Evidence for somatic selection of natural autoantibodies.

Natural autoantibodies are primarily immunoglobulin M (IgM) antibodies that bind to a variety of self-antigens, including self-IgG. Accounting for a large proportion of the early B cell repertoire, such polyspecific autoantibodies are speculated to contribute to the homeostasis and/or competence of the primary humoral immune system. Recent studies indicate that the leukemia cells from most patients with chronic lymphocytic leukemia (CLL) also express such IgM autoantibodies. Similarly, the leukemia cells from many CLL patients react with murine monoclonal antibodies (mAbs) specific for crossreactive idiotypes (CRIs) associated with human IgM autoantibodies. In particular, leukemic cells frequently react with G6, a mAb specific for an Ig heavy chain (H chain)-associated CRI, and/or with 17.109, a mAb that defines a kappa light chain (L chain)-associated CRI. Generated against IgM rheumatoid factor (RF) paraproteins, G6 and 17.109 each recognize a major CRI that is present in many IgM RF paraproteins. Furthermore, over 90% of the IgM paraproteins found to bear both H and L chain-associated CRIs also are found to have RF activity. Molecular characterization of these CRIs demonstrates that each is a serologic marker for expression of a highly conserved Ig V gene. As such, the frequent production of IgM polyspecific autoantibodies in CLL simply may reflect the frequent use of such highly conserved autoantibody-encoding Ig V genes with little or no somatic mutation. To test this hypothesis, we generated murine transfectomas to pair the 17.109-reactive kappa L chain of SMI, a 17.109/G6-reactive CLL population, with the Ig H chain of SMI or other G6-reactive leukemia cells or tonsillar lymphocytes. Cotransfection of vectors encoding the Ig H and L chains of SMI generated transfectomas that produce IgM kappa RF autoantibodies reactive with human IgG1 and IgG4. In contrast to G6/17.109-reactive IgM kappa RF Waldenstrom's paraproteins, the SMI IgM kappa also reacts with several other self-antigens, including myoglobin, actin, and ssDNA. However, cotransfection of the SMI L chain with a vector encoding any one of 10 different G6-reactive Ig H chains generated transfectomas that produce IgM kappa antibodies without detectable polyspecific autoantibody activity. These results indicate that polyspecific antiself-reactivity of G6/17.019-reactive Ig is dependent on the somatically generated Ig third complementarity determining region. Collectively, these studies imply that selection may be responsible for the frequent expression of polyspecific autoantibodies in CLL and early B cell ontogeny

Looking into the puparium: Micro-CT visualization of the internal morphological changes during metamorphosis of the blow fly, Calliphora vicina , with the first quantitative analysis of organ development in cyclorrhaphous dipterans

Uploaded is the initial online version of this Open Access manuscript.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. VC 2017 The Authors Journal of Morphology Published by Wiley Periodicals, Inc. This is the published version of the article

Resolving Confusion in the Use of Concepts and Terminology in Intrapuparial Development Studies of Cyclorrhaphous Diptera

This is freely available on the journal website.The attached document is the pre-print/pre-refereeing [Author's original version] version of the article. This article has been accepted for publication in Journal of Medical Entomology, Vol.53(6), 2016, published by Oxford University Press. DOI: http://dx.doi.org/10.1093/jme/tjw0

Constraining compressed supersymmetry using leptonic signatures

We study the impact of the multi-lepton searches at the LHC on supersymmetric models with compressed mass spectra. For such models the acceptances of the usual search strategies are significantly reduced due to requirement of large effective mass and missing E_T. On the other hand, lepton searches do have much lower thresholds for missing E_T and p_T of the final state objects. Therefore, if a model with a compressed mass spectrum allows for multi-lepton final states, one could derive constraints using multi-lepton searches. For a class of simplified models we study the exclusion limits using ATLAS multi-lepton search analyses for the final states containing 2-4 electrons or muons with a total integrated luminosity of 1-2/fb at \sqrt{s}=7 TeV. We also modify those analyses by imposing additional cuts, so that their sensitivity to compressed supersymmetric models increase. Using the original and modified analyses, we show that the exclusion limits can be competitive with jet plus missing E_T searches, providing exclusion limits up to gluino masses of 1 TeV. We also analyse the efficiencies for several classes of events coming from different intermediate state particles. This allows us to assess exclusion limits in similar class of models with different cross sections and branching ratios without requiring a Monte Carlo simulation.Comment: 18 pages, 5 figure

A systems-level approach to mapping the telomere length maintenance gene circuitry

