A Mouse with a Monoclonal Primary lmmunoglobulin Repertoire not Further Diversified by V-Gene Replacement

We have generated a monoclonal B-cell mouse by introducing homozygous, nonfunctional RAG-2 alleles and a λ1 light-chain transgene into the quasi-monoclonal (QM) mouse, which contains a “knocked-in” VHDJH rearrangement. Thus, this mouse, which we call MonoB, is devoid of T cells and contains preformed heavy- and light-chain genes encoding immunoglobulin with an anti-NP specificity. The MonoB mouse allows us to examine immunoglobulin diversity in the absence of processes mediated by V(D)J recombination and T cells. Here we report that not only is the MonoB's primary immunoglobulin repertoire monoclonal, but also that its secondary repertoire is not further diversified by V-gene replacement or gene conversion. Among 99 heavy-chain and 41 λ light-chain genes from peripheral B cells of the MonoB mouse, there were no V-gene replacements. When compared to the QM mouse, which has RAG activity, and for which V-gene replacement is the major diversifying mechanism, these data suggest that V-gene replacement is mediated by V(D)J recombination and not by other recombination systems

Automated Discovery of Relationships, Models, and Principles in Ecology

Ecological systems are the quintessential complex systems, involving numerous high-order interactions and non-linear relationships. The most used statistical modeling techniques can hardly accommodate the complexity of ecological patterns and processes. Finding hidden relationships in complex data is now possible using massive computational power, particularly by means of artificial intelligence and machine learning methods. Here we explored the potential of symbolic regression (SR), commonly used in other areas, in the field of ecology. Symbolic regression searches for both the formal structure of equations and the fitting parameters simultaneously, hence providing the required flexibility to characterize complex ecological systems. Although the method here presented is automated, it is part of a collaborative human-machine effort and we demonstrate ways to do it. First, we test the robustness of SR to extreme levels of noise when searching for the species-area relationship. Second, we demonstrate how SR can model species richness and spatial distributions. Third, we illustrate how SR can be used to find general models in ecology, namely new formulas for species richness estimators and the general dynamic model of oceanic island biogeography. We propose that evolving free-form equations purely from data, often without prior human inference or hypotheses, may represent a very powerful tool for ecologists and biogeographers to become aware of hidden relationships and suggest general theoretical models and principles.Peer reviewe

Paleoenvironmental evolution of estuarine systems during the last 14000 years - the case of Douro Estuary (NW Portugal)

Proceedings of the 8th International Coastal Symposium, ICS 2004, Itajaí/Itapema, Santa Catarina, Brazil, 14 to 19 March 200

TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen

© 2014, The American Society for Clinical InvestigationThe transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) controls differentiation of long-lived plasma cells, and almost 10% of individuals with common variable immunodeficiency (CVID) express either the C104R or A181E variants of TACI. These variants impair TACI function, and TACI-deficient mice exhibit a CVID-like disease. However, 1%-2% of normal individuals harbor the C140R or A181E TACI variants and have no outward signs of CVID, and it is not clear why TACI deficiency in this group does not cause disease. Here, we determined that TACI-deficient mice have low baseline levels of Ig in the blood but retain the ability to mutate Ig-associated genes that encode antigen-specific antibodies. The antigen-specific antibodies in TACI-deficient mice were produced in bursts and had higher avidity than those of WT animals. Moreover, mice lacking TACI were able to clear Citrobacter rodentium, a model pathogen for severe human enteritis, more rapidly than did WT mice. These findings suggest that the high prevalence of TACI deficiency in humans might reflect enhanced host defense against enteritis, which is more severe in those with acquired or inherited immunodeficiencies.This work was funded by NIH grants P01 HL079067-01 and R37 HL5229

Peces capturados en la campaña "CIGALA-79" a lo largo de la Plataforma Atlántica de la Península Ibérica (División IX-a del ICES)

En el presente trabajo se relacionan las especies de peces capturados en la Campaña "CIGALA -79 ", que tuvo lugar del 6 de agosto al 4 de setiembre de 1979 a lo largo de la División IX-a del ICES. Se expresa el número de ejemplares capturados de cada especie, por zona de latitud y estrato de profundidad. Se citan un total de 109 especies de peces.No presente traballo relacionam-se as especies de peixes capturados no Cruzeiro "CIGALA-79", que teve lugar de 6 de Agosto a 4 de Setembro de 1979 ao tongo da Dioistio IX-a do ICES. Expressa-se o número de exemplares capturados de cada espécie por zona de latitude e estrato de profuntlidade. Citam-se um total de 109 espécies de peixes.The following study relates the species of captured fishes in the survey "CIGALA- 79" that has been realized since the 6th August until the 4th September 1979 along the Division IX-a of ICES. It is reported the number of captured individuals of each species by area of latitude and stratum of depth, A total of 109 species of fishes are cited,Versión del editor

