APRIL:TACI axis is dispensable for the immune response to rabies vaccination.

There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens. Several studies have successfully employed the TNF family cytokine a proliferation-inducing ligand (APRIL) as a vaccine adjuvant. APRIL binds to the receptors TACI and B cell maturation antigen (BCMA)-expressed by B cells in various stages of maturation-with high affinity. We discovered that RABV-infected primary murine B cells upregulate APRIL ex vivo. Cytokines present at the time of antigen exposure affect the outcome of vaccination by influencing T and B cell activation and GC formation. Therefore, we hypothesized that the presence of APRIL at the time of RABV-based vaccine antigen exposure would support the generation of protective antibodies against RABV glycoprotein (G). In an effort to improve the response to RABV vaccination, we constructed and characterized a live recombinant RABV-based vaccine vector which expresses murine APRIL (rRABV-APRIL). Immunogenicity testing in mice demonstrated that expressing APRIL from the RABV genome does not impact the primary antibody response against RABV G compared to RABV alone. In order to evaluate the necessity of APRIL for the response to rabies vaccination, we compared the responses of APRIL-deficient and wild-type mice to immunization with rRABV. APRIL deficiency does not affect the primary antibody response to vaccination. Furthermore, APRIL expression by the vaccine did not improve the generation of long-lived antibody-secreting plasma cells (PCs) as serum antibody levels were equivalent in response to rRABV-APRIL and the vector eight weeks after immunization. Moreover, APRIL is dispensable for the long-lived antibody-secreting PC response to rRABV vaccination as anti-RABV G IgG levels were similar in APRIL-deficient and wild-type mice six months after vaccination. Mice lacking the APRIL receptor TACI demonstrated primary anti-RABV G antibody responses similar to wild-type mice following immunization with the vaccine vector indicating that this response is independent of TACI-mediated signals. Collectively, our findings demonstrate that APRIL and associated TACI signaling is dispensable for the immune response to RABV-based vaccination

Investigating the role for IL-21 in rabies virus vaccine-induced immunity.

Over two-thirds of the world\u27s population lives in regions where rabies is endemic, resulting in over 15 million people receiving multi-dose post-exposure prophylaxis (PEP) and over 55,000 deaths per year globally. A major goal in rabies virus (RABV) research is to develop a single-dose PEP that would simplify vaccination protocols, reduce costs associated with RABV prevention, and save lives. Protection against RABV infections requires virus neutralizing antibodies; however, factors influencing the development of protective RABV-specific B cell responses remain to be elucidated. Here we used a mouse model of IL-21 receptor-deficiency (IL-21R-/-) to characterize the role for IL-21 in RABV vaccine-induced immunity. IL-21R-/- mice immunized with a low dose of a live recombinant RABV-based vaccine (rRABV) produced only low levels of primary or secondary anti-RABV antibody response while wild-type mice developed potent anti-RABV antibodies. Furthermore, IL-21R-/- mice immunized with low-dose rRABV were only minimally protected against pathogenic RABV challenge, while all wild-type mice survived challenge, indicating that IL-21R signaling is required for antibody production in response to low-dose RABV-based vaccination. IL-21R-/- mice immunized with a higher dose of vaccine produced suboptimal anti-RABV primary antibody responses, but showed potent secondary antibodies and protection similar to wild-type mice upon challenge with pathogenic RABV, indicating that IL-21 is dispensable for secondary antibody responses to live RABV-based vaccines when a primary response develops. Furthermore, we show that IL-21 is dispensable for the generation of Tfh cells and memory B cells in the draining lymph nodes of immunized mice but is required for the detection of optimal GC B cells or plasma cells in the lymph node or bone marrow, respectively, in a vaccine dose-dependent manner. Collectively, our preliminary data show that IL-21 is critical for the development of optimal vaccine-induced primary but not secondary antibody responses against RABV infections

Global well-posedness for the KP-I equation on the background of a non localized solution

We prove that the Cauchy problem for the KP-I equation is globally well-posed for initial data which are localized perturbations (of arbitrary size) of a non-localized (i.e. not decaying in all directions) traveling wave solution (e.g. the KdV line solitary wave or the Zaitsev solitary waves which are localized in $x$ and $y$ periodic or conversely)

