CD23\u27s Role as a Negative Regulator of Allergic Disease: in vivo Effects of Murine CD23 Destabilization and Allelic Mutations

Through underexpression and overexpression studies, CD23 has been shown to negatively regulate IgE production. To investigate CD23 destabilization and its effects on CD23 shedding and IgE synthesis in vivo, we utilized an anti-CD23 stalk monoclonal (19G5) which has previously been shown to enhance proteolysis of CD23 in vitro. Compared to isotype control-treated mice, mice injected with 19G5 displayed enhanced serum soluble CD23 and IgE. Because 19G5 injection substantially enhanced CD23 shedding, it was useful in investigating the identity of the CD23 sheddase. 19G5 enhanced CD23 shedding in ADAM8-/-, ADAM9-/-ADAM15-/-, and ADAM9-/-ADAM12-/-ADAM15-/- mice, ruling out these ADAMs as candidate CD23 sheddases. Through the use of an ADAM10 inhibitor, we blocked CD23 shedding from murine B cells while increasing CD23 surface levels, and thus we identified ADAM10 as the CD23 sheddase. During the course of the ADAM investigation, we discovered that the 129/SvJ inbred mouse strain carried five amino acid substitutions within its CD23 gene. The mutations resulted in reduced CD23 surface expression and hyper IgE levels in vivo. The hyper IgE phenotype was consistent with a more rapid clearance of Nippostrongylus brasiliensis from the gut of 129/SvJ mice. B cells from 129/SvJ spleens proliferated more rapidly than those from BALB/c after stimulation with IL-4 and CD40 ligand trimer in vitro. However, in vitro IgE levels in supernatants from 129/SvJ B cells were significantly reduced, suggesting that the B cells were no longer responsive to IL-4 in vitro. Although the affinity of the IgE-129/SvJ CD23 interaction was similar to that of the BALB/c, 129/SvJ B cells exhibited a reduced number of IgE binding sites, demonstrating that high levels of CD23 are essential for controlling IgE synthesis. This finding was further confirmed in another disease model, namely the mouse asthma model. Mice overexpressing CD23 displayed suppressed allergic lung inflammation and reduced levels of IgE and Th2 cytokines and chemokines. Overall, the data provide a direct demonstration for CD23\u27s role in regulating IgE production in vivo and suggest that therapies aimed at stabilizing cell surface CD23 would inhibit proteolysis and increase surface expression, and thus would be beneficial in controlling allergic disease

Engaging first year lecturers with threshold learning outcomes and concepts in their disciplines

In this paper, we report on an investigation of what students need to learn in the first year in various discipline-based subjects to launch then on their way to meet specified discipline threshold learning outcomes (TLOs) by the time they graduate. We frame our investigation using both the threshold concepts that the students must master in first year in order to succeed in learning in the discipline and also the threshold learning outcomes that they need to achieve by third year. We describe and analyse workshops used to engage lecturers with the challenges of designing first year curriculum in their r discipline, suggest why threshold concepts are useful in focusing both lecturers and students on what is essential, and outline briefly some of the creative solutions the lecturers offered

Postoperative infection following strabismus surgery: case series and increased incidence in a single large referral center

Purpose To identify and analyze cases of postoperative infection following strabismus surgery at a large referral center and to report the incidence, risk factors, and outcomes. Methods An electronic database search identified strabismus procedures at Duke Eye Center from July 1996 to October 2017. Diagnosis codes for periocular infections were used to further identify patients with possible infections following strabismus surgery. Results Of 9,111 strabismus surgeries, 13 (0.14%) met criteria for probable infection, all occurring since October 2012 (0/6580 before vs 13/2531 [0.51%] after; P < 0.0001). Mean age of infection cases was 11.4 years; 11 patients (85%) were under 18 years of age. Associated previous diagnoses were genetic abnormalities with associated developmental delay (n = 5 [38%]), previous skin or ear infection (n = 4 [31%]), and acute or chronic rhinitis (n = 3 [23%]). Infection site cultures revealed methicillin-resistant Staphylococcus aureus (n = 3 [23%]), methicillin-sensitive S. aureus (n = 3 [23%]), and Streptococcus pyogenes/group-A Streptococcus (n = 2 [15%]). Only 1 case had bilateral infection. Infection remained extraocular in all cases, but one eye lost light perception secondary to optic atrophy. No common surgeon/procedure/preparation-related risks were identified. Conclusions A unifying explanation for the increase in post–strabismus surgery infections at Duke Eye Center was not identified. Potential risk factors include age <18 years, developmental delay, immune compromise, preceding nonocular infection, and bacterial colonization

Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys

Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys.BackgroundThe proliferation of mural epithelial cells is a major cause of progressive cyst enlargement in autosomal-dominant polycystic kidney disease (ADPKD). Adenosine 3′, 5′ cyclic monophosphate (cAMP) stimulates the proliferation of cells from ADPKD cysts, but not cells from normal human kidney cortex (HKC), through the activation of protein kinase A (PKA), mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK/MAPK). In the current study, we examined the signaling pathway between PKA and MEK in ADPKD and HKC cells.MethodsPrimary cultures of human ADPKD and HKC cells were prepared from nephrectomy specimens. We determined the effects of cAMP and epidermal growth factor (EGF) on the activation of ERK, B-Raf and Raf-1 in ADPKD and HKC cells by immune kinase assay and Western blot.Results8-Br-cAMP increased phosphorylated ERK (2.7- ± 0.6-fold, N = 7), and B-Raf kinase activity (3.6- ± 1.1-fold, N = 5) in cells from ADPKD kidneys; levels of phosphorylated Raf-1 were not changed. Inhibition of PKA by H89 strikingly decreased cAMP-stimulated phosphorylation of ERK and B-Raf, and MAPK inhibition by PD98059 blocked the effect of the nucleotide to activate ERK. By contrast, in HKC cells 8-Br-cAMP did not activate B-Raf and ERK. EGF stimulated the phosphorylation of ERK and Raf-1 in both ADPKD and HKC cells, but had no effect on B-Raf. 8-Br-cAMP and EGF conjointly increased ERK activation above that of either agonist alone in ADPKD cells, and this combined effect was abolished by PD98059, indicating that ERK was activated by EGF- and cAMP-responsive cascades that converge at MAPK.ConclusioncAMP activates ERK and increases proliferation of ADPKD epithelial cells, but not cells from normal human kidney cortex, through the sequential phosphorylation of PKA, B-Raf and MAPK in a pathway separate from, but complementary to, the classical receptor tyrosine kinase cascade. Consequently, cAMP and EGF have great potential to accelerate the progressive enlargement of renal cysts

Renewing first year curricula for social sciences and humanities in the context of discipline threshold standards

[Extract] This project evolved out of the work of the Deans of Arts, Social Sciences and Humanities (DASSH) network for Associate Deans Learning and Teaching (ADLT). As ADLTs, we wanted to better support and advise our colleagues on how to design first year curriculum in their own discipline. Our contexts were determined by Threshold Learning Outcomes (TLOs) that were developed for the Humanities and Social Science disciplines initially through an Australian Learning and Teaching Council (ALTC) project (Hay, 2012). We wanted to identify, understand, refine and be able to advocate for teaching and assessment strategies that would set first year students on their way to achieving TLOs in their chosen discipline by the time they graduate. The original aims of the project were to: i. determine the discipline-specific skills and standards that are required to be developed at the first year in order for students to achieve the TLOs and AQF standards prescribed for graduates in the selected disciplines in the Social Sciences and Humanities; ii. engage first year staff with first year pedagogy and curriculum renewal in the light of threshold standards; and iii. provide a toolkit with examples of discipline-specific assessments and activities that develop those skills in first year students

Designing first-year sociology curricula and practice

Many countries are now specifying standards for graduates in different disciplines, including sociology. In Australia, the Australian Sociological Association (TASA) has developed Threshold Learning Outcomes (TLOs) for sociology to provide the learning outcomes that students graduating with a bachelor’s degree in sociology should achieve. These TLOs have encouraged universities to think explicitly about their sociology curriculum in a holistic way. This paper reports on a project that investigated the skills and concepts sociology students need to learn in first year to meet the TLOs by the time they graduate. The project identified the needs of students as they transition from school or work into the study of sociology in first year through a study of literature of first-year pedagogy and a student survey. A workshop was held for sociology that involved 37 academics from 14 universities. The workshop was used to promote a rethink of teaching of sociology in the light of the new TLOs as well as to collect ideas from the participants. The student surveys, workshop ideas and relevant literature were analyzed and synthesized for each TLO to determine what skills and concepts first-year students needed to learn, identify what they might find difficult and propose strategies for teaching. The paper also provides practical ideas for engaging academics with thinking holistically about the sociology curriculum and for teaching and learning sociology in the first year of an undergraduate degree

Making makes me feel better: Designing for wellbeing and social values

This paper presents a design-led inquiry, which aimed to explore the benefits on wellbeing for people living with early stage dementia through participatory handcraft workshops. The project took place in a historically immersive environment at an open air living history museum involving a dementia friendly design team consisting of researchers, museum staff, volunteers and people living with dementia. Drawing on historic themes from the museum collections a range of new co-produced items were sold in the museum gift shop. The workshop activities enabled an understanding to be established of living with dementia, the value of making and the abilities of people with dementia. Through the experiences of this small group we unpick the rich detail of the participatory activities in terms of wellbeing. Valuing the contribution of each individual and working side by side we really got to know personalities by observing the nuances of body language, recognising abilities and shifts in confidence. We draw out the value of being ‘in the moment’ and also ‘significant moments of realisation’. Often the participants commented that concentrating on a creative activity in the moment could be absorbing, the close connection with materials was shown to be comforting. We observed a commitment and ownership of the project and increased levels of confidence in participants where they valued learning new skills and felt privileged to work and have access to the historic collections within the museum. The co-design project received positive feedback from the local community and visitor interest through sales. Through the project we sought to support the voice of people with dementia as one participant put it: ‘The trouble is you see, when you’re working everything is fast, you don’t have time to try new things and we’re not in a hurry, making makes me feel better.’ Participan

Every Day a New Discovery: Share History

This project aims to strengthen the sense of community and shared identity within VCU through a historical understanding of the interconnectedness of the formerly standalone institutions (i.e., the Medical College of Virginia and the Richmond Professional Institute). Additionally, it will seek to cultivate a sense of pride and greater esteem for our community by facilitating knowledge of the significant contributions to innovation that were developed at VCU

The Grizzly, November 8, 1985

Snyder Holds New Chair of Physics • Internships Problematic, but Necessary • Founder\u27s Day Filled with Science • Letters: The Good and Bad of Security • Science Makes its Stand in Liberal Arts Programs • In Search of Success: Jackson • Parsons Adds a Touch of Dutch Country • Playing Red/Gold in Recruitment • Freshman Urged to Begin Career Planning • Key Issues • Booters Play the Bridesmaid Again • Lady Bears Off to ECAC for Another Time • Bad Luck Strikes the Grizzlies • Box Lacrosse Popularity Grows • Successful Search for Liberal Arts Students • The Stand • Athlete of the Week • Education Department Offers Teaching Internshiphttps://digitalcommons.ursinus.edu/grizzlynews/1151/thumbnail.jp