CD105 Deficieny in Mouse Aorta-derived Mesenchymal Stem Cells Promotes An Enhanced Inflammatory Response to Lipolysaccharide.

Mesenchymal stem cells (MSCs) are being widely studied for their ability to regulate macrophage cell responses. Previous works have demonstrated that mouse aorta-derived MSC (mAo-MSC) support the macrophage inflammatory response. mAo-MSC have been characterized phenotypically for MSC-associated surface antigens and express CD90 and CD105 but do not express CD73. CD105, also known as endoglin, is a coreceptor in the TGFβ superfamily of receptors. Mouse adipose-derived MSC lacking CD105 have an increased capacity to regulate T-cells by reducing their proliferation while elevated CD105 expression is consistently associated with inflammatory disease. Therefore, we hypothesized that suppression of CD105 in mAo-MSC will reduce the immunosupportive capacity of the mAo-MSC. We used siRNA to reduce expression of CD105 in mAo- MSC and subsequently examined the effect of this deficiency on their response to lipopolysaccharide (LPS) and their ability to support the macrophage inflammatory response. Contrary to our hypothesis, CD105 deficient mAo-MSC cultured alone and in co-culture with macrophage secreted increased levels of the inflammatory indicators nitric oxide (NO) and interleukin 6 (IL-6) after exposure to LPS. The increase in NO and IL-6 observed in the co-cultures is additive and therefore points to the mAo- MSC as the primary origin. Overall our data suggest that CD105 acts as a regulator of the TLR-4 pathway and may represent an important target for modification of MSC to be used in therapeutics

Physical characteristics and non-keplerian orbital motion of "propeller" moons embedded in Saturn's rings

We report the discovery of several large "propeller" moons in the outer part of Saturn's A ring, objects large enough to be followed over the 5-year duration of the Cassini mission. These are the first objects ever discovered that can be tracked as individual moons, but do not orbit in empty space. We infer sizes up to 1--2 km for the unseen moonlets at the center of the propeller-shaped structures, though many structural and photometric properties of propeller structures remain unclear. Finally, we demonstrate that some propellers undergo sustained non-keplerian orbit motion. (Note: This arXiv version of the paper contains supplementary tables that were left out of the ApJL version due to lack of space).Comment: 9 pages, 4 figures; Published in ApJ

Evaluation of different DNA extraction methods and loop-mediated isothermal amplification primers for the detection of Mycobacterium ulcerans in clinical specimens

Background: Early diagnosis and treatment of Buruli ulcer is critical in order to avoid the debilitating effects of the disease. In this regard, the development of new diagnostic and point of care tools is encouraged. The loop-mediated isothermal amplification for the detection of Mycobacterium ulcerans represents one of the new tools with a good potential of being developed into a point of care test. There is however the need to standardize the assays, reduce sample preparation times, improve the detection/visualization system and optimize them for high-throughput screening, adaptable to low resourced laboratories. Methods: In this study, we assessed two DNA extraction protocols (modified Boom and EasyNAT methods), three previously published LAMP primer sets (BURULI, MU 2404 and BU-LAMP), and compared the sensitivity and specificity of LAMP assays on three DNA amplification platforms. Results: Our results show that Buruli ulcer diagnosis using primers targeting IS2404 for the LAMP method is sensitive (73.75-91.49%), depending on the DNA extraction method used. Even though the modified Boom DNA extraction method provided the best results, its instrumentation requirement prevent it from being field applicable. The EasyNAT method on the other hand is simpler and may represent the best method for DNA extraction in less resourced settings. Conclusions: For further work on the development and use of LAMP tests for Buruli diagnosis, it is recommended that the BURULI sets of primers be used, as these yielded the best results in terms of sensitivity (87.50-91.49%) and specificity (89.23-100%), depending on the DNA extraction methods used.This study was supported by the Swiss Agency for Development and Cooperation and the UBS Optimus Foundation through FIND, Geneva-Switzerland. The funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.S

Structural characterization of anti-inflammatory Immunoglobulin G Fc proteins

Immunoglobulin G (IgG) is a central mediator of host defense due to its ability to recognize and eliminate pathogens. The recognition and effector responses are encoded on distinct regions of IgGs. The diversity of the antigen recognition Fab domains accounts for IgG’s ability to bind with high specificity to essentially any antigen. Recent studies have indicated that the Fc effector domain also displays considerable heterogeneity, accounting for its complex effector functions of inflammation, modulation and immune suppression. Therapeutic anti-tumor antibodies, for example, require the pro-inflammatory properties of the IgG Fc to eliminate tumor cells, while the anti-inflammatory activity of Intravenous Immunoglobulin G (IVIG) requires specific Fc glycans for activity. In particular, the anti-inflammatory activity of IVIG is ascribed to a small population of IgGs in which the Asn297-linked complex N-glycans attached to each Fc C_H2 domain include terminal α2,6-linked sialic acids. We used chemoenzymatic glycoengineering to prepare fully di-sialylated IgG Fc and solved its crystal structure. Comparison of the structures of asialylated Fc, sialylated Fc, and F241A Fc, a mutant that displays increased glycan sialylation, suggests that increased conformational flexibility of the C_H2 domain is associated with the switch from pro- to anti-inflammatory activity of the Fc

Sexed up: theorizing the sexualization of culture

This paper reviews and examines emerging academic approaches to the study of ‘sexualized culture’; an examination made necessary by contemporary preoccupations with sexual values, practices and identities, the emergence of new forms of sexual experience and the apparent breakdown of rules, categories and regulations designed to keep the obscene at bay. The paper maps out some key themes and preoccupations in recent academic writing on sex and sexuality, especially those relating to the contemporary or emerging characteristics of sexual discourse. The key issues of pornographication and democratization, taste formations, postmodern sex and intimacy, and sexual citizenship are explored in detail. </p

The magnificent seven : A proposal for modest revision of the Van der Voo (1990) quality index

Thirty years ago, Rob Van der Voo proposed an elegant and simple system for evaluating the quality of paleomagnetic data. As a second-year Ph.D. student, the lead author remembers Rob waxing philosophical about the need to have an appropriate, but not overly rigid evaluation system. The end result was a 7-point system that assigned a (1) or (0) for any paleomagnetic result based on objective criteria. The goal was never to reject or blindly accept any particular result, but merely to indicate the degree of quality for any paleomagnetic pole. At the time, the global paleomagnetic database was burgeoning and it was deemed useful to rank older paleo magnetic results with the newer data being developed in modern laboratories. Van der Voo's, 1990 paper launched a silent revolution in paleomagnetism. Researchers began to evaluate their data against those seven criteria with the anticipation that reviewers would be similarly critical. Today, paleomagnetism is a mature science. Our methods, analyses, and results are more sophisticated than they were 30 years ago. Therefore, we feel it is appropriate to revisit the Van der Voo (1990) criteria in light of those developments. We hope to honor the intention of the original paper by keeping the criteria simple and easy to evaluate while also acknowledging the advances in science. This paper aims to update the criteria and modernize the process. We base our changes on advances in paleomagnetism and geochronology with a faithful adherence to the simplicity of the original publication. We offer the "Reliability" or "R" index as the next generation of the Van der Voo "Quality" or "Q" index. The new R-criteria evaluate seven different information items for each paleomagnetic pole including age, statistical requirements, identification of magnetic carriers, field tests, structural integrity, presence of reversals and an evaluation for possible remagnetization.Peer reviewe

Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes