A Borel-Cantelli lemma for intermittent interval maps

We consider intermittent maps T of the interval, with an absolutely continuous invariant probability measure \mu. Kim showed that there exists a sequence of intervals A_n such that \sum \mu(A_n)=\infty, but \{A_n\} does not satisfy the dynamical Borel-Cantelli lemma, i.e., for almost every x, the set \{n : T^n(x)\in A_n\} is finite. If \sum \Leb(A_n)=\infty, we prove that \{A_n\} satisfies the Borel-Cantelli lemma. Our results apply in particular to some maps T whose correlations are not summable.Comment: 7 page

Khinchin theorem for integral points on quadratic varieties

We prove an analogue the Khinchin theorem for the Diophantine approximation by integer vectors lying on a quadratic variety. The proof is based on the study of a dynamical system on a homogeneous space of the orthogonal group. We show that in this system, generic trajectories visit a family of shrinking subsets infinitely often.Comment: 19 page

Applying Unique Molecular Identifiers in Next Generation Sequencing Reveals a Constrained Viral Quasispecies Evolution under Cross-Reactive Antibody Pressure Targeting Long Alpha Helix of Hemagglutinin.

To overcome yearly efforts and costs for the production of seasonal influenza vaccines, new approaches for the induction of broadly protective and long-lasting immune responses have been developed in the past decade. To warrant safety and efficacy of the emerging crossreactive vaccine candidates, it is critical to understand the evolution of influenza viruses in response to these new immune pressures. Here we applied unique molecular identifiers in next generation sequencing to analyze the evolution of influenza quasispecies under in vivo antibody pressure targeting the hemagglutinin (HA) long alpha helix (LAH). Our vaccine targeting LAH of hemagglutinin elicited significant seroconversion and protection against homologous and heterologous influenza virus strains in mice. The vaccine not only significantly reduced lung viral titers, but also induced a well-known bottleneck effect by decreasing virus diversity. In contrast to the classical bottleneck effect, here we showed a significant increase in the frequency of viruses with amino acid sequences identical to that of vaccine targeting LAH domain. No escape mutant emerged after vaccination. These results not only support the potential of a universal influenza vaccine targeting the conserved LAH domains, but also clearly demonstrate that the well-established bottleneck effect on viral quasispecies evolution does not necessarily generate escape mutants

Development of a high-throughput microscale cell disruption platform for Pichia pastoris in rapid bioprocess design

The time and cost benefits of miniaturized fermentation platforms can only be gained by employing complementary techniques facilitating high-throughput at small sample volumes. Microbial cell disruption is a major bottleneck in experimental throughput and is often restricted to large processing volumes. Moreover, for rigid yeast species such as Pichia pastoris, no effective high-throughput disruption methods exist. This study describes the development of an automated, miniaturized, high-throughput, non-contact, scalable platform based on Adaptive Focused Acoustics (AFA) to disrupt P. pastoris and recover intracellular heterologous protein. Augmented modes of AFA were established by investigating vessel designs and a novel enzymatic pre-treatment step. Three different modes of AFA were studied and compared to the performance high pressure homogenization. For each of these modes of cell disruption, response models were developed to account for five different performance criteria. Using multiple responses not only demonstrated that different operating parameters are required for different response optima, with highest product purity requiring suboptimal values for other criteria, but also allowed for AFA-based methods to mimic large-scale homogenization processes. These results demonstrate that AFA-mediated cell disruption can be used for a wide range of applications including buffer development, strain selection, fermentation process development and whole bioprocess integration. This article is protected by copyright. All rights reserved

A virus-like particle vaccine candidate for influenza A virus based on multiple conserved antigens presented on hepatitis B tandem core particles

Existing Influenza A virus (IAV) vaccines target variable parts of the virus that may change between seasons. Vaccine design relies on predicting the predominant circulating influenza strains but when there is a mismatch between vaccine and circulating strains, efficacy is sub-optimal. Furthermore, current approaches provide limited protection against emerging influenza strains that may cause pandemics. One solution is to design vaccines that target conserved protein domains of influenza, which remain largely unchanged over time and are likely to be found in emergent variants. We present a virus-like particle (VLP), built using the hepatitis B virus tandem core platform, as an IAV vaccine candidate containing multiple conserved antigens. Hepatitis B core protein spontaneously assembles into a VLP that is immunogenic and confers immunogenicity to proteins incorporated into the major insertion region (MIR) of core monomers. However, insertion of antigen sequences may disrupt particle assembly preventing VLP formation or result in unstable particles. We have overcome these problems by genetically manipulating the hepatitis B core to express core monomers in tandem, ligated with a flexible linker, incorporating different antigens at each of the MIRs. Immunisation with this VLP, named Tandiflu1, containing 4 conserved antigens from matrix protein 2 ectodomain and hemagglutinin stalk, leads to production of cross-reactive and protective antibodies. The polyclonal antibodies induced by Tandiflu1 can bind IAV Group 1 hemagglutinin types H1, H5, H11, H9, H16 and a conserved epitope on matrix protein 2 expressed by most strains of IAV. Vaccination with Tandiflu1 results in 100% protection from a lethal influenza challenge with H1N1 IAV. Serum transfer from vaccinated animals is sufficient to confer protection from influenza-associated illness in naïve mice. These data suggest that a Tandem Core based IAV vaccine might provide broad protection against common and emergent H1 IAV strains responsible for seasonal and pandemic influenza in man

Geophysical and geochemical methods applied to investigate fissure-related hydrothermal systems on the summit area of Mt. Etna volcano (Italy)

A multidisciplinary approach integrating self-potential, soil temperature, heat flux, CO2 efflux and gravity gradiometry signals was used to investigate a relatively small fissure-related hydrothermal systemnear the summit of Mt. Etna volcano (Italy). Measurements were performed through two different surveys carried out at the beginning and at the end of July 2009, right after the end of the long-lived 2008–2009 flank eruption and in coincidencewith an increase in diffuse flank degassing related to a reactivation of the volcano, leading to the opening of a new summit vent (NSEC). The main goal was to use a multidisciplinary approach to the detection of hidden fractures in an area of evident near-surface hydrothermal activity. Despite the different methodologies used and the different geometry of the sampling grid between the surveys, all parameters concurred in confirming that the study area is crossed by faults related with the main fracture systems of the south flank of the volcano,where a continuous hydrothermal circulation is established. Results also highlighted that hydrothermal activity in this area changed both in space and in time. These changes were a clear response to variations in themagmatic system, notably tomigration of magma at various depth within the main feeder systemof the volcano. The results suggest that this specific area, initially chosen as the optimal test-site for the proposed approach, can be useful in order to get information on the potential reactivation of the summit craters of Mt. Etna