Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis.

OBJECTIVES: Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodies METHODS: We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities. RESULTS: Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis. CONCLUSIONS: Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms

Topoisomer Differentiation of Molecular Knots by FTICR MS: Lessons from Class II Lasso Peptides

Lasso peptides constitute a class of bioactive peptides sharing a knotted structure where the C-terminal tail of the peptide is threaded through and trapped within an N-terminalmacrolactamring. The structural characterization of lasso structures and differentiation from their unthreaded topoisomers is not trivial and generally requires the use of complementary biochemical and spectroscopic methods. Here we investigated two antimicrobial peptides belonging to the class II lasso peptide family and their corresponding unthreaded topoisomers: microcin J25 (MccJ25), which is known to yield two-peptide product ions specific of the lasso structure under collisioninduced dissociation (CID), and capistruin, for which CID does not permit to unambiguously assign the lasso structure. The two pairs of topoisomers were analyzed by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) upon CID, infrared multiple photon dissociation (IRMPD), and electron capture dissociation (ECD). CID and ECDspectra clearly permitted to differentiate MccJ25 from its non-lasso topoisomer MccJ25-Icm, while for capistruin, only ECD was informative and showed different extent of hydrogen migration (formation of c\bullet/z from c/z\bullet) for the threaded and unthreaded topoisomers. The ECD spectra of the triply-charged MccJ25 and MccJ25-lcm showed a series of radical b-type product ions {\eth}b0In{\TH}. We proposed that these ions are specific of cyclic-branched peptides and result from a dual c/z\bullet and y/b dissociation, in the ring and in the tail, respectively. This work shows the potentiality of ECD for structural characterization of peptide topoisomers, as well as the effect of conformation on hydrogen migration subsequent to electron capture

Factors affecting faculty use of learning technologies: Implications for models of technology adoption

This study examines factors associated with the use of learning technologies by higher education faculty. In an online survey in a UK university, 114 faculty respondents completed a measure of Internet self-efficacy, and reported on their use of learning technologies along with barriers to their adoption. Principal components analysis suggested two main barriers to adoption: structural constraints within the University and perceived usefulness of the tools. Regression analyses indicated both these variables, along with Internet self-efficacy, were associated with use of online learning technology. These findings are more consistent with models of technology engagement that recognize facilitating or inhibiting conditions (unified theory of acceptance and use of technology; decomposed theory of planned behavior) than the classic technology acceptance model (TAM). Practical implications for higher education institutions are that while faculty training and digital literacy initiatives may have roles to play, structural factors (e.g., provision of resources and technical support) must also be addressed for optimal uptake of learning technologies

Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of Chronic Neurodegeneration

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer’s disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signaling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease

Elimination of Active Trachoma after Two Topical Mass Treatments with Azithromycin 1.5% Eye Drops

Trachoma is the leading cause of infectious blindness worldwide, accounting for 1.3 million cases of blindness. Although it has disappeared in many regions of the world, trachoma is still endemic in Africa, Eastern Mediterranean, Latin America, Asia, and Australia. The WHO has currently set a target of 2020 for controlling trachoma to a low enough level that resulting blindness will not be a major public health concern. Topical tetracycline was for a long time the recommended treatment for active trachoma, but compliance to the regimen is extremely poor. Azithromycin has properties that make it an ideal treatment for Chlamydia trachomatis: high efficacy, intracellular accumulation, and a long tissue half-life. There is now a new mass treatment of trachoma by azithromycin 1.5% eye drops which is as effective as the oral route. In the test health district of Kolofata, Cameroon, the prevalence of trachoma among children dramatically decreased from 31% to less than 5% after 2 treatments. A third treatment was performed in January 2010. An epidemiological surveillance is implemented to see if this removal will be permanent. It also avoids misuse of oral azithromycin and the eye drops are directly treating the site of the infection

Which factors engage women in deprived neighbourhoods to participate in exercise referral schemes?

ABSTRACT: BACKGROUND: Exercise referral schemes (ERS) have become a popular way of promoting physical activity. The aim of these schemes is to encourage high risk patients to exercise. In evaluating these schemes, little attention has been paid to lower socio-economic groups in a multi-ethnic urban setting. This study aimed to explore the socio-demographic and psychosocial characteristics of female participants in ERS located in deprived neighbourhoods. The second aim was to determine which elements of the intervention make it appealing to participate in the scheme. METHODS: A mixed method approach was utilized, combining a cross-sectional descriptive study and a qualitative component. In the quantitative part of the study, all female participants (n=523) filled out a registration form containing questions about socio-demographic and psychosocial characteristics. Height and weight were also measured. In the qualitative part of the study, 38 of these 523 participants were interviewed. RESULTS: The majority of the participants had a migrant background, a low level of education, no paid job and a high body mass index. Although most participants were living sedentary lives, at intake they were quite motivated to start exercising. The ERS appealed to them because of its specific elements: facilitating role of the health professional, supportive environment, financial incentive, supervision and neighbourhood setting. CONCLUSIONS: This study supports the idea that ERS interventions appeal to women from lower socio-economic groups, including ethnic minorities. The ERS seems to meet their contextual, economic and cultural needs. Since the elements that enabled the women to start exercising are specific to this ERS, we should become aware of whether this population continues to exercise after the end of the schem

“cAMP Sponge”: A Buffer for Cyclic Adenosine 3′, 5′-Monophosphate

Background: While intracellular buffers are widely used to study calcium signaling, no such tool exists for the other major second messenger, cyclic AMP (cAMP). Methods/Principal Findings: Here we describe a genetically encoded buffer for cAMP based on the high-affinity cAMP-binding carboxy-terminus of the regulatory subunit $RI\beta$ of protein kinase A (PKA). Addition of targeting sequences permitted localization of this fragment to the extra-nuclear compartment, while tagging with mCherry allowed quantification of its expression at the single cell level. This construct (named “cAMP sponge”) was shown to selectively bind cAMP in vitro. Its expression significantly suppressed agonist-induced cAMP signals and the downstream activation of PKA within the cytosol as measured by FRET-based sensors in single living cells. Point mutations in the cAMP-binding domains of the construct rendered the chimera unable to bind cAMP in vitro or in situ. Cyclic AMP sponge was fruitfully applied to examine feedback regulation of gap junction-mediated transfer of cAMP in epithelial cell couplets. Conclusions: This newest member of the cAMP toolbox has the potential to reveal unique biological functions of cAMP, including insight into the functional significance of compartmentalized signaling events