The ends of eukaryotic chromosomes are protected by telomeres, nucleoprotein structures that are essential for chromosomal stability and integrity. Understanding how telomere length is controlled has significant medical implications, especially in the fields of aging and cancer. Two recent systematic genome-wide surveys measuring the telomere length of deleted mutants in the yeast Saccharomyces cerevisiae have identified hundreds of telomere length maintenance (TLM) genes, which span a large array of functional categories and different localizations within the cell. This study presents a novel general method that integrates large-scale screening mutant data with protein–protein interaction information to rigorously chart the cellular subnetwork underlying the function investigated. Applying this method to the yeast telomere length control data, we identify pathways that connect the TLM proteins to the telomere-processing machinery, and predict new TLM genes and their effect on telomere length. We experimentally validate some of these predictions, demonstrating that our method is remarkably accurate. Our results both uncover the complex cellular network underlying TLM and validate a new method for inferring such networks

Synthesis and structures of polyiodide radical cation salts of donors combining tetrathiafulvalene with multiple thiophene or oligo-thiophene substituents

A series of TTF and EDT-TTF derived donors bearing thiophene, bithiophene and terthiophene side chains is described, from which a group of six radical cation salts with polyiodide ions were formed and structurally characterised. Typically, they contain complex networks of pentaiodide or triiodide anions or both, in some cases including further iodine, with networks of eight, ten, twelve or sixteen iodine atoms. Donor monocations form face-to-face pairs, but tetrakis-substituted donors are slipped along their main axis so the donor side chains can wrap around each other

Chiral molecular conductor with an insulator-metal transition close to room temperature

Materials exhibiting both chirality and conductivity do not exist in nature and very few examples have been synthesised. We report here the synthesis of a chiral molecular metal which remains metallic down to at least 4.2K. This material also exhibits room-temperature switching capabilities with a transition upon cooling below 10°C

Antifungal prophylaxis in chemotherapy-associated neutropenia: a retrospective, observational study

<p>Abstract</p> <p>Background</p> <p>In August 2002, the antifungal prophylaxis algorithm for neutropenic hematology/oncology (NHO) patients at the Medical Center was changed from conventional amphotericin (AMB) to an azole (AZ) based regimen (fluconazole [FLU] in low-risk and voriconazole [VOR] in high-risk patients). The aim of our study was to compare outcomes associated with the two regimens, including breakthrough fungal infection, adverse drug events, and costs.</p> <p>Methods</p> <p>Adult, non-febrile, NHO patients who received prophylactic AMB from 8/01/01-7/30/02 or AZ from 8/01/02-7/30/03 were retrospectively evaluated.</p> <p>Results</p> <p>A total of 370 patients (AMB: n = 181; AZ: n = 216) associated with 580 hospitalizations (AMB: n = 259; AZ: n = 321) were included. The incidence of probable/definite breakthrough Aspergillus infections was similar among regimens (AMB: 1.9% vs AZ: 0.6%; p=0.19). A greater incidence of mild/moderate (24.7% vs. 5.3%; p < 0.0001) and severe renal dysfunction (13.5% vs. 4.4%; p < 0.0012) was observed with AMB. In contrast, patients treated with VOR were found to have an increased rate of severe hepatic toxicity (32.5%) compared with patients treated with either AMB (22.6%) or FLU (21.4%) (p = 0.05). While the AZ period was associated with a >$9,000 increase in mean total costs/hospitalization, the mean acquisition cost associated with AZ was only$947/hospitalization more than AMB.</p> <p>Conclusion</p> <p>While an AZ-based regimen is associated with increased cost, the reduced rate of nephrotoxicity and availability of oral dosage forms, suggests that azoles be used preferentially over AMB. However, an increased rate of severe hepatic toxicity may be associated with VOR.</p

Stellar Disk Truncations: Where do we stand ?

In the light of several recent developments we revisit the phenomenon of galactic stellar disk truncations. Even 25 years since the first paper on outer breaks in the radial light profiles of spiral galaxies, their origin is still unclear. The two most promising explanations are that these 'outer edges' either trace the maximum angular momentum during the galaxy formation epoch, or are associated with global star formation thresholds. Depending on their true physical nature, these outer edges may represent an improved size characteristic (e.g., as compared to D_25) and might contain fossil evidence imprinted by the galaxy formation and evolutionary history. We will address several observational aspects of disk truncations: their existence, not only in normal HSB galaxies, but also in LSB and even dwarf galaxies; their detailed shape, not sharp cut-offs as thought before, but in fact demarcating the start of a region with a steeper exponential distribution of starlight; their possible association with bars; as well as problems related to the line-of-sight integration for edge-on galaxies (the main targets for truncation searches so far). Taken together, these observations currently favour the star-formation threshold model, but more work is necessary to implement the truncations as adequate parameters characterising galactic disks.Comment: LaTeX, 10 pages, 6 figures, presented at the "Penetrating Bars through Masks of Cosmic Dust" conference in South Africa, proceedings published by Kluwer, and edited by Block, D.L., Freeman, K.C., Puerari, I., & Groess, R; v3 to match published versio

Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor–positive breast cancers

Introduction Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents. Methods Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor–positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed. Results By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid– and leucine-rich protein 1, an ER coactivator. Conclusions These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC