Expression of CD13/Aminopeptidase N by Synovial Fibroblasts: Novel Roles in the Pathogenesis of Rheumatoid Arthritis.

Aminopeptidase N/CD13 is a metallopeptidase that is highly expressed by fibroblast-like synoviocytes (FLS) and may play a role in rheumatoid arthritis (RA). The goal of this study was to define CD13 function in the RA joint by monitoring CD13 expression in vivo and in vitro, analyzing regulation by pro-inflammatory cytokines of CD13 expression on FLS, describing the mechanisms by which CD13 is released from FLS, and defining potential roles for CD13 in homing of T cells to the RA joint and in regulating the growth and migration of RA FLS. In overview, we find that CD13 is expressed in synovial fluids, sera, FLS lysates, and culture supernatants as measured by ELISA, with a significant increase of CD13 in RA synovial fluids when compared to osteoarthritis. In FLS, pro-inflammatory cytokines (TNFalpha, IFNgamma, IL-17) are able to upregulate CD13 mRNA. However, as surface expression of CD13 did not correlate with CD13 mRNA, and soluble CD13 is present in RA synovial fluid, potential mechanisms for CD13 release from FLS were examined. CD13 was detected in sera, synovial fluids, and FLS culture supernatants, on extracellular vesicles and in soluble form. The release of soluble CD13 from FLS could be blocked by metalloproteinase inhibitors and siRNA directed against MT1-MMP/MMP14. With regard to biological functions, recombinant human CD13 was chemotactic for cytokine activated T-cells (Tck) through a G-protein-coupled receptor and contributed to the chemotactic properties of synovial fluid independently of enzymatic activity. Furthermore, inhibition of CD13 function in FLS, using enzymatic activity inhibitors or anti-CD13 antibodies, resulted in decreased growth and diminished migration of RAFLS. We conclude that CD13 is upregulated in the RA joint by pro-inflammatory cytokines where it is released on extracellular vesicles and shed as a soluble molecule from the FLS surface by metalloproteinases, including MMP14. Following its release from the FLS surface, CD13 induces chemotaxis of Tck, a T cell population similar to that found in RA synovium. Moreover, CD13 increases FLS growth and migration, thereby contributing to synovial hyperplasia in RA. Our data implicates CD13 in the pathogenesis of RA through enhancement of both T cell infiltration and aggressive FLS outgrowth.PHDImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/110484/1/rlmorgan_1.pd

Der Glockenspielmord

In the city of Munich Germany, diary and journal entries written by an artist named Max Pfeiffer are found, detailing the horrendous way in which he created his first statue for the world-famous Glockenspiel on Marienplatz

Analysis induced reduction of a polyelectrolyte

The polymer, poly(diallyldimethylammonium chloride) (PDDA), is shown to undergo chemical change via a reduction mechanism during X-ray analysis. Examination of the N 1s spectrum of PDDA shows a time dependence on the degree of reduction, together with clear amplification of the extent of reduction through the charge compensation system and X-ray irradiation

Boronic acids for functionalisation of commercial multi-layer graphitic material as an alternative to diazonium salts

A novel radical-based functionalisation strategy for the synthesis of functionalised commercially obtained plasma-synthesised multi-layer graphitic material (MLG) is presented herein. 4-(trifluoromethyl)phenyl boronic acid was utilised as a source of 4-(trifluoromethyl)phenyl radicals to covalently graft upon the graphitic surface of MLG. Such a methodology provides a convenient and safer route towards aryl radical generation, serving as a potential alternative to hazardous diazonium salt precusors. The structure and morphology of the functionalised MLG (Arf-MLG) has been characterised using XPS, Raman, TGA, XRD, SEM, TEM and BET techniques. The XPS quantitative data and Raman spectra provide evidence of successful covalent attachment of 4-(trifluoromethyl)phenyl groups to MLG

Social learning strategies and cooperative behaviour: Evidence of payoff bias, but not prestige or conformity, in a social dilemma game

Human cooperation, occurring without reciprocation and between unrelated individuals in large populations, represents an evolutionary puzzle. One potential explanation is that cooperative behaviour may be transmitted between individuals via social learning. Using an online social dilemma experiment, we find evidence that participants’ contributions were more consistent with payoff-biased transmission than prestige-biased transmission or conformity. We also found some evidence for lower cooperation (i) when exposed to social information about peer cooperation levels than without such information, and (ii) in the prisoners’ dilemma game compared to the snowdrift game. A simulation model established that the observed cooperation was more likely to be caused by participants’ general propensity to cooperate than by the effect of social learning strategies employed within the experiment, but that this cooperative propensity could be reduced through selection. Overall, our results support previous experimental evidence indicating the role of payoff-biased transmission in explaining cooperative behaviour, but we find that this effect was small and was overwhelmed by participants’ general propensity for cooperation

An investment case analysis for the prevention and treatment of adolescent mental disorders and suicide in England

BackgroundAdolescent mental health (AMH) needs in England have increased dramatically and needs exceed treatment availability. This study undertook a comparative assessment of the health and economic return on investment (ROI) of interventions to prevent and treat mental disorders among adolescents (10–19 years) and examined intervention affordability and readiness.MethodsInterventions were identified following a review of published and grey literature. A Markov model followed a simulated adolescent cohort to estimate implementation costs and health, education, and economic benefits. Intervention affordability was assessed, comparing annual cost per adolescent with NHS England per capita spending, and an expert panel assessed intervention readiness using a validated framework.ResultsOver 10- and 80-year horizons, interventions to treat mild anxiety and mild depression were most cost-effective, with the highest individual lifetime ROI (GBP 5822 GBP 1 and GBP 257: GBP 1). Preventing anxiety and depression was most affordable and ‘implementation ready’ and offered the highest health and economic benefits. A priority package (anxiety and depression prevention; mild anxiety and mild depression treatment) would avert 5 million disability-adjusted life-years (DALYS) and achieve an ROI of GBP 15: GBP 1 over 10 years or 11.5 million DALYs (ROI of GBP 55: GBP 1) over 80 years.ConclusionThe economic benefits from preventing and treating common adolescent mental disorders equivalent to 25% of NHS England’s annual spending in 2021 over 10 years and 91% over 80 years. Preventing and early treatment for anxiety and depression had the highest ROIs and strong implementation readiness.<br/

The Polo-related kinase Cdc5 activates and is destroyed by the mitotic cyclin destruction machinery in S. cerevisiae

AbstractBackground: Following chromosome segregation in anaphase, ubiquitin-dependent degradation of mitotic cyclins contributes to the exit from mitosis. A key step in this process is catalyzed by a ubiquitin–protein ligase known as the anaphase-promoting complex (APC), the regulation of which is poorly understood. The Polo-related protein kinase Cdc5 in Saccharomyces cerevisiae might encode a regulator of the APC, because cdc5 mutant cells arrest with a late mitotic phenotype similar to that observed in cells with defective cyclin destruction.Results: We investigated the role of Cdc5 in the regulation of mitotic cyclin degradation. In cdc5-1 mutant cells, we observed a defect in the destruction of cyclins and a reduction in the cyclin–ubiquitin ligase activity of the APC. Overexpression of CDC5 resulted in increased APC activity and mitotic cyclin destruction in asynchronous cells or in cells arrested in metaphase. CDC5 mutation or overexpression did not affect the degradation of the APC substrate Pds 1, which is normally degraded at the metaphase-to-anaphase transition. Cyclin-specific APC activity in cells overexpressing CDC5 was reduced in the absence of the APC regulatory proteins Hct 1 and Cdc20. In G1, Cdc5 itself was degraded by an APC-dependent and Hct1-dependent mechanism.Conclusions: We conclude that Cdc5 is a positive regulator of cyclin-specific APC activity in late mitosis. Degradation of Cdc5 in G1 might provide a feedback mechanism by which the APC destroys its activator at the onset of the next cell cycle

Defining Epidermal Basal Cell States during Skin Homeostasis and Wound Healing Using Single-Cell Transcriptomics.

Our knowledge of transcriptional heterogeneities in epithelial stem and progenitor cell compartments is limited. Epidermal basal cells sustain cutaneous tissue maintenance and drive wound healing. Previous studies have probed basal cell heterogeneity in stem and progenitor potential, but a comprehensive dissection of basal cell dynamics during differentiation is lacking. Using single-cell RNA sequencing coupled with RNAScope and fluorescence lifetime imaging, we identify three non-proliferative and one proliferative basal cell state in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization. Pseudotemporal trajectory and RNA velocity analyses predict a quasi-linear differentiation hierarchy where basal cells progress from Col17a1Hi/Trp63Hi state to early-response state, proliferate at the juncture of these two states, or become growth arrested before differentiating into spinous cells. Wound healing induces plasticity manifested by dynamic basal-spinous interconversions at multiple basal transcriptional states. Our study provides a systematic view of epidermal cellular dynamics, supporting a revised "hierarchical-lineage" model of homeostasis

Representations of voluntary childlessness in the UK Press, 1990-2008

Representations of voluntary childlessness — the declaration by an individual that he or she does not wish to bear or raise children — were studied in 116 articles published in British national newspapers in the period 1990—2008. Media framing analysis was used to examine broad patterns of framing of the topic, identifying four frames: voluntary childlessness as an individual rights issue, as a form of resistance, as a social trend, and as a personal decision. These frames, it is argued, may act as potential ‘scripts’ for newspaper readers who are debating the decision to start a family