Development of aggressive vocalizations in male southern elephant seals (Mirounga leonina): maturation or learning?

Summary Vocalizations are an important component of male elephant seal agonistic behaviour. Acoustic and behavioural components of vocalizations emitted during agonistic contests show gross differences between young and old males, but the variation with age depends on the specific feature. Vocalizations become more frequent and effective at later ages. Acoustic features that are constrained by structural phenotype, which changes with age, also should change with age, while acoustic features that are independent from structural phenotype should show no relationship with age. We demonstrate that, in southern elephant seals, formant frequencies, which are constrained by the vocal tract length and, therefore, by body size, show a clear decrease with age, whereas temporal and structural features of sounds, which potentially are unconstrained, show no correlation with age. Formants ontogeny seems, therefore, to be mostly the result of body maturation, and hence formants may be reliable signals of age. In contrast, acoustic features such as temporal features and syllable structure, are free to change, and hence may serve as the raw material for vocal learning and individual recognition

Selective preservation of bone marrow mature recirculating but not marginal zone B cells in murine models of chronic inflammation

Inflammation promotes granulopoiesis over B lymphopoiesis in the bone marrow (BM). We studied B cell homeostasis in two murine models of T cell mediated chronic inflammation, namely calreticulin-deficient fetal liver chimeras (FLC), which develop severe blepharitis and alopecia due to T cell hyper responsiveness, and inflammatory bowel disease (IBD) caused by injection of CD4+ naïve T cells into lymphopenic mice. We show herein that despite the severe depletion of B cell progenitors during chronic, peripheral T cell-mediated inflammation, the population of BM mature recirculating B cells is unaffected. These B cells are poised to differentiate to plasma cells in response to blood borne pathogens, in an analogous fashion to non-recirculating marginal zone (MZ) B cells in the spleen. MZ B cells nevertheless differentiate more efficiently to plasma cells upon polyclonal stimulation by Toll-like receptor (TLR) ligands, and are depleted during chronic T cell mediated inflammation in vivo. The preservation of mature B cells in the BM is associated with increased concentration of macrophage migration inhibitory factor (MIF) in serum and BM plasma. MIF produced by perivascular dendritic cells (DC) in the BM provides a crucial survival signal for recirculating B cells, and mice treated with a MIF inhibitor during inflammation showed significantly reduced mature B cells in the BM. These data indicate that MIF secretion by perivascular DC may promote the survival of the recirculating B cell pool to ensure responsiveness to blood borne microbes despite loss of the MZ B cell pool that accompanies depressed lymphopoiesis during inflammation

IL-7 and IL-15 allow the generation of suicide gene–modified alloreactive self-renewing central memory human T lymphocytes

Abstract Long-term clinical remissions of leukemia, after allogeneic hematopoietic stem cell transplantation, depend on alloreactive memory T cells able to self-renew and differentiate into antileukemia effectors. This is counterbalanced by detrimental graft-versus-host disease (GVHD). Induction of a selective suicide in donor T cells is a current gene therapy approach to abrogate GVHD. Unfortunately, genetic modification reduces alloreactivity of lymphocytes. This associates with an effector memory (TEM) phenotype of gene-modified lymphocytes and may limit antileukemia effect. We hypothesized that alloreactivity of gene-modified lymphocytes segregates with the central memory (TCM) phenotype. To this, we generated suicide gene–modified TCM lymphocytes with a retroviral vector after CD28 costimulation and culture with IL-2, IL-7, or a combination of IL-7 and IL-15. In vitro, suicide gene–modified TCM cells self-renewed upon alloantigen stimulation and resisted activation-induced cell death. In a humanized mouse model, only suicide gene–modified T cells cultured with IL-7 and IL-15 persisted, differentiated in TEM cells, and were as potent as unmanipulated lymphocytes in causing GVHD. GVHD was halted through the activation of the suicide gene machinery. These results warrant the use of suicide gene–modified TCM cells cultured with IL-7 and IL-15 for the safe exploitation of the alloreactive response against cancer

AAV6-mediated Systemic shRNA Delivery Reverses Disease in a Mouse Model of Facioscapulohumeral Muscular Dystrophy

Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans

Selective Preservation of Bone Marrow Mature Recirculating but Not Marginal Zone B Cells in Murine Models of Chronic Inflammation

Inflammation promotes granulopoiesis over B lymphopoiesis in the bone marrow (BM). We studied B cell homeostasis in two murine models of T cell mediated chronic inflammation, namely calreticulin-deficient fetal liver chimeras (FLC), which develop severe blepharitis and alopecia due to T cell hyper responsiveness, and inflammatory bowel disease (IBD) caused by injection of CD4+ naïve T cells into lymphopenic mice. We show herein that despite the severe depletion of B cell progenitors during chronic, peripheral T cell-mediated inflammation, the population of BM mature recirculating B cells is unaffected. These B cells are poised to differentiate to plasma cells in response to blood borne pathogens, in an analogous fashion to non-recirculating marginal zone (MZ) B cells in the spleen. MZ B cells nevertheless differentiate more efficiently to plasma cells upon polyclonal stimulation by Toll-like receptor (TLR) ligands, and are depleted during chronic T cell mediated inflammation in vivo. The preservation of mature B cells in the BM is associated with increased concentration of macrophage migration inhibitory factor (MIF) in serum and BM plasma. MIF produced by perivascular dendritic cells (DC) in the BM provides a crucial survival signal for recirculating B cells, and mice treated with a MIF inhibitor during inflammation showed significantly reduced mature B cells in the BM. These data indicate that MIF secretion by perivascular DC may promote the survival of the recirculating B cell pool to ensure responsiveness to blood borne microbes despite loss of the MZ B cell pool that accompanies depressed lymphopoiesis during inflammation

Acoustic communication in elephant seals (Mirounga leonina): structural and functional correlates of male vocalizations

Southern elephant seals (SES, hereafter) show the most extremely polygynous mating system of all mammals, with a very intense competition among males for access to females. Vocalizations are the most important component of SES male agonistic behaviour. Notwithstanding this, the knowledge of SES vocalizations was scanty, and mostly anecdotal, before I started studying them. During my previous research, I focused on the acoustic structure and the individual variation of vocalizations. The goal of my PhD research project was to study the development of male vocalizations, to understand their functions, to explore their relationships with male phenotype, and to assess their potential use as honest signals. -- The first step was to analyze the male phenotypic traits that should be related to vocalizations. I studied body size and growth, as well as the development or the proboscis, a peculiar secondary sexual trait which role in vocalizations has always been controversial. I showed that the proboscis has indeed an active role in vocalization, and may serve as a way or elongating the vocal tract or the emitter, hence exaggerating the size information conveyed by acoustic signals with respect to the true size. -- I then focussed on the different acoustic features of vocalizations. I showed that the temporal macro-structure of vocalizations, which is not constrained by vocal tract length or shape, is probably learned by young males through imitation of the older, most successful, breeders. On the contrary, the frequency features or vocalizations (formants, in particular), which are constrained by the vocal tract length, have a predictable development pattern related to body growth. – Finally, I demonstrated that both source level and formant frequencies give reliable information about the phenotype of the emitter and, hence, are honest signals. But I also showed that the phenotypic information content of these signals is rather low. Vocalizations are, hence, a far from perfect assessment system, being very effective in settling contests between males when phenotypic differences are great, but not when interacting males have similar phenotypes

Opportunity for selection in southern elephant seals: the effect of spatial scale of analysis

Abstract The opportunity for selection, I, calculated as the variance in relative ®tness, sets an upper limit to the amount of adaptive change that selection may produce. Therefore, it is a potentially valuable, and frequently used, measure of the potential of action of phenotypic selection. Although many different aspects of I calculation and analysis have been explored, the effect of the spatial scale chosen for calculation received little attention, notwithstanding the growing evidence that natural populations are not homogeneous and present a hierarchical spatial structure. The effect of scale on the estimation of I was examined from data collected in two populations of southern elephant seals (Mirounga leonina), an easily observable and strongly polygynous species. A signi®cant effect of spatial scale on three important aspects of I calculation and analysis was found: dependence of I on mean ®tness, between population variation of I, and effect of local demography on I