PHARMACOGENETIC STUDY OF THE ACETYLATION PHENOTYPE IN A BULGARIAN POPULATION

N-acetyltransferase, an enzyme involved in the metabolic inactivation of drugs like isoniazide, some sulfonamides and others is well-known to he under polymorphic genetic control. The acetylation phenotype of the patients may serve as an important guide in foretelling the therapeutic efficacy or tolerahility of a particular drug. In the present study we investigated the distribution of the acetylaiion phenotypes in a group of 100 healthy volunteers of both sexes using sulfadimidine as a substrate. The distribution was found to follow a bimodal pattern, as aspected, with a slight predominance of the "slow" acetylators - in 58 % of the cases, a finding similar to literature data from neighbouring and other European countries. In the men's group the distribution was approximately the same as that in the whole group whilst in the women's one the "rapid" inactivators prevailed. This work represents the first modest attempt in Bulgaria for phenotyping the population according to the individual acetylaiion status

On the ill-posedness result for the BBM equation

We prove that the initial value problem (IVP) for the BBM equation is ill-posed for data in Hs(R), s < 0 in the sense that the ow-map u0 7! u(t) that associates to initial data u0 the solution u cannot be continuous at the origin from Hs(R) to even D0(R) at any _xed t > 0 small enough. This result is sharp.Fundação para a Ciência e a Tecnologia (FCT

Random data wave equations

Nowadays we have many methods allowing to exploit the regularising properties of the linear part of a nonlinear dispersive equation (such as the KdV equation, the nonlinear wave or the nonlinear Schroedinger equations) in order to prove well-posedness in low regularity Sobolev spaces. By well-posedness in low regularity Sobolev spaces we mean that less regularity than the one imposed by the energy methods is required (the energy methods do not exploit the dispersive properties of the linear part of the equation). In many cases these methods to prove well-posedness in low regularity Sobolev spaces lead to optimal results in terms of the regularity of the initial data. By optimal we mean that if one requires slightly less regularity then the corresponding Cauchy problem becomes ill-posed in the Hadamard sense. We call the Sobolev spaces in which these ill-posedness results hold spaces of supercritical regularity. More recently, methods to prove probabilistic well-posedness in Sobolev spaces of supercritical regularity were developed. More precisely, by probabilistic well-posedness we mean that one endows the corresponding Sobolev space of supercritical regularity with a non degenerate probability measure and then one shows that almost surely with respect to this measure one can define a (unique) global flow. However, in most of the cases when the methods to prove probabilistic well-posedness apply, there is no information about the measure transported by the flow. Very recently, a method to prove that the transported measure is absolutely continuous with respect to the initial measure was developed. In such a situation, we have a measure which is quasi-invariant under the corresponding flow. The aim of these lectures is to present all of the above described developments in the context of the nonlinear wave equation.Comment: Lecture notes based on a course given at a CIME summer school in August 201

The phase shift of line solitons for the KP-II equation

The KP-II equation was derived by [B. B. Kadomtsev and V. I. Petviashvili,Sov. Phys. Dokl. vol.15 (1970), 539-541] to explain stability of line solitary waves of shallow water. Stability of line solitons has been proved by [T. Mizumachi, Mem. of vol. 238 (2015), no.1125] and [T. Mizumachi, Proc. Roy. Soc. Edinburgh Sect. A. vol.148 (2018), 149--198]. It turns out the local phase shift of modulating line solitons are not uniform in the transverse direction. In this paper, we obtain the $L^\infty$-bound for the local phase shift of modulating line solitons for polynomially localized perturbations

Quasi-invariant Gaussian measures for the cubic fourth order nonlinear Schrödinger equation

We consider the cubic fourth order nonlinear Schr\"odinger equation on the circle. In particular, we prove that the mean-zero Gaussian measures on Sobolev spaces $H^s(\mathbb{T})$, $s > \frac34$, are quasi-invariant under the flow.Comment: 41 pages. To appear in Probab. Theory Related Field

Numerical study of oscillatory regimes in the Kadomtsev-Petviashvili equation

The aim of this paper is the accurate numerical study of the KP equation. In particular we are concerned with the small dispersion limit of this model, where no comprehensive analytical description exists so far. To this end we first study a similar highly oscillatory regime for asymptotically small solutions, which can be described via the Davey-Stewartson system. In a second step we investigate numerically the small dispersion limit of the KP model in the case of large amplitudes. Similarities and differences to the much better studied Korteweg-de Vries situation are discussed as well as the dependence of the limit on the additional transverse coordinate.Comment: 39 pages, 36 figures (high resolution figures at http://www.mis.mpg.de/preprints/index.html

O37 M5049, a novel potent and selective inhibitor of toll-like receptors 7 and 8 (TLR 7/8)

n/