T-cell immune adaptor SKAP1 regulates the induction of collagen-induced arthritis in mice

SKAP1 is an immune cell adaptor that couples the T-cell receptor with the ‘inside-out’ signalling pathway for LFA-1 mediated adhesion in T-cells. A connection of SKAP1 to the regulation of an autoimmune disorder has not previously been reported. In this study, we show that Skap1-deficient (skap1-/-) mice are highly resistant to the induction of collagen-induced arthritis (CIA), both in terms of incidence or severity. Skap1-/- T-cells were characterised by a selective reduction in the presence IL-17+ (Th17) in response to CII peptide and a marked reduction of joint infiltrating T-cells in Skap1-/- mice. SKAP1 therefore represents a novel connection to Th17 producing T-cells and is new potential target in the therapeutic intervention in autoimmune and inflammatory diseases

Small Molecule Inhibition of Glycogen Synthase Kinase 3 (GSK-3) Specifically Inhibits the Transcription of Inhibitory Co-Receptor LAG-3 for Enhanced Anti-Tumor Immunity

Immune checkpoint blockade using antibodies against negative co-receptors such as cytolytic T cell antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) has seen much success treating cancer. However, most patients are still not cured, underscoring the need for improved treatments and the possible development of small molecule inhibitors (SMIs) for improved immunotherapy. We previously showed that glycogen synthase kinase (GSK)- 3a/b is a central regulator of PD-1 expression, where GSK-3 inhibition down-regulates PD-1 and enhances CD8+ cytolytic T cell (CTL) function, reducing viral infections and tumor growth. Here, we demonstrate that GSK-3 also negatively regulates Lymphocyte Activation Gene-3 (LAG-3) expression on CD4+ and CD8+ T cells. GSK-3 SMIs are more effective than LAG-3 blockade alone in suppressing B16 melanoma growth, while their combination resulted in enhanced tumor clearance. This was linked to increased expression of the transcription factor, Tbet, which bound the LAG-3 promoter, inhibiting its transcription, and to increased granzyme B and interferong1 expression. Overall, we describe a small molecule approach to inhibit LAG-3, resulting in enhanced anti-tumor immunity

Active bacterioplankton community response to dissolved ‘free’ deoxyribonucleic acid (dDNA) in surface coastal marine waters

Seawater contains dissolved ‘free’ DNA (dDNA) that is part of a larger <0.2 μm pool of DNA (D-DNA) including viruses and uncharacterised bound DNA. Previous studies have shown that bacterioplankton readily degrade dDNA and culture-based approaches have identified several potential dDNA-utilising taxa. This study characterised the seasonal variation in D-DNA concentrations at Station L4, a coastal marine observatory in the Western English Channel, and linked changes in concentration to cognate physicochemical and biological factors. The impact of dDNA addition on active bacterioplankton communities at Station L4 was then determined using 16S rRNA high-throughput sequencing and RNA Stable Isotope Probing (RNA SIP) with 13C-labelled diatom-derived dDNA. Compared to other major bacterioplankton orders, the Rhodobacterales actively responded to dDNA additions in amended microcosms and RNA SIP identified two Rhodobacterales populations most closely associated with the genera Halocynthiibacter and Sulfitobacter that assimilated the 13C-labelled dDNA. Here we demonstrate that dDNA is a source of dissolved organic carbon for some members of the major bacterioplankton group the Marine Roseobacter Clade. This study enhances our understanding of roles of specific bacterioplankton taxa in dissolved organic matter cycling in coastal waters with potential implications for nitrogen and phosphorus regeneration processes

Validating the Philadelphia Mindfulness Scale [PMS] for Those with Fibromyalgia

Objectives: Dispositional mindfulness [DM] has become an important construct in understanding and treating fibromyalgia. However, few DM measures exist that have been validated in those with fibromyalgia. The Philadelphia Mindfulness Scale [PMS] is a self-report of DM. In the current study, we validate the PMS within a sample of individuals with fibromyalgia. Design: This was a cross-sectional online study. This enabled the recruitment of a larger sample of individuals with experiences of fibromyalgia than may have been achieved through face-to-face assessment. A cross-sectional approach was adopted to minimise resource demands. Method: The PMS alongside measures of fibromyalgia severity [The Revised Fibromyalgia Impact Questionnaire], affect [Positive and Negative Affect Scale] and decentring [Experiences Questionnaire] were completed online by a sample of N=936 individuals with fibromyalgia. Results: Confirmatory factor analysis supported a revised three-factor structure for the PMS. This factor structure excluded items which could overlap with hypervigilance within fibromyalgia. The three supported factors were Awareness, Non-judging/Control and Non-suppression/reactivity. Concurrent validity of the subscales was partially supported via correlations with positive affect [PA] and negative affect [NA] and decentring. Conclusions: The results support the use of the PMS in individuals with fibromyalgia, and in particular the use of this measure to compare those with and without experience of meditation. The PMS may be a useful tool in evaluating mindfulness-based interventions [MBIs] within this population. Limitations: The online design prevented more in-depth assessment of fibromyalgia. As the study was cross-sectional, test re-test reliability could not be assessed

Nurse led interventions to improve control of blood pressure in people with hypertension: systematic review and meta-analysis

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.OBJECTIVE: To review trials of nurse led interventions for hypertension in primary care to clarify the evidence base, establish whether nurse prescribing is an important intervention, and identify areas requiring further study. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Ovid Medline, Cochrane Central Register of Controlled Trials, British Nursing Index, Cinahl, Embase, Database of Abstracts of Reviews of Effects, and the NHS Economic Evaluation Database. STUDY SELECTION: Randomised controlled trials of nursing interventions for hypertension compared with usual care in adults. DATA EXTRACTION: Systolic and diastolic blood pressure, percentages reaching target blood pressure, and percentages taking antihypertensive drugs. Intervention effects were calculated as relative risks or weighted mean differences, as appropriate, and sensitivity analysis by study quality was undertaken. DATA SYNTHESIS: Compared with usual care, interventions that included a stepped treatment algorithm showed greater reductions in systolic blood pressure (weighted mean difference -8.2 mm Hg, 95% confidence interval -11.5 to -4.9), nurse prescribing showed greater reductions in blood pressure (systolic -8.9 mm Hg, -12.5 to -5.3 and diastolic -4.0 mm Hg, -5.3 to -2.7), telephone monitoring showed higher achievement of blood pressure targets (relative risk 1.24, 95% confidence interval 1.08 to 1.43), and community monitoring showed greater reductions in blood pressure (weighted mean difference, systolic -4.8 mm Hg, 95% confidence interval -7.0 to -2.7 and diastolic -3.5 mm Hg, -4.5 to -2.5). CONCLUSIONS: Nurse led interventions for hypertension require an algorithm to structure care. Evidence was found of improved outcomes with nurse prescribers from non-UK healthcare settings. Good quality evidence from UK primary health care is insufficient to support widespread employment of nurses in the management of hypertension within such healthcare systems.Scientific Foundation Board of the Royal College of General PractitionersSouth West GP Trus

The difference in blood pressure readings between arms and survival: primary care cohort study

addresses: Primary Care Research Group, Institute of Health Services Research, Peninsula College of Medicine and Dentistry, University of Exeter, Devon EX1 2LU, UK. [email protected]: PMCID: PMC3309155To determine whether a difference in systolic blood pressure readings between arms can predict a reduced event free survival after 10 years

Birth data accessibility via primary care health records to classify health status in a multi-ethnic population of children: an observational study

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/license/by/4.0

Alternating polarity for enhanced electrochemical synthesis

Synthetic electrochemistry has recently become an exciting technology for chemical synthesis. The majority of reported syntheses use either constant current or constant potential, however a few use nonlinear profiles – mostly alternating polarity – to maintain efficiency throughout the process, such as controlling deposits on electrodes or ensuring even use of electrodes. However, even though parameters that are associated with such profiles, such as the frequency, can have a major impact on the reaction outcome, they are often not investigated. Herein, we report the crucial impact that the applied frequency of the alternating polarity has on the observed reaction rate of Cu(I)–NHC complex formation and demonstrate that this can be manipulated to give enhanced yield that is stable over extended reaction times