Tissue requirements for establishing long-term CD4+ T cell-mediated immunity following Leishmania donovani infection

Organ-specific immunity is a feature of many infectious diseases, including visceral leishmaniasis caused by Leishmania donovani. Experimental visceral leishmaniasis in genetically susceptible mice is characterized by an acute, resolving infection in the liver and chronic infection in the spleen. CD4+ T cell responses are critical for the establishment and maintenance of hepatic immunity in this disease model, but their role in chronically infected spleens remains unclear. In this study, we show that dendritic cells are critical for CD4+ T cell activation and expansion in all tissue sites examined. We found that FTY720-mediated blockade of T cell trafficking early in infection prevented Ag-specific CD4+ T cells from appearing in lymph nodes, but not the spleen and liver, suggesting that early CD4+ T cell priming does not occur in liver-draining lymph nodes. Extended treatment with FTY720 over the first month of infection increased parasite burdens, although this associated with blockade of lymphocyte egress from secondary lymphoid tissue, as well as with more generalized splenic lymphopenia. Importantly, we demonstrate that CD4+ T cells are required for the establishment and maintenance of antiparasitic immunity in the liver, as well as for immune surveillance and suppression of parasite outgrowth in chronically infected spleens. Finally, although early CD4+ T cell priming appeared to occur most effectively in the spleen, we unexpectedly revealed that protective CD4+ T cell-mediated hepatic immunity could be generated in the complete absence of all secondary lymphoid tissues.

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense. © 2012 Nature America, Inc. All rights reserved.

An algebraic theory of functional and multivalued dependencies in relational databases

Computation of the dependency basis is the fundamental step in solving the membership problem for functional dependencies (FDs) and multivalued dependencies (MVDs) in relational database theory. We examine this problem from an algebraic perspective. We introduce the notion of the inference basis of a set M of MVDs and show that it contains the maximum information about the logical consequences of M. We propose the notion of a dependency-lattice and develop an algebraic characterization of inference basis using simple notions from lattice theory. We also establish several interesting properties of dependency-lattices related to the implication problem. Founded on our characterization, we synthesize efficient algorithms for (a): computing the inference basis of a given set M of MVDs; (b): computing the dependency basis of a given attribute set w.r.t. M; and (c): solving the membership problem for MVDs. We also show that our results naturally extend to incorporate FDs also in a way that enables the solution of the membership problem for both FDs and MVDs put together. We finally show that our algorithms are more efficient than existing ones, when used to solve what we term the ‘generalized membership problem’.

Algebraic and geometric intersection numbers for free groups

We show that the algebraic intersection number of Scott and Swarup for splittings of free groups Coincides With the geometric intersection number for the sphere complex of the connected sum of copies of S-2 x S-1. (C) 2009 Elsevier B.V. All rights reserved.

Algebraic characterization of decentralized fixed modes

An input-output, frequency-domain characterization of decentralized fixed modes is given in this paper, using only standard block-diagram algebra, well-known determinantal expansions and the Binet-Cauchy formula.

Breastmilk-saliva interactions boost innate immunity by regulating the oral microbiome in early infancy

Introduction Xanthine oxidase (XO) is distributed in mammals largely in the liver and small intestine, but also is highly active in milk where it generates hydrogen peroxide (H2O2). Adult human saliva is low in hypoxanthine and xanthine, the substrates of XO, and high in the lactoperoxidase substrate thiocyanate, but saliva of neonates has not been examined. Results Median concentrations of hypoxanthine and xanthine in neonatal saliva (27 and 19 μM respectively) were ten-fold higher than in adult saliva (2.1 and 1.7 μM). Fresh breastmilk contained 27.3±12.2 μM H2O2 but mixing baby saliva with breastmilk additionally generated >40 μM H2O2, sufficient to inhibit growth of the opportunistic pathogens Staphylococcus aureus and Salmonella spp. Oral peroxidase activity in neonatal saliva was variable but low (median 7 U/L, range 2–449) compared to adults (620 U/L, 48–1348), while peroxidase substrate thiocyanate in neonatal saliva was surprisingly high. Baby but not adult saliva also contained nucleosides and nucleobases that encouraged growth of the commensal bacteria Lactobacillus, but inhibited opportunistic pathogens; these nucleosides/bases may also promote growth of immature gut cells. Transition from neonatal to adult saliva pattern occurred during the weaning period. A survey of saliva from domesticated mammals revealed wide variation in nucleoside/base patterns. Discussion and Conclusion During breast-feeding, baby saliva reacts with breastmilk to produce reactive oxygen species, while simultaneously providing growth-promoting nucleotide precursors. Milk thus plays more than a simply nutritional role in mammals, interacting with infant saliva to produce a potent combination of stimulatory and inhibitory metabolites that regulate early oral–and hence gut–microbiota. Consequently, milk-saliva mixing appears to represent unique biochemical synergism which boosts early innate immunity.

Algebraic design techniques for reliable stabilization

In this paper we study two problems in feedback stabilization. The first is the simultaneous stabilization problem, which can be stated as follows. Given plantsG_{0}, G_{1},..., G_{l}, does there exist a single compensatorCthat stabilizes all of them? The second is that of stabilization by a stable compensator, or more generally, a "least unstable" compensator. Given a plantG, we would like to know whether or not there exists a stable compensatorCthat stabilizesG; if not, what is the smallest number of right half-place poles (counted according to their McMillan degree) that any stabilizing compensator must have? We show that the two problems are equivalent in the following sense. The problem of simultaneously stabilizingl + 1plants can be reduced to the problem of simultaneously stabilizinglplants using a stable compensator, which in turn can be stated as the following purely algebraic problem. Given2lmatricesA_{1}, ..., A_{l}, B_{1}, ..., B_{l}, whereA_{i}, B_{i}are right-coprime for alli, does there exist a matrixMsuch thatA_{i} + MB_{i}, is unimodular for alli?Conversely, the problem of simultaneously stabilizinglplants using a stable compensator can be formulated as one of simultaneously stabilizingl + 1plants. The problem of determining whether or not there exists anMsuch thatA + BMis unimodular, given a right-coprime pair (A, B), turns out to be a special case of a question concerning a matrix division algorithm in a proper Euclidean domain. We give an answer to this question, and we believe this result might be of some independent interest. We show that, given twon times mplantsG_{0} and G_{1}we can generically stabilize them simultaneously provided eithernormis greater than one. In contrast, simultaneous stabilizability, of two single-input-single-output plants, g0and g1, is not generic.

Induction of partial immunity in both males and females is sufficient to protect females against sexual transmission of Chlamydia

Sexually transmitted Chlamydia trachomatis causes infertility, and because almost 90% of infections are asymptomatic, a vaccine is required for its eradication. Mathematical modeling studies have indicated that a vaccine eliciting partial protection (non-sterilizing) may prevent Chlamydia infection transmission, if administered to both sexes before an infection. However, reducing chlamydial inoculum transmitted by males and increasing infection resistance in females through vaccination to elicit sterilizing immunity has yet to be investigated experimentally. Here we show that a partially protective vaccine (chlamydial major outer membrane protein (MOMP) and ISCOMATRIX (IMX) provided sterilizing immunity against sexual transmission between immunized mice. Immunizing male or female mice before an infection reduced chlamydial burden and disease development, but did not prevent infection. However, infection and inflammatory disease responsible for infertility were absent in 100% of immunized female mice challenged intravaginally with ejaculate collected from infected immunized males. In contrast to the sterilizing immunity generated following recovery from a previous chlamydial infection, protective immunity conferred by MOMP/IMX occurred independent of resident memory T cells. Our results demonstrate that vaccination of males or females can further protect the opposing sex, whereas vaccination of both sexes can synergize to elicit sterilizing immunity against Chlamydia sexual transmission.

An algebraic algorithm for the design and analysis of linear dynamical systems

In an earlier paper [1], it has been shown that velocity ratio, defined with reference to the analogous circuit, is a basic parameter in the complete analysis of a linear one-dimensional dynamical system. In this paper it is shown that the terms constituting velocity ratio can be readily determined by means of an algebraic algorithm developed from a heuristic study of the process of transfer matrix multiplication. The algorithm permits the set of most significant terms at a particular frequency of interest to be identified from a knowledge of the relative magnitudes of the impedances of the constituent elements of a proposed configuration. This feature makes the algorithm a potential tool in a first approach to a rational design of a complex dynamical filter. This algorithm is particularly suited for the desk analysis of a medium size system with lumped as well as distributed elements.

Antitumor immunity in rats against Yoshida ascites sarcoma after treatment with antibiotics

Chromomycin A3, mithramycin, olivomycin and actinomycin D, four antitumor antibiotics inhibit growth of Yoshida ascites sarcoma (YAS). The antibiotic treated tumor-free rats exhibit antitumor immunity as judged by rejection of subsequent tumor transplant. The lymphocytes from immune rats are able to inhibit tumor growth in syngenic animals.

An algebraic approach to the restoration of images

Two different matrix algorithms are described for the restoration of blurred pictures. These are illustrated by numerical examples.