Tumor necrosis factor-alpha regulates the expression of inducible costimulator receptor ligand on CD34+ progenitor cells during differentiation into antigen presenting cells

The inducible costimulator receptor (ICOS) is a third member of the CD28 receptor family that regulates T cell activation and function. ICOS binds to a newly identified ligand on antigen presenting cells different from the CD152 ligands CD80 and CD86. We used soluble ICOSIg and a newly developed murine anti-human ICOS ligand (ICOSL) monoclonal antibody to further characterize the ICOSL during ontogeny of antigen presenting cells. In a previous study, we found that ICOSL is expressed on monocytes, dendritic cells, and B cells. To define when ICOSL is first expressed on myeloid antigen presenting cells, we examined ICOSL expression on CD34 cells in bone marrow. We found that CD34bright cells regardless of their myeloid commitment were ICOSL , whereas ICOSL was first expressed when CD34 expression diminished and the myeloid marker CD33 appeared

Pink1 and Parkin regulate Drosophila intestinal stem cell proliferation during stress and aging.

Intestinal stem cells (ISCs) maintain the midgut epithelium in Drosophila melanogaster Proper cellular turnover and tissue function rely on tightly regulated rates of ISC division and appropriate differentiation of daughter cells. However, aging and epithelial injury cause elevated ISC proliferation and decreased capacity for terminal differentiation of daughter enteroblasts (EBs). The mechanisms causing functional decline of stem cells with age remain elusive; however, recent findings suggest that stem cell metabolism plays an important role in the regulation of stem cell activity. Here, we investigate how alterations in mitochondrial homeostasis modulate stem cell behavior in vivo via RNA interference-mediated knockdown of factors involved in mitochondrial dynamics. ISC/EB-specific knockdown of the mitophagy-related genes Pink1 or Parkin suppresses the age-related loss of tissue homeostasis, despite dramatic changes in mitochondrial ultrastructure and mitochondrial damage in ISCs/EBs. Maintenance of tissue homeostasis upon reduction of Pink1 or Parkin appears to result from reduction of age- and stress-induced ISC proliferation, in part, through induction of ISC senescence. Our results indicate an uncoupling of cellular, tissue, and organismal aging through inhibition of ISC proliferation and provide insight into strategies used by stem cells to maintain tissue homeostasis despite severe damage to organelles

Mood instability and psychosis : analyses of British national survey data

Background: We used British national survey data to test specific hypotheses that mood instability (1) is associated with psychosis and individual psychotic phenomena, (2) predicts the later emergence of auditory hallucinations and paranoid ideation, and (3) mediates the link between child sexual abuse and psychosis. Methods: We analyzed data from the 2000 and 2007 UK national surveys of psychiatric morbidity (N = 8580 and 7403, respectively). The 2000 survey included an 18-month follow-up of a subsample (N = 2406). Mood instability was assessed from the Structured Clinical Interview for DSM-IV Axis II (SCID-II) questionnaire. Our dependent variables comprised auditory hallucinations, paranoid ideation, the presence of psychosis overall, and a 15-item paranoia scale. Results: Mood instability was strongly associated in cross-sectional analyses with psychosis (2000: OR: 7.5; 95% CI: I 4.1–13.8; 2007: OR: 21.4; CI: 9.7–41.2), paranoid ideation (2000: OR: 4.7; CI: 4.1–5.4; 2007: OR: 5.7; CI: 4.9–6.7), auditory hallucinations (2000: OR: 3.4; CI: 2.6–4.4; 2007: OR 3.5; CI: 2.7–4.7), and paranoia total score (2000: Coefficient: 3.6; CI: 3.3–3.9), remaining so after adjustment for current mood state. Baseline mood instability significantly predicted 18-month inceptions of paranoid ideation (OR: 2.3; CI: 1.6–3.3) and of auditory hallucinations (OR: 2.6; CI: 1.5–4.4). Finally, it mediated a third of the total association of child sexual abuse with psychosis and persecutory ideation and a quarter of that with auditory hallucinations. Conclusions: Mood instability is a prominent feature of psychotic experience and may have a role in its genesis. Targeting mood instability could lead to innovative treatments for psychosis

Overcoming the Challenges Associated with Image-based Mapping of Small Bodies in Preparation for the OSIRIS-REx Mission to (101955) Bennu

The OSIRIS-REx Asteroid Sample Return Mission is the third mission in NASA's New Frontiers Program and is the first U.S. mission to return samples from an asteroid to Earth. The most important decision ahead of the OSIRIS-REx team is the selection of a prime sample-site on the surface of asteroid (101955) Bennu. Mission success hinges on identifying a site that is safe and has regolith that can readily be ingested by the spacecraft's sampling mechanism. To inform this mission-critical decision, the surface of Bennu is mapped using the OSIRIS-REx Camera Suite and the images are used to develop several foundational data products. Acquiring the necessary inputs to these data products requires observational strategies that are defined specifically to overcome the challenges associated with mapping a small irregular body. We present these strategies in the context of assessing candidate sample-sites at Bennu according to a framework of decisions regarding the relative safety, sampleability, and scientific value across the asteroid's surface. To create data products that aid these assessments, we describe the best practices developed by the OSIRIS-REx team for image-based mapping of irregular small bodies. We emphasize the importance of using 3D shape models and the ability to work in body-fixed rectangular coordinates when dealing with planetary surfaces that cannot be uniquely addressed by body-fixed latitude and longitude.Comment: 31 pages, 10 figures, 2 table

The effects of induced emotions on pro-social behaviour

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Emotions are commonly experienced and expressed in human societies; however, their consequences on economic behaviour have received only limited attention. This paper investigates the effects of induced positive and negative emotions on cooperation and sanctioning behaviour in a one-shot voluntary contributions mechanism game, where personal and social interests are at odds. We concentrate on two specific emotions: anger and happiness. Our findings provide clear evidence that measures of social preferences are sensitive to subjects' current emotional states. Specifically, angry subjects contribute, on average, less than happy subjects and overall welfare as measured by average net earnings is lower when subjects are in an angry mood. We also find that how punishment is used is affected by moods: angry subjects punish harsher than happy subjects, ceteris paribus. These findings suggest that anger, when induced, can have a negative impact on economic behaviour

Detrimental NFKB1 missense variants affecting the Rel-homology domain of p105/p50

Most of the currently known heterozygous pathogenic NFKB1 (Nuclear factor kappa B subunit 1) variants comprise deleterious defects such as severe truncations, internal deletions, and frameshift variants. Collectively, these represent the most frequent monogenic cause of common variable immunodeficiency (CVID) identified so far. NFKB1 encodes the transcription factor precursor p105 which undergoes limited proteasomal processing of its C-terminal half to generate the mature NF-kappa B subunit p50. Whereas p105/p50 haploinsufficiency due to devastating genetic damages and protein loss is a well-known disease mechanism, the pathogenic significance of numerous NFKB1 missense variants still remains uncertain and/or unexplored, due to the unavailability of accurate test procedures to confirm causality. In this study we functionally characterized 47 distinct missense variants residing within the N-terminal domains, thus affecting both proteins, the p105 precursor and the processed p50. Following transient overexpression of EGFP-fused mutant p105 and p50 in HEK293T cells, we used fluorescence microscopy, Western blotting, electrophoretic mobility shift assays (EMSA), and reporter assays to analyze their effects on subcellular localization, protein stability and precursor processing, DNA binding, and on the RelA-dependent target promoter activation, respectively. We found nine missense variants to cause harmful damage with intensified protein decay, while two variants left protein stability unaffected but caused a loss of the DNA-binding activity. Seven of the analyzed single amino acid changes caused ambiguous protein defects and four variants were associated with only minor adverse effects. For 25 variants, test results were indistinguishable from those of the wildtype controls, hence, their pathogenic impact remained elusive. In summary, we show that pathogenic missense variants affecting the Rel-homology domain may cause protein-decaying defects, thus resembling the disease-mechanisms of p105/p50 haploinsufficiency or may cause DNA-binding deficiency. However, rare variants (with a population frequency of less than 0.01%) with minor abnormalities or with neutral tests should still be considered as potentially pathogenic, until suitable tests have approved them being benign.Peer reviewe

Self-Potential as a Predictor of Seawater Intrusion in Coastal Groundwater Boreholes

This work was supported by the Natural Environment Research Council in the UK, as part of the Science and Solutions for a Changing Planet Doctor Training Partnership, run by the Grantham Institute for Climate Change at Imperial College London. We thank Southern Water for access to the boreholes at Saltdean and Balsdean. We thank Southern Water and Atkins Global for funding the installation of the equipment. We also thank Dr Amadi Ijioma for providing a prototype of the electrodynamic modelling code in MATLAB, which has since been adapted for use in a coastal chalk aquifer. Three anonymous reviewers are thanked for their comments, which greatly helped to improve the manuscript. The data used in this paper are in the tables, figures and cited information. The authors have no conflicts of interest to declare.Peer reviewedPublisher PDFPublisher PD

Upregulation of CENP-H in tongue cancer correlates with poor prognosis and progression

<p>Abstract</p> <p>Background</p> <p>Centromere protein H (CENP-H) is one of the fundamental components of the human active kinetochore. Recently, CENP-H was identified to be associated with tumorigenesis. This study was aimed to investigate the clinicopathologic significance of CENP-H in tongue cancer.</p> <p>Methods</p> <p>RT-PCR, real time RT-PCR and Western blot were used to examine the expression of CENP-H in tongue cancer cell lines and biopsies. CENP-H protein level in paraffin-embedded tongue cancer tissues were tested by immunohistochemical staining and undergone statistical analysis. CENP-H-knockdown stable cell line was established by infecting cells with a retroviral vector pSuper-retro-CENP-H-siRNA. The biological function of CENP-H was tested by MTT assay, colony formation assay, and Bromodeoxyuridine (BrdU) incorporation assay.</p> <p>Results</p> <p>CENP-H expression was higher in tongue cancer cell lines and cancer tissues (T) than that in normal cell and adjacent noncancerous tongue tissues (N), respectively. It was overexpressed in 55.95% (94/168) of the paraffin-embedded tongue cancer tissues, and there was a strong correlation between CENP-H expression and clinical stage, as well as T classification. CENP-H can predict the prognosis of tongue cancer patients especially those in early stage. Depletion of CENP-H can inhibit the proliferation of tongue cancer cells (Tca8113) and downregulate the expression of Survivin.</p> <p>Conclusion</p> <p>These findings suggested that CENP-H involves in the development and progression of tongue cancer. CENP-H might be a valuable prognostic indicator for tongue cancer patients within early stage.</p