated side-by-side with synthetic M2e peptide for its immunogenicity and protective efficacy in a murine influenza challenge model. Here we demonstrate that M2e fused to the tetramerizing protein induces an accelerated, augmented and more broadly reactive antibody response than does M2e peptide as measured in two different assays. Most importantly, vaccination with M2e-NSP4 caused a significant decrease in lung virus load early after challenge with influenza A virus and maintained its efficacy against a lethal challenge even at very low vaccine doses. Based on the results presented in this study M2e-NSP4 merits further investigation as a candidate for or as a component of a universal influenza A vaccine

Emerging patterns of simulated regional climatic changes for the 21st century due to anthropogenic forcings

We analyse temperature and precipitation changes for the late decades of the 21st century (with respect to present day conditions) over 23 land regions of the world from 18 recent transient climate change experiments with coupled atmosphere‐ocean General Circulation Models (AOGCMs). The analysis involves two different forcing scenarios and nine models, and it focuses on model agreement in the simulated regional changes for the summer and winter seasons. While to date very few conclusions have been presented on regional climatic changes, mostly limited to some broad latitudinal bands, our analysis shows that a number of consistent patterns of regional change across models and scenarios are now emerging. For temperature, in addition to maximum winter warming in northern high latitudes, warming much greater than the global average is found over Central Asia, Tibet and the Mediterranean region in summer. Consistent warming lower than the global average is found in some seasons over Southern South America, Southeast Asia and South Asia, while cases of inconsistent warming amplification compared to the global average occur mostly in some tropical and southern sub‐tropical regions. Consistent increase in winter precipitation is found in northern high latitude regions, as well as Central Asia, Tibet, Western and Eastern North America, and Western and Eastern Africa regions. The experiments also indicate an increase in South Asia and East Asia summer monsoon precipitation. A number of regions show a consistent decrease in precipitation, such as Southern Africa and Australia in winter, the Mediterranean region in summer and Central America in both seasons. Possible physical mechanisms that lead to the simulated changes are discussed

Multipliers for p-Bessel sequences in Banach spaces

Multipliers have been recently introduced as operators for Bessel sequences and frames in Hilbert spaces. These operators are defined by a fixed multiplication pattern (the symbol) which is inserted between the analysis and synthesis operators. In this paper, we will generalize the concept of Bessel multipliers for p-Bessel and p-Riesz sequences in Banach spaces. It will be shown that bounded symbols lead to bounded operators. Symbols converging to zero induce compact operators. Furthermore, we will give sufficient conditions for multipliers to be nuclear operators. Finally, we will show the continuous dependency of the multipliers on their parameters.Comment: 17 page

Hepatitis C prevalence in Denmark -an estimate based on multiple national registers

Background: A national survey for chronic hepatitis C has not been performed in Denmark and the prevalence is unknown. Our aim was to estimate the prevalence of chronic hepatitis C from public registers and the proportion of these patients who received specialized healthcare. Methods: Patients with a diagnosis of chronic hepatitis C were identified from four national registers: a laboratory register, the Hospital Discharge Register, a clinical database of chronic viral hepatitis and the Register of Communicable Diseases. The total population diagnosed with hepatitis C was estimated by capture-recapture analysis. The population with undiagnosed hepatitis C was derived from the national register of drug users by comparing diagnosed and tested persons. Results: A total of 6,935 patients diagnosed with chronic hepatitis C were identified in the four registers and the estimated population diagnosed with the disease was 9,166 persons (95% C.I. interval 8,973 – 9,877), corresponding to 0.21% (95% CI 0.21%-0.23%) of the Danish population over 15years of age. The prevalence was highest among persons 40–49years old (0.39%) and males (0.28%). It was estimated that 40% of the diagnosed patients lived in the capital region, and 33.5% had attended specialised healthcare. It was estimated that 46% of hepatitis C patients had not been diagnosed and the total population with chronic hepatitis C in Denmark was 16,888 (95% C.I. 16,474-18,287), corresponding to 0.38% (95% CI 0.37-0.42) of the population over 15years of age. Conclusions: The estimated prevalence of chronic hepatitis C in Denmark was 0.38%. Less than half of the patients with chronic hepatitis C in Denmark have been identified and among these patients, one in three has attended specialised care

