Small GTPase regulation in epithelial polarity remodelling and morphogenesis

Small GTPases are a class of proteins implicated in the regulation of a wide range of processes in epithelial cells, from cell polarity and adhesion to migration. These proteins exist in `on' and `off' states, the transition between which is controlled by GEFs and GAPs. In particular, the RhoGTPases Rho1 and Cdc42 are required for many essential developmental programs in epithelial cells and tissues. Cdc42 is a key regulator of apical-basal polarity in epithelial cells. In its active form it supports Par6-aPKC recruitment at the apical pole of epithelial cells, which allows for separation of apical and junctional domains. This process is required for apical differentiation and cell-cell adhesion. Rho1 is also required for the integrity of adhesion junctions in Drosophila epithelial cells. As well as their role in cell polarity, both Cdc42 and Rho1 have been shown to antagonise each other to regulate the apical area and geometry of epithelial cells. The Drosophila retina is an ideal model system in which to study RhoGTPase function in epithelial polarity and morphogenesis, and how they relate to cell adhesions and the cytoskeleton. However, the GEFs and GAPs regulating Cdc42 and Rho1 during epithelial polarity and apical area determination are unknown. During my Thesis I have addressed this issue by performing a reverse genetic screen in the fly retina. I identified and characterised three potential regulators of RhoGTPases and sought to connect them to Cdc42 and Rho1, as well as fit them into the wider context of retinal development and morphogenesis. In addition I have generated and characterized de novo mutations for each of these genes using CRISPR/Cas9 technology

The Learner Profiles of Novice Literacy Coaches

Literacy coaches need support developing their professional capacities for coaching (Kern et al., 2018). This study explored the ways novice literacy coaches developed literacy coaching discourses during coursework in two reading specialist master’s degree programs. Through qualitative and discourse analysis of transcribed coaching videos and assignments, novice literacy coaching discourse was compared to professional literacy coaching discourse. Findings revealed candidates used coaching language and stances with varying degrees of success, but the discourse of novice and professional differed greatly. Five learner profiles of novice literacy coaching are presented: the interviewer, the role-player, the curious learner, the cheerleader, and the natural novice. Implications on literacy coach preparation and research are discussed, including the use of the learner profiles as a pedagogical tool for online course delivery

‘A lot of the time it’s dealing with victims who don’t want to know, it’s all made up, or they’ve got mental health’: Rape myths in a large English police force

Despite an increase in the reporting of rape, convictions in England and Wales have fallen significantly in recent years. Previous research has found high rape myth acceptance among police officers. Given that the police act as gatekeepers to the criminal justice system, subscribing to rape myths may have significant effects upon victim attrition and conviction rates. This study explores police officers’ use of rape myths and how these may impact investigations and prosecutions. A total of 17 semi-structured interviews were conducted with police officers from a large English police force. The interview data were analysed using the qualitative method of thematic analysis. Although there were instances where officers demonstrated some awareness of the need to dispel or counter rape myths, rape myths were employed by most officers, with the most common relating to (1) victim fabrication (‘women lie’) and (2) victim precipitation (‘women ask for it’). Recommendations are made around screening and training for police officers

A High Angular Resolution Survey of Massive Stars in Cygnus OB2: Results from the Hubble Space Telescope Fine Guidance Sensors

We present results of a high angular resolution survey of massive OB stars in the Cygnus OB2 association that we conducted with the Fine Guidance Sensor 1R (FGS1r) on the Hubble Space Telescope. FGS1r is able to resolve binary systems with a magnitude difference delta-V < 4 down to separations as small as 0.01 arcsec. The sample includes 58 of the brighter members of Cyg OB2, one of the closest examples of an environment containing a large number of very young and massive stars. We resolved binary companions for 12 targets and confirmed the triple nature of one other target, and we offer evidence of marginally resolved companions for two additional stars. We confirm the binary nature of 11 of these systems from complementary adaptive optics imaging observations. The overall binary frequency in our study is 22% to 26% corresponding to orbital periods ranging from 20 - 20,000 years. When combined with the known short-period spectroscopic binaries, the results supports the hypothesis that the binary fraction among massive stars is > 60%. One of the new discoveries is a companion to the hypergiant star MT 304 = Cyg OB2-12, and future measurements of orbital motion should provide mass estimates for this very luminous star.Comment: accepted for AJ, 84 pages, 61 figure