Histone H2A and H2B Are Monoubiquitinated at AID-Targeted Loci

Background: Somatic hypermutation introduces base substitutions into the rearranged and expressed immunoglobulin (Ig) variable regions to promote immunity. This pathway requires and is initiated by the Activation Induced Deaminase (AID) protein, which deaminates cytidine to produce uracils and UG mismatches at the Ig genes. Subsequent processing of uracil by mismatch repair and base excision repair factors contributes to mutagenesis. While selective for certain genomic targets, the chromatin modifications which distinguish hypermutating from non-hypermutating loci are not defined. Methodology/Principal Findings: Here, we show that AID-targeted loci in mammalian B cells contain ubiquitinated chromatin. Chromatin immunoprecipitation (ChIP) analysis of a constitutively hypermutating Burkitt\u27s B cell line, Ramos, revealed the presence of monoubiquitinated forms of both histone H2A and H2B at two AID-associated loci, but not at control loci which are expressed but not hypermutated. Similar analysis using LPS activated primary murine splenocytes showed enrichment of the expressed V(H) and S gamma 3 switch regions upon ChIP with antibody specific to AID and to monoubiquitinated H2A and H2B. In the mechanism of mammalian hypermutation, AID may interact with ubiquitinated chromatin because confocal immunofluorescence microscopy visualized AID colocalized with monoubiquitinated H2B within discrete nuclear foci. Conclusions/Significance: Our results indicate that monoubiquitinated histones accompany active somatic hypermutation, revealing part of the histone code marking AID-targeted loci. This expands the current view of the chromatin state during hypermutation by identifying a specific nucleosome architecture associated with somatic hypermutation

Transfer of Small Resting B Cells into Immunodeficient Hosts Results in the Selection of a Self-renewing Activated B Cell Population

We studied the role of bone marrow B cell production in the renewal of peripheral B cells and the feedback mechanisms that control the entry of newly formed B cells into the peripheral B cell pools. When resting lymph node B cells are injected into B cell–deficient hosts, a fraction of the transferred cells expands and constitutes a highly selected population that survives for prolonged periods of time by continuous cell renewal at the periphery. Although the number of donor B cells recovered is low, a significant fraction shows an activated phenotype, and the serum immunoglobulin (Ig)M levels are as in normal mice. This population of activated B cells is resistant to replacement by a new cohort of B cells and is able to feedback regulate both the entry of newly formed B cells into the peripheral pool and terminal differentiation. These findings suggest that peripheral B cell selection follows the first come, first served rule and that IgM-secreting cells are generated from a pool of stable activated B cells with an independent homeostasis

Mice Deficient in Nucleoporin Nup210 Develop Peripheral T Cell Alterations

The nucleopore is an essential structure of the eukaryotic cell, regulating passage between the nucleus and cytoplasm. While individual functions of core nucleopore proteins have been identified, the role of other components, such as Nup210, are poorly defined. Here, through the use of an unbiased ENU mutagenesis screen for mutations effecting the peripheral T cell compartment, we identified a Nup210 mutation in a mouse strain with altered CD4/CD8 T cell ratios. Through the generation of Nup210 knockout mice we identified Nup210 as having a T cell-intrinsic function in the peripheral homeostasis of T cells. Remarkably, despite the deep evolutionary conservation of this key nucleopore complex member, no other major phenotypes developed, with viable and healthy knockout mice. These results identify Nup210 as an important nucleopore complex component for peripheral T cells, and raise further questions of why this nucleopore component shows deep evolutionary conservation despite seemingly redundant functions in most cell types

Two Genetic Determinants Acquired Late in Mus Evolution Regulate the Inclusion of Exon 5, which Alters Mouse APOBEC3 Translation Efficiency

Mouse apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3 (mA3), an intracellular antiviral factor, has 2 allelic variations that are linked with different susceptibilities to beta- and gammaretrovirus infections among various mouse strains. In virus-resistant C57BL/6 (B6) mice, mA3 transcripts are more abundant than those in susceptible BALB/c mice both in the spleen and bone marrow. These strains of mice also express mA3 transcripts with different splicing patterns: B6 mice preferentially express exon 5-deficient (Δ5) mA3 mRNA, while BALB/c mice produce exon 5-containing full-length mA3 mRNA as the major transcript. Although the protein product of the Δ5 mRNA exerts stronger antiretroviral activities than the full-length protein, how exon 5 affects mA3 antiviral activity, as well as the genetic mechanisms regulating exon 5 inclusion into the mA3 transcripts, remains largely uncharacterized. Here we show that mA3 exon 5 is indeed a functional element that influences protein synthesis at a post-transcriptional level. We further employed in vitro splicing assays using genomic DNA clones to identify two critical polymorphisms affecting the inclusion of exon 5 into mA3 transcripts: the number of TCCT repeats upstream of exon 5 and the single nucleotide polymorphism within exon 5 located 12 bases upstream of the exon 5/intron 5 boundary. Distribution of the above polymorphisms among different Mus species indicates that the inclusion of exon 5 into mA3 mRNA is a relatively recent event in the evolution of mice. The widespread geographic distribution of this exon 5-including genetic variant suggests that in some Mus populations the cost of maintaining an effective but mutagenic enzyme may outweigh its antiviral function

Inflammation-induced formation of fat-associated lymphoid clusters

Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses