A unique homologue of the eukaryotic protein-modifier ubiquitin present in the bacterium Bacteroides fragilis, a predominant resident of the human gastrointestinal tract

In the complete genome sequences of Bacteroides fragilis NCTC9343 and 638R, we have discovered a gene, ubb, the product of which has 63 % identity to human ubiquitin and cross-reacts with antibodies raised against bovine ubiquitin. The sequence of ubb is closest in identity (76 %) to the ubiquitin gene from a migratory grasshopper entomopoxvirus, suggesting acquisition by inter-kingdom horizontal gene transfer. We have screened clinical isolates of B. fragilis from diverse geographical regions and found that ubb is present in some, but not all, strains. The gene is transcribed and the mRNA is translated in B. fragilis, but deletion of ubb did not have a detrimental effect on growth. BfUbb has a predicted signal sequence; both full-length and processed forms were detected in whole-cell extracts, while the processed form was found in concentrated culture supernatants. Purified recombinant BfUbb inhibited in vitro ubiquitination and was able to covalently bind the human E1 activating enzyme, suggesting it could act as a suicide substrate in vivo. B. fragilis is one of the predominant members of the normal human gastrointestinal microbiota with estimates of up to >1011 cells per g faeces by culture. These data indicate that the gastro-intestinal tract of some individuals could contain a significant amount of aberrant ubiquitin with the potential to inappropriately activate the host immune system and/or interfere with eukaryotic ubiquitin activity. This discovery could have profound implications in relation to our understanding of human diseases such as inflammatory bowel and autoimmune diseases

B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells

B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6–secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell–specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6–sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6–producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell–driven pathogenesis in T cell–mediated autoimmune disease such as EAE and MS

Minimal residual disease is an independent predictor for 10-year survival in CLL

Minimal residual disease (MRD) negativity, defined as <1 chronic lymphocytic leukemia (CLL) cell detectable per 10 000 leukocytes, has been shown to independently predict for clinical outcome in patients receiving combination chemoimmunotherapy in the frontline setting. However, the long-term prognostic value of MRD status in other therapeutic settings remains unclear. Here, we retrospectively analyzed, with up to 18 years follow-up, all patients at our institution who achieved at least a partial response (PR) with various therapies between 1996 and 2007, and received a bone marrow MRD assessment at the end of treatment according to the international harmonized approach. MRD negativity correlated with both progression-free survival (PFS) and overall survival (OS) independent of the type and line of treatment, as well as known prognostic factors including adverse cytogenetics. The greatest impact of achieving MRD negativity was seen in patients receiving frontline treatment, with 10-year PFS of 65% vs 10% and 10-year OS of 70% vs 30% for MRD-negative vs MRD-positive patients, respectively. Our results demonstrate the long-term benefit of achieving MRD negativity, regardless of the therapeutic setting and treatment modality, and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL

EIRFLAT-1: A FlatSat platform for the development and testing of the 2U CubeSat EIRSAT-1

The Educational Irish Research Satellite (EIRSAT-1) is a 2U CubeSat being designed, built and tested at University College Dublin. A FlatSat platform known as EIRFLAT-1 has been constructed to enable the testing and development of the CubeSat. EIRFLAT-1 facilitates the electrical connections between CubeSat components while leaving key interfaces accessible for test equipment and allowing for the hot swapping of components. Commercial Off The Shelf and in-house developed hardware has been tested using EIRFLAT-1 at component, subsystem and full system level. In addition, the FlatSat has been used for flight software development. This paper describes the design of EIRFLAT-1 including electrical and mechanical components and additional ground support equipment developed to assist in the testing and development activities. EIRFLAT-1 has proven to be an invaluable tool for testing and has led to the discovery of issues and unexpected behaviour with flight hardware which would have contributed to schedule delays if undiscovered until after the satellite was assembled. Moreover, EIRFLAT-1 facilitated early and incremental testing of both software and operations procedures. The schematics for the electrical design of EIRFLAT-1, which is compatible with all CubeSat Kit PC/104 components, has been made publicly available for use by other educational CubeSat team

Lifestyle information and commercial weight management groups to support maternal postnatal weight management and positive lifestyle behaviour: the SWAN feasibility randomised controlled trial

Objectives: To assess feasibility of a future randomised controlled trial (RCT) of clinical and cost-effectiveness of lifestyle information and commercial weight-management groups to support postnatal weight management to 12 months post-birth. Design: Two-arm feasibility trial, with nested mixed-methods process evaluation. Setting: Inner-city unit, South England. Population: Women with BMIs ≥25kg/m2 at pregnancy booking or normal BMIs (18.5kg/m2-24.9kg/m2) identified with excessive gestational weight gain at 36 weeks gestation. Methods: Randomised to standard care plus commercial weight-management sessions commencing 8-16 weeks postnatally or standard care only. Main outcomes: Feasibility outcomes included assessment of recruitment, retention, acceptability, and economic data collation. Primary and secondary endpoints included difference between groups in weight 12 months postnatally compared with booking (proposed primary outcome for a future trial), diet, physical activity, smoking, alcohol, mental health, infant feeding, NHS resource use. Results: 193 women were randomised; 98 intervention and 95 control; only four women had excessive gestational weight gain. A slightly greater weight change was found among intervention women at 12 months, with greatest benefit. among women attending 10+ weight management sessions. There was >80% follow-up to 12 months, low risk of contamination and no group differences in trial completion. Conclusion: It was feasible to recruit and retain women with BMIs≥25kg/m2 to an intervention to support postnatal weight management; identification of excessive gestational weight gain requires consideration. Economic modelling could inform out-of-trial costs and benefits in a future trial. A definitive trial is an important next step

Cost-effectiveness of screening tools for identifying depression in early pregnancy: a decision tree model

Background: Although the effectiveness of screening tools for detecting depression in pregnancy has been investigated, there is limited evidence on the cost-effectiveness. This is vital in providing full information to decision makers. This study aimed to explore the cost-effectiveness of different screening tools to identify depression in early pregnancy compared to no screening. Methods: A decision tree was developed to model the identification and treatment pathways of depression from the first antenatal appointment to 3-months postpartum using the Whooley questions, the Edinburgh Postnatal Depression Scale (EPDS) and the Whooley questions followed by the EPDS, compared to no screening. The economic evaluation took an NHS and Personal Social Services perspective. Model parameters were taken from a combination of sources including a cross-sectional survey investigating the diagnostic accuracy of screening tools, and other published literature. Cost-effectiveness was assessed in terms of the incremental cost per quality adjusted life years (QALYs). Cost-effectiveness planes and cost-effectiveness acceptability curves were produced using a net-benefit approach based on Monte Carlo simulations of cost-outcome data. Results: In a 4-way comparison, the Whooley, EPDS and Whooley followed by the EPDS each had a similar probability of being cost-effective at around 30% for willingness to pay values from £20,000–30,000 per QALY compared to around 20% for the no screen option. Conclusions: All three screening approaches tested had a higher probability of being cost-effective than the no-screen option. In the absence of a clear cost-effectiveness advantage for any one of the three screening options, the choice between the screening approaches could be made on other grounds, such as clinical burden of the screening options. Limitations include data availability and short time horizon, thus further research is needed

Development and Psychometric Validation of the Pandemic-Related Traumatic Stress Scale for Children and Adults

To assess the public health impact of the COVID-19 pandemic on mental health, investigators from the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) research program developed the Pandemic-Related Traumatic Stress Scale (PTSS). Based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) acute stress disorder symptom criteria, the PTSS is designed for adolescent (13–21 years) and adult self-report and caregiver-report on 3–12-year-olds. To evaluate psychometric properties, we used PTSS data collected between April 2020 and August 2021 from non-pregnant adult caregivers (n = 11,483), pregnant/postpartum individuals (n = 1,656), adolescents (n = 1,795), and caregivers reporting on 3–12-year-olds (n = 2,896). We used Mokken scale analysis to examine unidimensionality and reliability, Pearson correlations to evaluate relationships with other relevant variables, and analyses of variance to identify regional, age, and sex differences. Mokken analysis resulted in a moderately strong, unidimensional scale that retained nine of the original 10 items. We detected small to moderate positive associations with depression, anxiety, and general stress, and negative associations with life satisfaction. Adult caregivers had the highest PTSS scores, followed by adolescents, pregnant/postpartum individuals, and children. Caregivers of younger children, females, and older youth had higher PTSS scores compared to caregivers of older children, males, and younger youth, respectively

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Drivers of creativity within advertising agencies: How structural configuration can affect and improve creative development

There has been a surprising dearth of research that investigates the effects of structural elements on creative outputs in an advertising agency context. This article explores how structural elements may be applied to achieve different flavors of creativity via their effects on originality and strategy. The study examined 554 campaigns in a field study of Australia-and New Zealand-based advertising-agency professionals from Sydney, Melbourne, and Auckland. Findings suggest that agencies can deploy their servicelevel resources flexibly, but not all structural configurations lead to the best outputs, depending on the client context. Managerial implications, limitations, and directions for future research are discussed