Specification of Change Mechanisms in Pregnant Smokers for Malleable Target Identification: A Novel Approach to a Tenacious Public Health Problem

Maternal smoking during pregnancy (MSDP) continues to be a leading modifiable risk factor for perinatal complications and a range of neurodevelopmental and cardio-metabolic outcomes across the lifespan. Despite 40 years of intervention research less than one in five pregnant smokers who receive an intervention quit by delivery. Within this context, recognition of pregnancy is commonly associated with abrupt suspension or reduction of smoking in the absence of intervention, yet has not been investigated as a volitional target. The goal of this article is to provide the empirical foundation for a novel direction of research aimed at identifying malleable targets for intervention through the specification of behavior change mechanisms specific to pregnant women. To do so, we: (1) summarize progress on MSDP in the United States generated from conventional empirical approaches to health behavior change; (2) discuss the phenomenon of spontaneous change in the absence of intervention among pregnant smokers to illustrate the need for mechanistic specification of behavior change motivated by concern for fetal well-being; (3) summarize component processes in neurobiological models of parental and non-parental social behaviors as a conceptual framework for understanding change mechanisms during pregnancy; (4) discuss the evidence for the malleability of these processes to support their translational relevance for preventive interventions; and (5) propose a roadmap for validating the proposed change mechanism using an experimental medicine approach. A greater understanding of social and interpersonal processes that facilitate health behavior change among expectant mothers and how these processes differ interindividually could yield novel volitional targets for prenatal interventions. More broadly, explicating other-oriented mechanisms of behavior change during pregnancy could serve as a paradigm for understanding how social and interpersonal processes positively influence health behaviors across the lifespan

Angiotensin II stimulates superoxide production by nitric oxide synthase in thick ascending limbs

Angiotensin II (Ang II) causes nitric oxide synthase (NOS) to become a source of superoxide (O2 (-)) via a protein kinase C (PKC)-dependent process in endothelial cells. Ang II stimulates both NO and O2 (-) production in thick ascending limbs. We hypothesized that Ang II causes O2 (-) production by NOS in thick ascending limbs via a PKC-dependent mechanism. NO production was measured in isolated rat thick ascending limbs using DAF-FM, whereas O2 (-) was measured in thick ascending limb suspensions using the lucigenin assay. Consistent stimulation of NO was observed with 1 nmol/L Ang II (P \u3c 0.001; n = 9). This concentration of Ang II-stimulated O2 (-) production by 50% (1.77 ± 0.26 vs. 2.62 ± 0.36 relative lights units (RLU)/s/μg protein; P \u3c 0.04; n = 5). In the presence of the NOS inhibitor L-NAME, Ang II-stimulated O2 (-) decreased from 2.02 ± 0.29 to 1.10 ± 0.11 RLU/s/μg protein (P \u3c 0.01; n = 8). L-arginine alone did not change Ang II-stimulated O2 (-) (2.34 ± 0.22 vs. 2.29 ± 0.29 RLU/s/μg protein; n = 5). In the presence of Ang II plus the PKC α/β1 inhibitor Gö 6976, L-NAME had no effect on O2 (-) production (0.78 ± 0.23 vs. 0.62 ± 0.11 RLU/s/μg protein; n = 7). In the presence of Ang II plus apocynin, a NADPH oxidase inhibitor, L-NAME did not change O2 (-) (0.59 ± 0.04 vs. 0.61 ± ×0.08 RLU/s/μg protein; n = 5). We conclude that: (1) Ang II causes NOS to produce O2 (-) in thick ascending limbs via a PKC- and NADPH oxidase-dependent process; and (2) the effect of Ang II is not due to limited substrate

How to do it: the neurological consultation with an autistic patient

Autism is a neurodevelopmental condition with a very heterogeneous presentation. Autistic people are more likely to have unmet healthcare needs, making it essential that healthcare professionals are ‘autism-aware’. In this article, we provide an overview of how autism presents and use case studies to illustrate how a neurological consultation in an outpatient clinic environment could prove challenging for a autistic person. We suggest how to improve communication with autistic patients in clinic and highlight the importance of a patient-centred and flexible approach

A Young Super Star Cluster in the Nuclear Region of NGC 253

We present observations of a massive star cluster near the nuclear region of the nearby starburst galaxy NGC 253. The peak of near-infrared emission, which is spatially separated by 4" from the kinematic center of the galaxy, is coincident with a super star cluster whose properties we examine with low-resolution (R ~ 1,200) infrared CTIO spectroscopy and optical/near-infrared HST imaging. Extinction, measured from [FeII] lines, is estimated at Av = 17.7 +/- 2.6. The age of the cluster is estimated at 5.7 Myr, based on Bry equivalent width for an instantaneous burst using Starburst99 modeling. However, a complex star formation history is inferred from the presence of both recombination emission and photospheric CO absorption. The ionizing photon flux has a lower limit of 7.3 +/- 2.5 x 10^53 inverse seconds, corrected for extinction. Assuming a Kroupa IMF, we estimate a cluster mass of 1.4 +/- 0.4 x 10^7 solar masses. We observe a strong Wolf-Rayet signature at 2.06 microns and report a weak feature at 2.19 microns which may be due to a massive stellar population, consistent with the derived mass and age of this cluster.Comment: 8 pages, 5 figures, accepted for publication in Ap

When are “Dish of the Day” nudges most effective to increase vegetable selection?

Previous research has suggested that featuring vegetable-rich dishes as “Dish of the day” (DoD) could be an operationally feasible and straightforward strategy to promote healthier food choices in restaurants. However, the available evidence regarding the effect of DoD on food choices is limited, and little is known about the conditions of its effectiveness in the field. This study investigates the effect of introducing DoD options in a real self-service restaurant setting on the selection of vegetable-rich options. The objectives are to (1) replicate and measure the DoD effect in this situation; and (2) investigate the moderating role of two features of the choice set: (i) the type of option set as DoD and (ii) the number of alternatives options to choose from. In a living lab experiment, 294 consumers came for lunch to a self-service restaurant and chose between a target vegetable-based dish (vg1) and respectively one, or two, alternatives: a meat-based dish (nvg) and another vegetable dish (vg2). Five choice task conditions were tested, in a between-subjects design: three conditions examined dish choices when two options were available (vg1 versus nvg): no DoD (T1-0); vg1 as DoD (T1a); or nvg as DoD (T1b). Two further conditions used three options (vg1 versus nvg versus vg2): no nudge (T2-0), or vg1 as DoD (T2a). In neutral conditions T1-0 and T2-0 respectively, 34.4% and 23.3% of consumers chose vg1. The DoD effect was observed in all conditions: choices in favour of vg1 increased by 25.2% when in was DoD by 25.2% in T1a vs. T1-0 and by 30% in T2a vs T2-0; while 7.6% more consumers chose nvg in T1b vs T1-0. Regarding the conditions of DoD effectiveness, the size of the DoD effect was larger for the initially less popular dish vg1 (T1a) compared with nvg (T1b). Introducing more options also increased the relative effect of DoD in favour of vg1, from 73% (T1a) to 129% (T2a). There were no effects of the condition on consumer satisfaction with the dish chosen, nor on the amount of food wasted. This research gives insight into the elements of the choice task to consider when setting up nudges, and could help choice architect to better design efficient and acceptable nudges in foodservice settings

Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors:a systematic review

Background: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.Methods: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.Results: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.Conclusions: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.</p