Interleukin-10 Overexpression Promotes Fas-Ligand-Dependent Chronic Macrophage-Mediated Demyelinating Polyneuropathy

BACKGROUND:Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. PRINCIPAL FINDINGS:Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL)-mediated Schwann cell death. SIGNIFICANCE:These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP) and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP) or Guillain-Barré syndrome

HARP/ACSIS: A submillimetre spectral imaging system on the James Clerk Maxwell Telescope

This paper describes a new Heterodyne Array Receiver Programme (HARP) and Auto-Correlation Spectral Imaging System (ACSIS) that have recently been installed and commissioned on the James Clerk Maxwell Telescope (JCMT). The 16-element focal-plane array receiver, operating in the submillimetre from 325 to 375 GHz, offers high (three-dimensional) mapping speeds, along with significant improvements over single-detector counterparts in calibration and image quality. Receiver temperatures are $\sim$120 K across the whole band and system temperatures of $\sim$300K are reached routinely under good weather conditions. The system includes a single-sideband filter so these are SSB figures. Used in conjunction with ACSIS, the system can produce large-scale maps rapidly, in one or more frequency settings, at high spatial and spectral resolution. Fully-sampled maps of size 1 square degree can be observed in under 1 hour. The scientific need for array receivers arises from the requirement for programmes to study samples of objects of statistically significant size, in large-scale unbiased surveys of galactic and extra-galactic regions. Along with morphological information, the new spectral imaging system can be used to study the physical and chemical properties of regions of interest. Its three-dimensional imaging capabilities are critical for research into turbulence and dynamics. In addition, HARP/ACSIS will provide highly complementary science programmes to wide-field continuum studies, and produce the essential preparatory work for submillimetre interferometers such as the SMA and ALMA.Comment: MNRAS Accepted 2009 July 2. 18 pages, 25 figures and 6 table

"Author! Author!" : Shakespeare and biography

Original article can be found at: http://www.informaworld.com/smpp/title~content=t714579626~db=all Copyright Informa / Taylor & Francis Group. DOI: 10.1080/17450910902764454Since 1996, not a year has passed without the publication of at least one Shakespeare biography. Yet for many years the place of the author in the practice of understanding literary works has been problematized, and even on occasions eliminated. Criticism reads the “works”, and may or may not refer to an author whose “life” contributed to their meaning. Biography seeks the author in the works, the personality that precedes the works and gives them their characteristic shape and meaning. But the form of literary biography addresses the unusual kind of “life” that puts itself into “works”, and this is particularly challenging where the “works” predominate massively over the salient facts of the “life”. This essay surveys the current terrain of Shakespeare biography, and considers the key questions raised by the medium: can we know anything of Shakespeare's “personality” from the facts of his life and the survival of his works? What is the status of the kind of speculation that inevitably plays a part in biographical reconstruction? Are biographers in the end telling us as much about themselves as they tell us about Shakespeare?Peer reviewe

A blind detection of a large, complex, Sunyaev--Zel'dovich structure

We present an interesting Sunyaev-Zel'dovich (SZ) detection in the first of the Arcminute Microkelvin Imager (AMI) 'blind', degree-square fields to have been observed down to our target sensitivity of 100{\mu}Jy/beam. In follow-up deep pointed observations the SZ effect is detected with a maximum peak decrement greater than 8 \times the thermal noise. No corresponding emission is visible in the ROSAT all-sky X-ray survey and no cluster is evident in the Palomar all-sky optical survey. Compared with existing SZ images of distant clusters, the extent is large (\approx 10') and complex; our analysis favours a model containing two clusters rather than a single cluster. Our Bayesian analysis is currently limited to modelling each cluster with an ellipsoidal or spherical beta-model, which do not do justice to this decrement. Fitting an ellipsoid to the deeper candidate we find the following. (a) Assuming that the Evrard et al. (2002) approximation to Press & Schechter (1974) correctly gives the number density of clusters as a function of mass and redshift, then, in the search area, the formal Bayesian probability ratio of the AMI detection of this cluster is 7.9 \times 10^4:1; alternatively assuming Jenkins et al. (2001) as the true prior, the formal Bayesian probability ratio of detection is 2.1 \times 10^5:1. (b) The cluster mass is MT,200 = 5.5+1.2\times 10^14h-1M\odot. (c) Abandoning a physical model with num- -1.3 70 ber density prior and instead simply modelling the SZ decrement using a phenomenological {\beta}-model of temperature decrement as a function of angular distance, we find a central SZ temperature decrement of -295+36 {\mu}K - this allows for CMB primary anisotropies, receiver -15 noise and radio sources. We are unsure if the cluster system we observe is a merging system or two separate clusters.Comment: accepted MNRAS. 12 pages, 9 figure

High-mobility group box-1 protein, lipopolysaccharide-binding protein, interleukin-6 and C-reactive protein in children with community acquired infections and bacteraemia: a prospective study

<p>Abstract</p> <p>Introduction</p> <p>Even though sepsis is one of the common causes of children morbidity and mortality, specific inflammatory markers for identifying sepsis are less studied in children. The main aim of this study was to compare the levels of high-mobility group box-1 protein (HMGB1), Lipopolysaccharide-binding protein (LBP), Interleukin-6 (IL-6) and C-reactive protein (CRP) between infected children without systemic inflammatory response syndrome (SIRS) and children with severe and less severe sepsis. The second aim was to examine HMGB1, LBP, IL6 and CRP as markers for of bacteraemia.</p> <p>Methods</p> <p>Totally, 140 children with suspected or proven infections admitted to the Children's Clinical University Hospital of Latvia during 2008 and 2009 were included. Clinical and demographical information as well as infection focus were assessed in all patients. HMGB1, LBP, IL-6 and CRP blood samples were determined. Children with suspected or diagnosed infections were categorized into three groups of severity of infection: (i) infected without SIRS (n = 36), (ii) sepsis (n = 91) and, (iii) severe sepsis (n = 13). They were furthermore classified according bacteraemia into (i) bacteremia (n = 30) and (ii) no bacteraemia (n = 74).</p> <p>Results</p> <p>There was no statistically significant difference in HMGB1 levels between children with different levels of sepsis or with and without bacteraemia. The levels of LBP, IL-6 and CRP were statistically significantly higher among patients with sepsis compared to those infected but without SIRS (<it>p </it>< 0.001). Furthermore, LBP, IL-6 and CRP were significantly higher in children with severe sepsis compared to those ones with less severe sepsis (<it>p </it>< 0.001). Median values of LBP, IL6 and CRP were significantly higher in children with bacteraemia compared to those without bacteraemia. The area under the receiver operating curve (ROC) for detecting bacteraemia was 0.87 for both IL6 and CRP and 0.82 for LBP, respectively.</p> <p>Conclusion</p> <p>Elevated levels of LBP, IL-6 and CRP were associated with a more severe level of infection in children. Whereas LBP, IL-6 and CRP seem to be good markers to detect patients with bacteraemia, HMGB1 seem to be of minor importance. LBP, IL-6 and CRP levels may serve as good biomarkers for identifying children with severe sepsis and bacteraemia and, thus, may be routinely used in clinical practice.</p

Interleukin-10 Promotes Pathological Angiogenesis by Regulating Macrophage Response to Hypoxia during Development

Aberrant angiogenesis in the eye is the most common cause of blindness. The current study examined the role of interleukin-10 (IL-10) in ischemia-induced pathological angiogenesis called neovascularization during postnatal development. IL-10 deficiency resulted in significantly reduced pathological retinal angiogenesis. In contrast to the choroicapillaris where IL-10 interferes with macrophage influx, IL-10 did not prevent anti-angiogenic macrophages from migrating to the retina in response to hypoxia. Instead, IL-10 promoted retinal angiogenesis by altering macrophage angiogenic function, as macrophages from wild-type mice demonstrated increased vascular endothelial growth factor (VEGF) and nitric oxide (NO) compared to IL-10 deficient macrophages. IL-10 appears to directly affect macrophage responsiveness to hypoxia, as macrophages responded to hypoxia with increased levels of IL-10 and STAT3 phosphorylation as opposed to IL-10 deficient macrophages. Also, IL-10 deficient macrophages inhibited the proliferation of vascular endothelial cells in response to hypoxia while wild-type macrophages failed to do so. These findings suggest that hypoxia guides macrophage behavior to a pro-angiogenic phenotype via IL-10 activated pathways

HLA B27 allele types in homogeneous groups of juvenile idiopathic arthritis patients in Latvia

Juvenile idiopathic arthritis (JIA) is a heterogeneous condition and therapeutic strategies vary in different JIA types. The routinely accepted practice to start with Sulphasalazine (SS) as the first line treatment in patients with HLA B27 positive JIA proves to be ineffective in a large proportion of children

Selective Estrogen Receptor Down-Regulator and Selective Estrogen Receptor Modulators Differentially Regulate Lactotroph Proliferation

occupation, differentially modulates the biological outcome of anti-estrogens. expression and release, as well as ERE-mediated transcriptional activity. expression

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study

Background: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. Methods: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. Findings: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. Interpretation: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics

Expression of Xhdsi-1VOC, a novel member of the vicinal oxygen chelate (VOC) metalloenzyme superfamily, is up-regulated in leaves and roots during desiccation in the resurrection plant Xerophyta humilis (Bak) Dur and Schinz

The annotation of novel plant genes is frequently based on sequence and structural similarity to known protein motifs. Understanding the biological function of these genes is dependent on identifying conditions under which they are activated, however. The resurrection plant, Xerophyta humilis is a good model system for identifying and characterizing genes which are important for desiccation tolerance. Desiccation induced-1 (dsi-1VOC), a previously uncharacterized plant gene, is up-regulated during desiccation in leaves, roots, and seeds in X. humilis. The X. humilis desiccation induced-1 gene, Xhdsi-1VOC, shares structural homology with the vicinal oxygen chelate (VOC) metalloenzyme superfamily. Proteins in this superfamily share little sequence similarity, but are characterized by a common βαβββ structural fold. A number of plant orthologues of XhDsi-1VOC have been identified, including Arabidopsis thaliana At1g07645, which is currently annotated as a glyoxalase I-like gene, and many ESTs derived from seed cDNA libraries. Xhdsi-1VOC and its orthologues do not, however, contain the glutathione and zinc binding sites conserved in glyoxalase I genes. Furthermore, expression of Xhdsi-1VOC in yeast failed to rescue a yeast glyoxalase I mutant. Messenger RNA transcripts for At1g07645 accumulate during seed maturation, but are not induced by water loss, salt or mannitol stress in vegetative tissue in Arabidopsis. It is concluded that dsi-1VOC is a seed-specific gene in desiccation-sensitive plants that is activated by water loss in vegetative tissues in the resurrection plant X. humilis and plays an important role in allowing plant tissues to survive loss of 95% of their relative water content