Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria

SIGNR1, a member of a new family of mouse C-type lectins, is expressed at high levels in macrophages (Mφ) within the splenic marginal zone, lymph node medulla, and in some strains, in peritoneal cavity. We previously reported that SIGNR1 captures gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium, as well as Candida albicans. We have now investigated the precise ligands and innate responses that involve SIGNR1. The interaction of SIGNR1 with FITC-dextran and E. coli was completely inhibited by LPS from E. coli and Salmonella minnesota. Using LPS from various types of rough mutants of Salmonella, we found that SIGNR1 primarily recognizes oligosaccharides in the non-reductive end of the LPS core region. In transfectants, expression of SIGNR1 enhanced the oligomerization of Toll-like receptor (TLR) 4 molecules as well as the degradation of IκB-α after stimulation with E. coli under low-serum conditions. The enhanced TLR4 oligomerization was inhibited by pre-treatment of the cells with anti-SIGNR1 mAb or with mannan. A physical association between SIGNR1 and the TLR4-MD-2 complex was also observed by immunoprecipitation. Finally, we found that transfection of SIGNR1 into the macrophage-like RAW264.7 cells resulted in significant augmentation of cytokine production. These results suggest that SIGNR1 associates with TLR4 to capture gram-negative bacteria and facilitate signal transduction to activate innate Mφ responses

Widespread duplications in the genomes of laboratory stocks of Dictyostelium discoideum.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: Duplications of stretches of the genome are an important source of individual genetic variation, but their unrecognized presence in laboratory organisms would be a confounding variable for genetic analysis. RESULTS: We report here that duplications of 15 kb or more are common in the genome of the social amoeba Dictyostelium discoideum. Most stocks of the axenic 'workhorse' strains Ax2 and Ax3/4 obtained from different laboratories can be expected to carry different duplications. The auxotrophic strains DH1 and JH10 also bear previously unreported duplications. Strain Ax3/4 is known to carry a large duplication on chromosome 2 and this structure shows evidence of continuing instability; we find a further variable duplication on chromosome 5. These duplications are lacking in Ax2, which has instead a small duplication on chromosome 1. Stocks of the type isolate NC4 are similarly variable, though we have identified some approximating the assumed ancestral genotype. More recent wild-type isolates are almost without large duplications, but we can identify small deletions or regions of high divergence, possibly reflecting responses to local selective pressures. Duplications are scattered through most of the genome, and can be stable enough to reconstruct genealogies spanning decades of the history of the NC4 lineage. The expression level of many duplicated genes is increased with dosage, but for others it appears that some form of dosage compensation occurs. CONCLUSION: The genetic variation described here must underlie some of the phenotypic variation observed between strains from different laboratories. We suggest courses of action to alleviate the problem.Published versio

The thermal and two-particle stress-energy must be ill-defined on the 2-d Misner space chronology horizon

We show that an analogue of the (four dimensional) image sum method can be used to reproduce the results, due to Krasnikov, that for the model of a real massless scalar field on the initial globally hyperbolic region IGH of two-dimensional Misner space there exist two-particle and thermal Hadamard states (built on the conformal vacuum) such that the (expectation value of the renormalised) stress-energy tensor in these states vanishes on IGH. However, we shall prove that the conclusions of a general theorem by Kay, Radzikowski and Wald still apply for these states. That is, in any of these states, for any point b on the Cauchy horizon and any neighbourhood N of b, there exists at least one pair of non-null related points (x,x'), with x and x' in the intersection of IGH with N, such that (a suitably differentiated form of) its two-point function is singular. (We prove this by showing that the two-point functions of these states share the same singularities as the conformal vacuum on which they are built.) In other words, the stress-energy tensor in any of these states is necessarily ill-defined on the Cauchy horizon.Comment: 6 pages, LaTeX, RevTeX, no figure

The reliability horizon for semi-classical quantum gravity: Metric fluctuations are often more important than back-reaction

In this note I introduce the notion of the ``reliability horizon'' for semi-classical quantum gravity. This reliability horizon is an attempt to quantify the extent to which we should trust semi-classical quantum gravity, and to get a better handle on just where the Planck regime resides. I point out that the key obstruction to pushing semi-classical quantum gravity into the Planck regime is often the existence of large metric fluctuations, rather than a large back-reaction. There are many situations where the metric fluctuations become large long before the back-reaction is significant. Issues of this type are fundamental to any attempt at proving Hawking's chronology protection conjecture from first principles, since I shall prove that the onset of chronology violation is always hidden behind the reliability horizon.Comment: 6 pages; ReV_TeX 3.0; two-column format. Revisions: Central definitions and results essentially unchanged. Discussion of the relationship between this letter and the Kay-Radzikowski-Wald singularity theorems greatly extended and clarified. Discussion of reliability horizon near curvature singularities modified. Several references added. Minor typos fixed. Technical TeX modification

Molecular cloning and nucleotide sequence of cDNA encoding the entire precursor of rat liver medium chain acyl coenzyme A dehydrogenase.

