Kimberlite eruptions driven by slab flux and subduction angle.

Kimberlites are sourced from thermochemical upwellings which can transport diamonds to the surface of the crust. The majority of kimberlites preserved at the Earth's surface erupted between 250 and 50 million years ago, and have been attributed to changes in plate velocity or mantle plumes. However, these mechanisms fail to explain the presence of strong subduction signatures observed in some Cretaceous kimberlites. This raises the question whether there is a subduction process that unifies our understanding of the timing of kimberlite eruptions. We develop a novel formulation for calculating subduction angle based on trench migration, convergence rate, slab thickness and density to connect the influx of slab material into the mantle with the timing of kimberlite eruptions. We find that subduction angles combined with peaks in slab flux predict pulses of kimberlite eruptions. High rates of subducting slab material trigger mantle return flow that stimulates fertile reservoirs in the mantle. These convective instabilities transport slab-influenced melt to the surface at a distance inbound from the trench corresponding to the subduction angle. Our deep-time slab dip formulation has numerous potential applications including modelling the deep carbon and water cycles, and an improved understanding of subduction-related mineral deposits.

NEOTROPICAL CARNIVORES: a data set on carnivore distribution in the Neotropics.

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data.

Toxoplasma gondii antibodies in wild white-lipped peccary (Tayassu pecari) from Peru.

In the Peruvian Amazon, the white-lipped peccary (Tayassu pecari) is a desirable game species and is important for the local rural economy. Blood samples from 101 white-lipped peccaries from Peru were collected from 3 different conservation areas located in the municipalities of Manu and Tambopata, southeastern region of the Peruvian Amazon. Antibodies were assayed using the modified agglutination test (MAT, cut of value of 25). Antibodies to Toxoplasma gondii were found in 89.1% (90 of 101) of animals, with titers of 1 ∶ 25 in 9, 1 ∶ 50 in 25, 1 ∶ 100 in 20, 1 ∶ 200 in 14, 1 ∶ 400 in 12, 1 ∶ 800 in 9, and 1 ∶ 3,200 in 1; 87.7% and 89.2% of males and females, respectively, tested positively, and no association (P ≥ 0.05) with gender and occurrence of antibodies was observed.

CD69 down-modulation and inhibition of thymic egress by short- and long-term selective chemical agonism of sphingosine 1-phosphate receptors.

Thymic development requires proliferation, selection, maturation and release of mature single-positive CD4 and CD8 T cells into the periphery. In mice, non-selective sphingosine-1 phosphate (S1P) receptor agonists, active on four of the five known S1P receptors, alter thymocyte phenotype and egress. Here, we show that down-modulation of CD69 occurs acutely and transiently at a discrete and late stage of medullary development after a single-dose administration of S1P(1) receptor-selective agonist, which induces long-term tonic receptor activation in the absence of receptor degradation. In addition, agonist acutely inhibited egress of mature thymocytes into peripheral lymphoid organs, suggesting that both the phenotype and migration of medullary thymocytes are regulated simultaneously and coordinately by agonism of S1P(1) alone. Long-term dosing shifted the early/late medullary thymocyte ratio with an expansion of the late medullary compartment, as mature CD69(-) thymocytes were retained within the thymus. Therefore, chemical agonism of S1P(1) accelerates medullary phenotypic maturation and inhibits egress, leading to the expansion and accumulation of the recent thymocyte emigrant population in the medulla. However, chemical agonism fails to replicate the S1P(1)-null CD69(hi) late medullary phenotype, suggesting that agonism and gene deletion operate by distinct mechanisms, and that functional receptor antagonism may not be required for lymphocyte sequestration.

Egress: a receptor-regulated step in lymphocyte trafficking.

Blood lymphocyte numbers, which are maintained by recirculation through secondary lymphoid organs, are essential for the efficient development of immune responses. Recirculating populations of B and T lymphocytes are regulated by the sphingosine-1-phosphate (S1P) receptor-dependent control of lymphocyte egress. T-cell egress from thymus into blood, egress from lymph node and Peyer's patch into lymph, and B-cell egress into lymph are rapidly and completely inhibited by agonism of S1P receptors. Mesenteric lymph nodes show log-jamming of lymphocytes subjacent to sinus-lining endothelium. Agonism of S1P receptors produces rapid peripheral blood lymphopenia, which is maintained in the presence of receptor agonist. Effector CD4+ and CD8+ T cells, produced by clonal expansion in draining lymph node in response to antigen, are sequestered in lymph node and fail to reach the peripheral blood. The S1P receptor system may represent an early physiological link between the non-specific inflammatory response and the alteration of lymphocyte traffic through draining lymph nodes. Pharmacological subversion of the S1P receptor system, through systemic S1P agonist-induced inhibition of lymphocyte egress, suppresses antigenic responses to peripheral, but not to systemically, delivered antigen. This inhibition induces significant immunosuppression in models of transplantation and autoimmune tissue damage that may prove to be of clinical benefit.

H2-O influence on antigen presentation in H2-E-expressing mice.

MHC class II molecules sample peptides generated in the endosomal/lysosomal system for cell surface presentation to CD4+ T cells. Peptide loading requires the endosomal/lysosomal resident HLA-DM (DM; H2-DM, mouse), but in B cells, DM is tightly associated with HLA-DO (DO; H2-O, mouse). We have previously shown that H2-O differentially modulates the processing and presentation of different antigenic epitopes on H2-Ab molecules. Using H2-Ead-transgenic mice, we here show that presentation of different epitopes by H2-Ed/b molecules is similarly influenced by H2-O after membrane immunoglobulin-mediated uptake of antigen. In addition, B cells from H2-Ead-transgenic mice (which co-express H2-Ab and H2-Ed/b molecules) show an altered pattern of presentation of H2-Ab-restricted epitopes. In H2-Ead-transgenic, H2-O-deficient mice, further changes in the peptide repertoire were observed. Thus, H2-Ed/b expression influences the epitopes presented by H2-Ab, and this effect is further altered by expression of H2-O.

Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist.

Only a small number of T cells generated in the thymus each day are selected to replenish the peripheral T cell pool. Much is known about thymic selection; however, little is known of the mechanisms regulating medullary maturation and the release of mature T cells into the blood. Here we demonstrate a rapid acceleration of medullary thymocyte phenotypic maturation through loss of CD69 induced by sphingosine 1-phosphate (S1P) receptor agonist. Low nanomolar agonist concentrations selectively induce changes in CD69(int) CD62L(high) single positive T cells, resulting in down-modulation of CD69 within 2 h. While CD69 loss is accelerated, egress of mature T cells into blood is inhibited >95% within 2 h. Both processes exhibit parallel sensitivities and dose-responses. Together, these data reveal a potent means for rapidly regulating thymic export where S1P receptor agonism alters both phenotypic maturation and egress of thymocytes into blood during late thymic maturation. The S1P system is now shown to acutely regulate both thymic and lymph node egress. Inhibition of lymphocyte egress from thymus and lymph node can contribute synergistically to clinically useful immunosupression by disrupting recirculation of peripheral T cells.

Analysis of H2-O influence on antigen presentation by B cells.

HLA-DM (DM; in mouse H2-DM) promotes the exchange of MHC class II-associated peptides, resulting in the accumulation of stable MHC class II-peptide complexes. In naive (but not germinal center) B cells, a large part of DM is tightly associated with HLA-DO (DO; in mouse H2-O), but the functional consequence of this association for Ag presentation is debated. Here, we have extended previous studies by examining the presentation of multiple epitopes after Ag internalization by fluid phase endocytosis or receptor-mediated uptake by membrane Ig (mIg) receptors. We find that the effects of H2-O are more complex than previously appreciated; thus, while only minor influences on Ag presentation could be detected after fluid phase uptake, many epitopes were substantially affected after mIg-mediated uptake. Unexpectedly, the presentation of different epitopes was found to be enhanced, diminished, or unaffected in the absence of H2-O, depending on the specificity of the mIg used for Ag internalization. Interestingly, epitopes from the same Ag did not necessarily show the same H2-O dependency. This finding suggests that H2-O may control the repertoire of peptides presented by B cells depending on the mIg-Ag interaction. The absence of DO/H2-O from germinal center B cells suggests that this control may be released during B cell maturation.

Specific role for cathepsin S in the generation of antigenic peptides in vivo.

To address the role of different proteases in degradation of antigen destined for MHC class II-restricted presentation, we generated cathepsin-deficient mice carrying a transgenic B cell receptor (BCR) specific for hen egg lysozyme (HEL). We demonstrate that degradation of HEL in B lymphocytes is highly processive and does not result in discrete processing intermediates. Moreover, degradation of HEL does not require initial unlocking of the antigen by any of the cathepsins tested. Using mass spectrometry and microsequencing, we show that all major cathepsins (CatS, CatL, CatB, and CatD) digest HEL in vitro with considerable redundancy, although some preferential cleavages are evident. These observations have a functional correlate: when triggered by cathepsin S-deficient antigen-presenting cells, T cells that recognize different HEL epitopes fail to present two HEL-derived epitopes, while a third epitope is presented independently of the activity of cysteine proteases. We conclude that the proteolytic processing machinery is redundant, and that several proteases can substitute for each other to degrade a given antigen. However, a certain degree of proteolytic specificity is demonstrable for the generation of particular epitopes, notably by CatS.

Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate.

Sphingosine 1-phosphate (S1P) influences heart rate, coronary artery caliber, endothelial integrity, and lymphocyte recirculation through five related high affinity G-protein-coupled receptors. Inhibition of lymphocyte recirculation by non-selective S1P receptor agonists produces clinical immunosuppression preventing transplant rejection but is associated with transient bradycardia. Understanding the contribution of individual receptors has been limited by the embryonic lethality of the S1P(1) knock-out and the unavailability of selective agonists or antagonists. A potent, S1P(1)-receptor selective agonist structurally unrelated to S1P was found to activate multiple signals triggered by S1P, including guanosine 5'-3-O-(thio)triphosphate binding, calcium flux, Akt and ERK1/2 phosphorylation, and stimulation of migration of S1P(1)- but not S1P(3)-expressing cells in vitro. The agonist also alters lymphocyte trafficking in vivo. Use of selective agonism together with deletant mice lacking S1P(3) receptor reveals that agonism of S1P(1) receptor alone is sufficient to control lymphocyte recirculation. Moreover, S1P(1) receptor agonist plasma levels are causally associated with induction and maintenance of lymphopenia. S1P(3), and not S1P(1), is directly implicated in sinus bradycardia. The sustained bradycardia induced by S1P receptor non-selective immunosuppressive agonists in wild-type mice is abolished in S1P(3)-/- mice, whereas S1P(1)-selective agonist does not produce bradycardia. Separation of receptor subtype usage for control of lymphocyte recirculation and heart rate may allow the identification of selective immunosuppressive S1P(1) receptor agonists with an enhanced therapeutic window. S1P(1)-selective agonists will be of broad utility in understanding cell functions in vitro, and vascular physiology in vivo, and the success of the chemical approach for S1P(1) suggests that selective tools for the resolution of function across this broad lipid receptor family are now possible.