Adaptation of topoisomerase I paralogs to nuclear and mitochondrial DNA

Topoisomerase I is essential for DNA metabolism in nuclei and mitochondria. In yeast, a single topoisomerase I gene provides for both organelles. In vertebrates, topoisomerase I is divided into nuclear and mitochondrial paralogs (Top1 and Top1mt). To assess the meaning of this gene duplication, we targeted Top1 to mitochondria or Top1mt to nuclei. Overexpression in the fitting organelle served as control. Targeting of Top1 to mitochondria blocked transcription and depleted mitochondrial DNA. This was also seen with catalytically inactive Top1 mutants, but not with Top1mt overexpressed in mitochondria. Targeting of Top1mt to the nucleus revealed that it was much less able to interact with mitotic chromosomes than Top1 overexpressed in the nucleus. Similar experiments with Top1/Top1mt hybrids assigned these functional differences to structural divergences in the DNA-binding core domains. We propose that adaptation of this domain to different chromatin environments in nuclei and mitochondria has driven evolutional development and conservation of organelle-restricted topoisomerase I paralogs in vertebrates

Confronting experimental data with heavy-ion models: Rivet for heavy ions

The Rivet library is an important toolkit in particle physics, and serves as a repository for analysis data and code. It allows for comparisons between data and theoretical calculations of the final state of collision events. This paper outlines several recent additions and improvements to the framework to include support for analysis of heavy ion collision simulated data. The paper also presents examples of these recent developments and their applicability in implementing concrete physics analyses

Frequency dependent specific heat of viscous silica

We apply the Mori-Zwanzig projection operator formalism to obtain an expression for the frequency dependent specific heat c(z) of a liquid. By using an exact transformation formula due to Lebowitz et al., we derive a relation between c(z) and K(t), the autocorrelation function of temperature fluctuations in the microcanonical ensemble. This connection thus allows to determine c(z) from computer simulations in equilibrium, i.e. without an external perturbation. By considering the generalization of K(t) to finite wave-vectors, we derive an expression to determine the thermal conductivity \lambda from such simulations. We present the results of extensive computer simulations in which we use the derived relations to determine c(z) over eight decades in frequency, as well as \lambda. The system investigated is a simple but realistic model for amorphous silica. We find that at high frequencies the real part of c(z) has the value of an ideal gas. c'(\omega) increases quickly at those frequencies which correspond to the vibrational excitations of the system. At low temperatures c'(\omega) shows a second step. The frequency at which this step is observed is comparable to the one at which the \alpha-relaxation peak is observed in the intermediate scattering function. Also the temperature dependence of the location of this second step is the same as the one of the $\alpha-$peak, thus showing that these quantities are intimately connected to each other. From c'(\omega) we estimate the temperature dependence of the vibrational and configurational part of the specific heat. We find that the static value of c(z) as well as \lambda are in good agreement with experimental data.Comment: 27 pages of Latex, 8 figure

Evaluation Research and Institutional Pressures: Challenges in Public-Nonprofit Contracting

This article examines the connection between program evaluation research and decision-making by public managers. Drawing on neo-institutional theory, a framework is presented for diagnosing the pressures and conditions that lead alternatively toward or away the rational use of evaluation research. Three cases of public-nonprofit contracting for the delivery of major programs are presented to clarify the way coercive, mimetic, and normative pressures interfere with a sound connection being made between research and implementation. The article concludes by considering how public managers can respond to the isomorphic pressures in their environment that make it hard to act on data relating to program performance.This publication is Hauser Center Working Paper No. 23. The Hauser Center Working Paper Series was launched during the summer of 2000. The Series enables the Hauser Center to share with a broad audience important works-in-progress written by Hauser Center scholars and researchers