cDNA encoding the precursor of rat liver medium chain acyl-CoA dehydrogenase (EC 1.3.99.3) was cloned and sequenced. The longest cDNA insert isolated was 1866 bases in length. This cDNA encodes the entire protein of 421-amino acids including a 25-amino acid leader peptide and a 396-amino acid mature polypeptide. The identity of the medium chain acyl-CoA dehydrogenase clone was confirmed by matching the amino acid sequence predicted from the cDNA to the NH2-terminal and nine internal tryptic peptide sequences derived from pure rat liver medium chain acyl-CoA dehydrogenase. The calculated molecular masses of the precursor medium chain acyl-CoA dehydrogenase, the mature medium chain acyl-CoA dehydrogenase, and the leader peptide are 46,600, 43,700, and 2,900 daltons, respectively. The leader peptide contains five basic amino acids and only one acidic amino acid; thus, it is positively charged, overall. Cysteine residues are unevenly distributed in the mature portion of the protein; five of six are found within the NH2-terminal half of the polypeptide. Comparison of medium chain acyl-CoA dehydrogenase sequence to other flavoproteins and enzymes which act on coenzyme A ester substrates did not lead to unambiguous identification of a possible FAD-binding site nor a coenzyme A-binding domain. The sequencing of other homologous acyl-CoA dehydrogenases will be informative in this regard

Models for Chronology Selection

In this paper, we derive an expression for the grand canonical partition function for a fluid of hot, rotating massless scalar field particles in the Einstein universe. We consider the number of states with a given energy as one increases the angular momentum so that the fluid rotates with an increasing angular velocity. We find that at the critical value when the velocity of the particles furthest from the origin reaches the speed of light, the number of states tends to zero. We illustrate how one can also interpret this partition function as the effective action for a boosted scalar field configuration in the product of three dimensional de Sitter space and $S^1$. In this case, we consider the number of states with a fixed linear momentum around the $S^1$ as the particles are given more and more boost momentum. At the critical point when the spacetime is about to develop closed timelike curves, the number of states again tends to zero. Thus it seems that quantum mechanics naturally enforces the chronology protection conjecture by superselecting the causality violating field configurations from the quantum mechanical phase space.Comment: 20 pages, Late

The changing landscape of biosimilars in rheumatology

Biosimilars remain a hot topic in rheumatology, and some physicians are cautious about their application in the real world. With many products coming to market and a wealth of guidelines and recommendations concerning their use, there is a need to understand the changing landscape and the real clinical and health-economic potential offered by these agents. Notably, rheumatologists will be at the forefront of the use of biosimilar monoclonal antibodies/soluble receptors. Biosimilars offer cost savings and health gains for our patients and will play an important role in treating rheumatic diseases. We hope that these lower costs will compensate for inequities in access to therapy based on economic differences across countries. Since approved biosimilars have already demonstrated highly similar efficacy, it will be most important to establish pharmacovigilance databases across countries that are adequate to monitor long-term safety after marketing approval

An Ambystoma mexicanum EST sequencing project: analysis of 17,352 expressed sequence tags from embryonic and regenerating blastema cDNA libraries

BACKGROUND: The ambystomatid salamander, Ambystoma mexicanum (axolotl), is an important model organism in evolutionary and regeneration research but relatively little sequence information has so far been available. This is a major limitation for molecular studies on caudate development, regeneration and evolution. To address this lack of sequence information we have generated an expressed sequence tag (EST) database for A. mexicanum. RESULTS: Two cDNA libraries, one made from stage 18-22 embryos and the other from day-6 regenerating tail blastemas, generated 17,352 sequences. From the sequenced ESTs, 6,377 contigs were assembled that probably represent 25% of the expressed genes in this organism. Sequence comparison revealed significant homology to entries in the NCBI non-redundant database. Further examination of this gene set revealed the presence of genes involved in important cell and developmental processes, including cell proliferation, cell differentiation and cell-cell communication. On the basis of these data, we have performed phylogenetic analysis of key cell-cycle regulators. Interestingly, while cell-cycle proteins such as the cyclin B family display expected evolutionary relationships, the cyclin-dependent kinase inhibitor 1 gene family shows an unusual evolutionary behavior among the amphibians. CONCLUSIONS: Our analysis reveals the importance of a comprehensive sequence set from a representative of the Caudata and illustrates that the EST sequence database is a rich source of molecular, developmental and regeneration studies. To aid in data mining, the ESTs have been organized into an easily searchable database that is freely available online

Massive scalar field in multiply connected flat spacetimes

The vacuum expectation value of the stress-energy tensor $\left\langle 0\left| T_{\mu\nu} \right|0\right\rangle$ is calculated in several multiply connected flat spacetimes for a massive scalar field with arbitrary curvature coupling. We find that a nonzero field mass always decreases the magnitude of the energy density in chronology-respecting manifolds such as $R^3 \times S^1$, $R^2 \times T^2$, $R^1 \times T^3$, the M\"{o}bius strip, and the Klein bottle. In Grant space, which contains nonchronal regions, whether $\left\langle 0\left| T_{\mu\nu} \right|0\right\rangle$ diverges on a chronology horizon or not depends on the field mass. For a sufficiently large mass $\left\langle 0\left| T_{\mu\nu} \right|0\right\rangle$ remains finite, and the metric backreaction caused by a massive quantized field may not be large enough to significantly change the Grant space geometry.Comment: 19 pages, REVTeX, 5 figures in separate uuencoded compressed fil

Face processing limitation to own species in primates: a comparative study in brown capuchins, Tonkean macaques and humans

Most primates live in social groups which survival and stability depend on individuals' abilities to create strong social relationships with other group members. The existence of those groups requires to identify individuals and to assign to each of them a social status. Individual recognition can be achieved through vocalizations but also through faces. In humans, an efficient system for the processing of own species faces exists. This specialization is achieved through experience with faces of conspecifics during development and leads to the loss of ability to process faces from other primate species. We hypothesize that a similar mechanism exists in social primates. We investigated face processing in one Old World species (genus Macaca) and in one New World species (genus Cebus). Our results show the same advantage for own species face recognition for all tested subjects. This work suggests in all species tested the existence of a common trait inherited from the primate ancestor: an efficient system to identify individual faces of own species only